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Bile acids for liver-transplanted patients (Review)
Poropat G Giljaca V Stimac D Gluud C
This is a reprint of a Cochrane review prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library2010 Issue 3
httpwwwthecochranelibrarycom
Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
T A B L E O F C O N T E N T S
1HEADER
1ABSTRACT
2PLAIN LANGUAGE SUMMARY
2BACKGROUND
3OBJECTIVES
3METHODS
6RESULTS
Figure 1 8
Figure 2 9
Figure 3 12
13DISCUSSION
14AUTHORSrsquo CONCLUSIONS
14ACKNOWLEDGEMENTS
14REFERENCES
18CHARACTERISTICS OF STUDIES
32DATA AND ANALYSES
Analysis 11 Comparison 1 Bile acids for liver-transplanted patients Outcome 1 All-cause mortality at maximum follow-
up 33
Analysis 12 Comparison 1 Bile acids for liver-transplanted patients Outcome 2 All-cause mortality worst-best case and
best-worst case scenarios 34
Analysis 13 Comparison 1 Bile acids for liver-transplanted patients Outcome 3 Subgroup analyses all-cause mortality at
maximum follow-up according to time of start of bile acids 35
Analysis 14 Comparison 1 Bile acids for liver-transplanted patients Outcome 4 Subgroup analyses all cause mortality at
maximum follow-up according to treatment duration 36
Analysis 15 Comparison 1 Bile acids for liver-transplanted patients Outcome 5 Number of deaths related to rejection at
maximum follow-up 37
Analysis 16 Comparison 1 Bile acids for liver-transplanted patients Outcome 6 Number of retransplantations at maximum
follow-up 38
Analysis 17 Comparison 1 Bile acids for liver-transplanted patients Outcome 7 Number of patients with acute cellular
rejection at maximum follow-up 38
Analysis 18 Comparison 1 Bile acids for liver-transplanted patients Outcome 8 Subgroup analysis number of patients
with acute cellular rejection according to time of start of bile acid 39
Analysis 19 Comparison 1 Bile acids for liver-transplanted patients Outcome 9 Subgroup analysis number of patients
with acute cellular rejection according to treatment duration 41
Analysis 110 Comparison 1 Bile acids for liver-transplanted patients Outcome 10 Number of patients with chronic
rejection at maximum follow-up 42
Analysis 111 Comparison 1 Bile acids for liver-transplanted patients Outcome 11 Number of patients with steroid-
resistant rejection at maximum follow-up 42
Analysis 112 Comparison 1 Bile acids for liver-transplanted patients Outcome 12 Serum bilirubin (mgdl) at the end of
treatment 43
Analysis 113 Comparison 1 Bile acids for liver-transplanted patients Outcome 13 Number of days of hospitalisation after
liver transplantation 43
Analysis 114 Comparison 1 Bile acids for liver-transplanted patients Outcome 14 Adverse events 44
44APPENDICES
48WHATrsquoS NEW
48HISTORY
48CONTRIBUTIONS OF AUTHORS
48DECLARATIONS OF INTEREST
48SOURCES OF SUPPORT
49DIFFERENCES BETWEEN PROTOCOL AND REVIEW
49INDEX TERMS
iBile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
[Intervention Review]
Bile acids for liver-transplanted patients
Goran Poropat1 Vanja Giljaca1 Davor Stimac1 Christian Gluud2
1Department of Gastroenterology Clinical Hospital Centre Rijeka Rijeka Croatia 2Cochrane Hepato-Biliary Group Copenhagen
Trial Unit Centre for Clinical Intervention Research Department 3344 Rigshospitalet Copenhagen University Hospital Copenhagen
Denmark
Contact address Goran Poropat Department of Gastroenterology Clinical Hospital Centre Rijeka Kresimirova 42 Rijeka 51000
Croatia goran_poropatyahoocom
Editorial group Cochrane Hepato-Biliary Group
Publication status and date New search for studies and content updated (no change to conclusions) published in Issue 3 2010
Review content assessed as up-to-date 8 February 2010
Citation Poropat G Giljaca V Stimac D Gluud C Bile acids for liver-transplanted patients Cochrane Database of Systematic Reviews2010 Issue 3 Art No CD005442 DOI 10100214651858CD005442pub2
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
A B S T R A C T
Background
Liver transplantation has become a widely accepted form of treatment for numerous end-stage liver diseases Bile acids may decrease
allograft rejection after liver transplantation by changing the expression of major histocompatibility complex class molecules in bile
duct epithelium and central vein endothelium
Objectives
To assess the beneficial and harmful effects of bile acids for liver-transplanted patients
Search strategy
We performed searches of The Cochrane Hepato-Biliary Group Controlled Trials Register The Cochrane Central Register of ControlledTrials in The Cochrane Library MEDLINE EMBASE and Science Citation Expanded to September 2009
Selection criteria
Randomised clinical trials comparing any dose of bile acids or duration of treatment in liver-transplanted patients versus placebo no
intervention or another intervention We included randomised clinical trials irrespective of blinding language and publication status
Data collection and analysis
Two review authors extracted and checked data independently We evaluated the risk of bias of the trials from the method of allocation
sequence generation allocation concealment blinding outcome data analysis outcome data reporting and other potential sources
of bias We used the intention-to-treat principle to perform meta-analyses and presented the outcomes as relative risks (RR) or mean
differences (MD) both with 95 confidence intervals (CI)
Main results
The updated search resulted in no new trials meeting the inclusion criteria of this review thus leaving it to the seven already included
randomised trials (six evaluating ursodeoxycholic acid versus placebo or no intervention and one evaluating tauro-ursodeoxycholic
acid versus no intervention) enrolling a total of 335 participants The administration of bile acids began one day or more after liver
transplantation All patients received the standard triple-drug immunosuppressive regimen (steroids azathioprine and cyclosporine or
tacrolimus) to suppress the allograft rejection response after liver transplantation Bile acids compared with placebo or no intervention
1Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
did not significantly change all-cause mortality (RR 085 95 CI 053 to 136) mortality related to allograft rejection (RR 030
95 CI 001 to 712) retransplantation (RR 076 95 CI 020 to 286) acute cellular rejection or number of patients with steroid-
resistant rejection Bile acids significantly reduced the number of patients who had chronic rejection in a fixed-effect model but not in
a random-effects model meta-analysis Bile acids were safe and well tolerated by liver-transplanted patients However this observation
is based on data analysis from three trials with only 187 patients
Authorsrsquo conclusions
We did not find evidence to support or refute bile acids for liver-transplanted patients Further randomised trials are necessary before
bile acids can be recommended to liver-transplanted patients
P L A I N L A N G U A G E S U M M A R Y
Bile acids for liver-transplanted patients
Liver transplantation is a major surgical procedure that has been practiced for more than forty years and has nowadays become a
generally accepted treatment option in patients with end-stage liver disease The most common cause for liver transplantation in adults
is cirrhosis caused by various types of liver injuries such as infections (hepatitis B and C) alcohol autoimmune liver diseases early-
stage liver cancer metabolic and hereditary disorders but also diseases of unknown aetiology All transplant recipients need lifetime
immunosuppressive therapy to prevent transplant rejection
Bile acids are being used for a variety of chronic liver diseases mainly primary biliary cirrhosis and primary sclerosing cholangitis
However their mechanisms of action and beneficial and harmful effects are poorly understood This has led to the idea of the potential
use of bile acids to prevent rejection in liver-transplanted patients
Results of the seven randomised clinical trials included in the review in which patients received standard immunosuppressive treatment
(steroids azathioprine and cyclosporine or tacrolimus) with or without bile acids after liver transplantation did not show any significant
effects of bile acids on all-cause mortality mortality related to rejection acute cellular rejection steroid resistant rejection or need for
retransplantation One analysis suggested that bile acids might beneficially influence number of patients with chronic rejection but was
contradicted by the analyses The evidence that the use of ursodeoxycholic acid might have beneficial effects on chronic rejection and
length of hospitalisation is weak as it is produced from trials with high risk of bias and insufficient number of included patients That
bile acids seemed well tolerated with no reports of serious adverse events is good knowledge but much more research is needed before
their use is acquitted None of the randomised clinical trials assessed the effects of bile acids on quality of life or cost-effectiveness
B A C K G R O U N D
Liver transplantation has become a widely accepted treatment
for numerous end-stage liver diseases (Hussain 2002 Thalheimer
2002) Previous studies report an incidence of acute cellular rejec-
tion to range from 50 to 80 in adult recipients (Ascher 1988
Klintmalm 1989 Adams 1990 Wiesner 1992 FK506 1994)
However recent data suggest that the proportion of patients with
rejection is currently down to 30 (Hirschfield 2009 Knechtle
2009) Despite advances in immunosuppressive treatment and
care-quality of liver-transplanted patients allograft rejection is still
a major problem in the post-transplantation period
Acute cellular rejection usually occurs within the first 15 to 30 days
after transplantation even if immunosuppression is achieved with
tacrolimus or cyclosporine (FK506 1994 Haddad 2006 Corbani
2008) The cellular mechanisms of acute liver allograft rejection
are not completely understood (Krams 1993) Initiation of al-
lograft rejection is thought to involve the recognition of donor
class II major histocompatibility complex alloantigens by recipient
CD4+ T cells (Vierling 1992) Activated CD4+ T cells produce
cytokines that induce lymphocyte proliferation and the matura-
tion of CD8+ cytotoxic T cells which are specific for donor class I
major histocompatibility complex antigens (Calmus 1990) Both
the bile duct epithelium and central vein endothelium are rich in
class I and class II major histocompatibility complex antigens dur-
ing rejection whereas hepatocytes display a relative paucity of class
I antigens and virtually no class II antigen (Vierling 1992) There-
2Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
fore the bile duct epithelium and central vein endothelium are
the primary targets attacked by cytotoxic T cells during rejection
Impairment of the bile flow in the grafted liver may also cause re-
jection (Ericzon 1990) Mild cholestasis is a common finding after
liver transplantation and its association with clinically significant
pathology is unlikely Nevertheless severe cholestasis should be
treated as a potential cause of allograft rejection (Corbani 2008)
In the study by Fusai 2006 the development of cholestasis was sig-
nificantly related to prolonged warm ischaemia of the liver trans-
plant Cholestasis can induce hyper-expression of major histocom-
patibility complex class I molecules by hepatocytes and thereby
lymphocyte CD8+-dependent cytotoxicity (Calmus 1992)
Bile acids include chenodeoxycholic acid deoxycholic acid litho-
cholic acid and ursodeoxycholic acid (UDCA) (Fuchs 1999)
In the course of cholestasis intrahepatic accumulation of chen-
odeoxycholic acid and deoxycholic acid is thought to induce liver
damage (Palmer 1972) In fact the direct damage of membrane
phospholipids and cholesterol components caused by the deter-
gent-like properties of hydrophobic bile acids results in hepato-
cyte necrosis (Sholmerich 1984 Perez 2009) It is also suggested
that oxidative stress induced by hydrophobic bile acids plays an
important role in liver damage during cholestasis These effects
can be prevented by the addition of UDCA which modifies the
bile acid pool resulting in an increase of the hydrophilic frac-
tion and stabilisation of the cell membranes (Armstrong 1982
Perez 2009) Several studies on animal models showed evidence
of potential immunomodulatory beneficial effects of UDCA and
tauro-ursodeoxycholic acid (TUDCA) by suppressing cytokine
and immunoglobulin production and T-cell mediated cytotoxic-
ity (Yoshikawa 1998) In the study by Calmus 1990 it has been
observed that UDCA down-regulates the expression of abnormal
major histocompatibility complex class I molecules in periportal
hepatocytes in patients with primary biliary cirrhosis Treatment
with UDCA has been reported to have potential beneficial ef-
fects in various cholestatic liver conditions including primary bil-
iary cirrhosis (Gong 2008) primary sclerosing cholangitis (Chen
2003a) and cystic fibrosis (Cheng 2002)
It has previously been suggested that UDCA and perhaps tauro-
UDCA (TUDCA) may reduce the incidence of acute rejection
and steroid-resistant rejection in liver-transplanted patients when
administered with combination of immunosuppressive treatment
There are several potential mechanisms by which UDCA may in-
hibit allograft rejection in liver transplant recipients (Okolicsanyi
1986 Merion 1989 Calmus 1990 Terasaki 1991 Heuman 1993
Al-Quaiz 1994 Friman 1994 Soderdahl 1998 Yoshikawa 1998
Assy 2007 Perez 2009) However most of these studies included
a relatively small number of patients were not randomised and
often did not include histological information (Persson 1990
Friman 1992 Koneru 1993 Sharara 1995)
The previous version of this review by Chen 2003b stated that
there was no convincing beneficial effects from the use of bile acids
in liver-transplanted patients the risk of bias in the seven included
trials was high The review also found that there was a low occur-
rence of adverse events and hence the use of bile acids could be
considered safe It should be noted however that this observation
is based on reports from four trials with few patients We have
been unable to identify any other meta-analyses or systematic re-
views either This review represents an update of the Chen 2003b
Cochrane hepato-Biliary Group review
O B J E C T I V E S
To evaluate the beneficial and harmful effects of bile acids for liver-
transplanted patients by comparing bile acids versus placebo no
intervention or another intervention in randomised clinical trials
M E T H O D S
Criteria for considering studies for this review
Types of studies
We included randomised clinical trials irrespective of blinding
publication status year of publication or language We assessed
both included and excluded studies for the report of adverse events
We listed all studies reporting on adverse events in an additional
table (Table 1) However only data from the included trials were
used in the statistical analysis
Table 1 Adverse events
Study Pts in experimental
group
Patients in control
group
AE in experimental
group
AE in control group Authorrsquos conclusion
Barnes 1997 28 24 Diarrhoea (1 pt) Diarrhoea (1 pt) Adverse
reactions attributable
to study medication
were rare
3Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Table 1 Adverse events (Continued)
Keiding 1997 54 48 Diarrhoea and diffi-
culties in swallowing
capsules (5 pts)
Diarrhoea and diffi-
culties in swallowing
capsules (5 pts)
No other presumed
drug-induced side ef-
fects were observed
Angelico 1999 16 17 No AE No AE TUDCA administra-
tion was well tol-
erated in all pa-
tients and no drug-
related side effects
were recorded
Assy 2007 14 12 Mild diarrhoea (1 pt) No AE No dose reduction
was required
pt(s) = patient(s)
AE = adverse events
Types of participants
Patients who underwent liver transplantation
Types of interventions
Any dose of a bile acid or duration of treatment versus placebo
no intervention or another intervention
We allowed co-interventions if received equally by the intervention
groups within a trial
Types of outcome measures
The primary outcome measures were
1 All-cause mortality
2 Death due to allograft rejection (acute cellular rejection or
chronic rejection or liver retransplantation because of rejection)
Acute cellular rejection was diagnosed by the combination of ab-
normal liver biochemical variables (bilirubin aspartate transam-
inase alanine transaminase alkaline phosphatases andor gam-
maglutamyl transpeptidase) clinical signs such as fever and liver
histological changes including mononuclear portal inflammation
bile duct damage and subendothelial inflammation of portal or
terminal hepatic veins (IWP 1995) Chronic rejection was charac-
terised by liver histological changes including the progressive loss
of interlobular bile ducts and arteriopathy characterised by foam
cell infiltration of the arterial intima
The secondary outcome measures were
3 Number of patients who experienced rejection - irrespective of
the type acute cellular rejection chronic rejection or both types
of rejections
4 Number of patients with acute cellular rejection
5 Number of patients with chronic rejection
6 Number of patients with steroid-resistant rejection
7 Biochemical responses serum activities of alkaline phos-
phatases gammaglutamyl transpeptidase alanine aminotrans-
ferase and aspartate aminotransferase and serum bilirubin con-
centration andor number of patients with abnormal liver bio-
chemical variables mentioned above
8 Adverse events Adverse events were defined as any untoward
medical occurrence not necessarily having a causal relationship
with the treatment but resulting in a dose reduction or discontin-
uation of treatment (ICH-GCP 1997)
9 Quality of life
10 Cost-effectiveness
Search methods for identification of studies
We performed searches of The Cochrane Hepato-Biliary GroupControlled Trials Register (September 2009)(Gluud 2010) and TheCochrane Central Register of Controlled Trials (CENTRAL) in TheCochrane Library (Issue 3 2009) by combining the terms rsquoliverrsquo
and rsquotransplantationrsquo with the individual bile acid name (litho-
cholic acid chenodeoxycholic acid ursodeoxycholic acid deoxy-
cholic acid dehydrocholic acid and tauro-ursodeoxycholic acid)
We searched MEDLINE (January 1966 to September 2009) EM-BASE (January 1980 to September 2009) and Science Citation In-dex Expanded (1945 to September 2009) by using the terms rsquoliverrsquo
4Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
and rsquotransplantationrsquo in combination with the bile acids mentioned
above (Royle 2003) The search strategies with the time span of
the searches are given in Appendix 1 We contacted the Chinese
Cochrane Centre regarding the search of The Chinese BiomedicalDatabase and received a reply that they are unable to help us with
this search Therefore the latter database could not be included
in the search strategy of this update
Further trials were identified by reading the reference lists of the
identified studies We wrote to the principal authors of the reports
of the identified randomised clinical trials in September 2009 and
enquired about additional trials which they might know of The
first team of authors had also written to pharmaceutical companies
involved in the production of bile acids to obtain information on
published or unpublished randomised clinical trials in 2002 but
no information had been received at that time
Data collection and analysis
The update of this review was conducted according to the proto-
col previously published in The Cochrane Library (Chen 2003b)
and following the recommendations given by the Cochrane Hand-book for Systematic Reviews of Interventions (Higgins 2008) and the
Cochrane Hepato-Biliary Group Module (Gluud 2010)
Trial identification
Identified trials were listed and the two review authors evaluated
whether the trials fulfilled the inclusion criteria Excluded trials
were listed with the reasons for exclusion
Data extraction
GP and VG extracted the data independently and disagreements
were resolved by discussion or by CG We extracted the following
characteristics from each trial primary author number of patients
randomised patient inclusion and exclusion criteria methodolog-
ical quality follow-up (number and reasons for withdrawal) sam-
ple size calculation intention-to-treat analysis intervention reg-
imens mean age proportion of males and females aetiology of
liver disease origin of allograft matching criteria between donor
and recipient time to follow-up number of outcomes and num-
ber and type of adverse events in both the intervention and the
control groups Additional information was sought by correspon-
dence with the principal investigator or co-investigators of the trial
in cases where the relevant data were not published
Assessment of risk of bias
Risk of bias was defined as the confidence that the study design and
reporting restricted bias in the intervention comparison (Schulz
1995 Moher 1998 Kjaergard 2001 Wood 2008) Due to the risk
of overestimation of intervention effects in randomised trials with
unclear or inadequate components we assessed the risk of bias by
separate domains
Allocation sequence generation
bull Adequate if the allocation sequence was generated by a
computer or random number table Drawing of lots tossing of a
coin shuffling of cards or throwing dice was considered as
adequate if a person who was not otherwise involved in the
recruitment of participants performed the procedure
bull Unclear if the trial was described as randomised but the
method used for the allocation sequence generation was not
described
bull Inadequate if a system involving dates names or
admittance numbers were used for the allocation of patients
Such quasi-randomised studies were excluded
Allocation concealment
bull Adequate if the allocation of patients involved a central
independent unit on-site locked computer identically appearing
numbered drug bottles or containers prepared by an
independent pharmacist or investigator or serially numbered
sealed and opaque envelopes
bull Unclear if the trial was described as randomised but the
method used to conceal the allocation was not described
bull Inadequate if the allocation sequence was known to the
investigators who assigned participants or if the study was quasi-
randomised The latter studies were excluded
Blinding
bull Adequate the trial was described as blinded the parties that
were blinded and the method of blinding was described so that
knowledge of allocation was adequately prevented during the
trial
bull Unclear the trial was described as double blind but the
method of blinding was not described so that knowledge of
allocation was possible during the trial
bull Not performed the trial was not blinded so that the
allocation was known during the trial
Incomplete outcome data
bull Adequate if the numbers and reasons for dropouts and
withdrawals in all intervention groups were described or if it was
specified that there were no dropouts or withdrawals
bull Unclear if the report gave the impression that there had
been no dropouts or withdrawals but this was not specifically
stated
bull Inadequate if the number or reasons for dropouts and
withdrawals were not described
Selective outcome reporting
bull Adequate if study protocol is available and all pre-specified
outcomes are reported in the manuscript or if the study protocol
is not available but it is clear that the report includes all expected
outcomes
bull Unclear if there are no sufficient information to permit
judgement
bull Inadequate if not all of the pre-specified outcomes were
reported andor were reported incompletely or one or more
reported outcomes were not pre-specified
Baseline imbalance
5Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
bull Adequate if there is no baseline imbalance in the main
characteristics
bull Unclear if there is no sufficient information to assess
baseline characteristics
bull Inadequate if there was a baseline imbalance due to chance
or due to imbalanced exclusion after randomisation
Early stopping
bull Adequate if sample size calculation was reported and the
trial was not stopped or the trial was stopped early by formal
stopping rules at a point where the likelihood of observing an
extreme intervention effect due to chance was low
bull Unclear if sample size calculation was not reported and it is
not clear whether the trial was stopped early or not
bull Inadequate if the trial was stopped early due to informal
stopping rules or the trial was stopped early by a formal stopping
rule at a point where the likelihood of observing an extreme
intervention effect due to chance was high
Furthermore we registered whether the randomised clinical trials
had used an intention-to-treat analysis (Gluud 2001) and had
calculated a sample size estimate
Statistical methods
We performed the analyses in RevMan 5 (RevMan 2008) Anal-
yses included all patients irrespective of compliance or follow-up
according to the intention-to-treat principle and using the last
reported observed response (rsquocarry forwardrsquo) Regarding death
both a worst-best-case scenario analysis considering all dropped-
out patients in the bile acid group as dead and the dropped-out
patients in the control group as alive and a best-worst-case sce-
nario analysis considering all dropped-out patients in the bile acid
group as alive and the dropped-out patients in the control group as
dead were performed Both a random-effects model (DerSimonian
1986) and a fixed-effect model (DeMets 1987) were used The re-
sults of the fixed-effect model were reported if there were no differ-
ences between the results produced by the two models otherwise
we reported the results produced by both models We presented
binary outcome measures as relative risks (RR) with 95 confi-
dence intervals (CI) and continuous outcome measures as mean
differences (MD) with 95 CI
The risk of type I errors increases in single trials with interim anal-
yses To avoid type I errors group sequential monitoring bound-
aries (Lan 1983) can be performed when deciding to terminate the
trial earlier than planned This requires analyses at different time
intervals to record when the P-value has become sufficiently small
that is when the cumulative Z-curve will cross the monitoring
boundaries Sequential monitoring boundaries the so called rsquotrial
sequential monitoring boundariesrsquo can also be applied to meta-
analyses In a trial sequential analysis (TSA) every trial that is
added in a cumulative meta-analysis is regarded as an interim meta-
analysis and the information it adds on helps on deciding if more
trials need to be included
The interpretation of the TSA is as follows if the cumulative Z-
curve has crossed the boundary a sufficient level of evidence is
reached and no further trials may be needed If the Z-curve has
not crossed the boundary then the evidence is insufficient in order
to reach a conclusion To construct the trial sequential monitor-
ing boundaries information size is needed It is calculated as the
minimum number of participants needed in a well-powered single
trial (Pogue 1997 Pogue 1998 Brok 2008 Wetterslev 2008) We
applied TSA since it prevents an increase of the risk of type I error
due to sparse and multiple updating in a cumulative meta-analysis
and provides us with important information in order to estimate
the level of evidence of the experimental intervention Addition-
ally TSA provides us with important information regarding the
need for additional trials and the required information size We
applied trial sequential monitoring boundaries according to an in-
formation size suggested by the trials with low risk of bias and a
50 relative risk reduction (RRR)
Subgroup analyses
We planned to perform the following subgroup analyses on the
main outcome measures (all-cause mortality and number of pa-
tients with acute rejection)
1 Risk of bias of the trials comparing the intervention effect for
trials with low risk of bias components to the intervention effect
in trials with unclear or high risk of bias components
2 Dose and duration of treatment with bile acids comparing the
intervention effect in trials administrating bile acid at or above the
median dose multiplied by duration to the intervention effect of
trials administrating bile acid at less than the median dose multi-
plied by duration
3 Time between transplantation and the start of bile acids com-
paring the intervention effect of trials having less than three days
between transplantation and starting bile acid intake to the inter-
vention effect of trials with a duration of three days or more be-
tween transplantation and the start of bile acid intake (Neuberger
1999)
4 Co-interventions comparing the intervention effect of trials
with co-interventions to the intervention effect of trials without
co-interventions
Funnel plot analysis
We planned to explore bias by funnel plot analysis (Egger 1997)
R E S U L T S
Description of studies
See Characteristics of included studies Characteristics of excluded
studies
The performed electronic searches resulted in a total of 378 ref-
erences We excluded 362 duplicates or irrelevant references by
reading abstracts We excluded eight of the 16 further assessed ref-
erences because they were observational studies case series or ran-
6Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
domised clinical trials with a different reason for exclusion They
are listed under rsquoCharacteristic of excluded studiesrsquo with reasons
for exclusion Seven references already included in the previous
version of this review and one new reference referring to an al-
ready included trial (Barnes 1997) were included in this review
We were not able to identify more trials by reading the reference
lists of the identified studies contacting the principle authors of
the identified trials or approaching pharmaceutical companies for
unpublished trials
Seven publications included in the review (five full publications
and two abstracts) were randomised clinical trials that reported
the random allocation of liver-transplanted patients into groups
receiving bile acid placebo or no treatment We listed these trials
in the table of Characteristics of included studies All seven trials
were published in English Three randomised clinical trials were
from the United States (Koneru 1993 Barnes 1997 Fleckenstein
1998) two from Italy (Sama 1991 Angelico 1999) one from
France (Pageaux 1995) and one from Denmark (Keiding 1997)
Patients
In the included trials all patients received blood group-compatible
grafts The median size of the seven trials was 40 patients (range
29 to 102 patients) In total 335 patients were randomised
Five trials were published as full publications (Pageaux 1995
Barnes 1997 Keiding 1997 Fleckenstein 1998 Angelico 1999)
which allowed us to extract detailed information on 263 of the
patients The mean age of the patients ranged from 44 to 51 years
One trial (Keiding 1997) also enrolled children ranging in age
from 0 to 13 years (median 15 years) The male to female ratio in
these five trials was 159104 The diseases that led to liver trans-
plantation were alcoholic cirrhosis in 51 patients (194) cirrho-
sis caused by chronic hepatitis C in 40 patients (152) primary
biliary cirrhosis in 36 patients (137) cryptogenic cirrhosis in
22 patients (84) metabolic diseases in 19 patients (72) pri-
mary sclerosing cholangitis in 17 patients (65) non-specified
post-hepatitis cirrhosis in 17 patients (65) cirrhosis caused by
chronic hepatitis B in 13 patients (49) 9 with autoimmune
hepatitis and cirrhosis (34) six with liver cancer (23) five
with biliary atresia (19) and 28 with other diseases (106)
Only one trial reported the severity of liver function according to
the Child-Pugh class (Barnes 1997)
Bile acids and collateral interventions
Six trials (Sama 1991 Koneru 1993 Pageaux 1995 Barnes
1997 Keiding 1997 Fleckenstein 1998) compared UDCA versus
placebo or no intervention One trial (Angelico 1999) compared
TUDCA versus no intervention Bile acid treatment began one
day after transplantation in the Keiding 1997 trial three days after
transplantation in the Koneru 1993 trial three or five days in the
Fleckenstein 1998 and Pageaux 1995 trials five days after trans-
plantation in the Barnes 1997 and Angelico 1999 trials and five
or seven days after transplantation in the Sama 1991 trial
Patients received UCDA (10 to 15 mgkg body weightday) for
two months in the Pageaux 1995 trial for three months in the
Koneru 1993 Barnes 1997 Keiding 1997 and Fleckenstein 1998
trials and for six months in the Sama 1991 trial In the Barnes
1997 trial patients were followed up for 18 months Patients in the
Fleckenstein 1998 trial and the Keiding 1997 trial were followed
up for nine months There was no post-treatment follow-up in
three trials (Sama 1991 Koneru 1993 Pageaux 1995) Patients
received TUDCA (500 mgday) for one year and no follow-up
was conducted in the Angelico 1999 trial
In addition to the bile acids or control intervention all patients
in the seven trials received standard triple-drug regimens (steroids
azathioprine and cyclosporine or tacrolimus) The patients who
had steroid-resistant rejection received treatment with immuno-
suppressive antibodies (OKT3)
Outcome measures
The outcome measures reported by most trials were all-cause mor-
tality and acute cellular rejection Three trials reported on death
related to rejection (Barnes 1997 Keiding 1997 Angelico 1999)
two trials reported the number of patients who received retrans-
plantation due to rejection (Keiding 1997 Fleckenstein 1998)
three trials reported the number of patients with chronic rejection
(Barnes 1997 Keiding 1997 Fleckenstein 1998) and four trials
reported the number of patients with steroid-resistant rejection
(Pageaux 1995 Barnes 1997 Keiding 1997 Fleckenstein 1998)
Four trials had adverse events as outcome measures (Barnes 1997
Keiding 1997 Fleckenstein 1998 Angelico 1999) Serum biliru-
bin level was only reported by the Fleckenstein 1998 trial No tri-
als provided data on other liver biochemical parameters quality
of life or cost-effectiveness
Risk of bias in included studies
Two trials reported adequate allocation sequence generation by
using computer-generated random tables (Barnes 1997 Angelico
1999) One trial (Keiding 1997) reported adequate allocation con-
cealment by using sealed serially numbered envelopes Three tri-
als (Barnes 1997 Keiding 1997 Fleckenstein 1998) reported ad-
equate blinding by using placebo with an identical appearance
and taste Five trials (Pageaux 1995 Barnes 1997 Keiding 1997
Fleckenstein 1998 Angelico 1999) reported adequate description
of incomplete outcome data by the number of withdrawals the
reasons for withdrawal or no patients dropped out The trial by
Keiding 1997 is the only one free of selective reporting since all
the pre-specified outcomes were fairly reported Two trials (Barnes
1997 Keiding 1997) performed sample-size calculations Only
the trial by Keiding 1997 seemed to be free of baseline imbalance
and it is the only trial achieving the calculated sample size and
therefore probably the only that was not terminated early Other
trials did not perform sample size calculation or the authors did
not report whether the calculated sample size was achieved The
lack of this information made it unclear for us to judge whether
7Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
a trial was terminated early that is before an adequate number
of patients was included in the trial Three trials (Barnes 1997
Keiding 1997 Fleckenstein 1998) stated that intention-to-treat
analyses were used (Figure 1 Figure 2)
Figure 1 Methodological quality graph review authorsrsquo judgements about each methodological quality
item presented as percentages across all included studies
8Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Figure 2 Methodological quality summary review authorsrsquo judgements about each methodological quality
item for each included study
9Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Following the assessment of risk of bias domains none of the seven
trials were considered to have low risk of bias that is having all
the nine domains for risk of bias assessed as adequate
Effects of interventions
We were able to include seven randomised clinical trials in this
review Six trials with 306 liver-transplanted patients compared
ursodeoxycholic acid (UDCA) with placebo or no intervention
and one trial with 29 liver-transplanted patients compared tauro-
UDCA (TUDCA) with no intervention
All-cause mortality
Five trials including 257 liver-transplanted patients reported on
all-cause mortality at the end of treatment or at maximum follow-
up Bile acids did not significantly reduce all-cause mortality (RR
085 95 CI 053 to 136) there were 26 deaths among 132
patients treated with bile acids (197) versus 29 deaths among
125 patients in the control groups (232) (Analysis 11) There
was no statistically significant heterogeneity (I2 = 141)
Four trials (Sama 1991 Barnes 1997 Keiding 1997 Fleckenstein
1998) showed that UDCA did not significantly reduce all-cause
mortality (RR 080 95 CI 049 to 130) 23 deaths among 116
patients treated with UCDA (198) versus 27 deaths among
108 patients in the control groups (250) The Angelico 1999
trial demonstrated that TUDCA was not able to reduce all-cause
mortality (RR 159 95 CI 030 to 833) there were 3 deaths
among 16 patients (188) versus 2 deaths among 17 patients
(118)
The Fleckenstein 1998 trial and the Sama 1991 trial did not report
the causes of deaths In the three other trials the deaths were
considered to be caused by infections (n = 11) hepatic failure (n =
7) abdominal bleeding (n = 3) renal failure (n = 2) multiple organ
failure (n = 2) hepatitis B virus fibrosis (n = 2) acute rejection
(n = 1) hepatic artery thrombosis (n = 1) encephalitis (n = 1)
lymphoproliferative disorder (n = 1) cerebral haemorrhage (n =
1) or other reasons (n = 6)
Worst-best case and best-worst case scenario analyses
In the worst-best case scenario analysis bile acids did not signif-
icantly reduce all-cause mortality when compared with placebo
or no intervention (RR 130 95 CI 086 to 196) 40 deaths
among 132 patients on bile acids (303) versus 29 deaths among
125 patients in the control groups (232) However all-cause
mortality was significantly reduced by bile acids in the best-worst
case scenario analysis (RR 058 95 CI 038 to 090) 26 deaths
among 132 patients (197) versus 42 deaths among 125 patients
in the control groups (336) (Analysis 12)
Subgroup analyses
We performed subgroup analyses regarding the time that bile acid
intake was started The Keiding 1997 trial started bile acid intake
less than three days after liver transplantation and demonstrated
no significant effect of UDCA on all-cause mortality (RR 124
95 CI 061 to 254) 14 deaths out of 54 patients (259)
versus 10 out of 48 control patients (208) The same effect
was noticed in the four other trials (Sama 1991 Barnes 1997
Fleckenstein 1998 Angelico 1999) which started bile acids three
days or more after liver transplantation (RR 063 95 CI 033
to 120) 12 deaths among 78 patients (154) versus 9 deaths
among 77 control patients (247) (Analysis 13) There were no
statistically significant differences between the two estimates
We also performed subgroup analyses regarding the duration of
bile acid treatment Bile acids were administrated for less than six
months in three trials (Barnes 1997 Keiding 1997 Fleckenstein
1998) and were not able to significantly decrease all-cause mor-
tality (RR 078 95 CI 045 to 138) 18 deaths in a group of
96 treated patients (188) versus 21 deaths among 88 control
patients (239) In the other two trials (Sama 1991 Angelico
1999) patients were treated with bile acids for six months or more
The treatment did not show statistically significant decrease in all-
cause mortality (RR 102 95 CI 043 to 24) 8 deaths in a
group of 36 treated patients (222) versus 8 deaths in a group
of 37 control patients (216) (Analysis 14) There were no sta-
tistically significant differences between the two estimates
Mortality related to allograft rejection
We did not find statistically significant reduction in mortality re-
lated to allograft rejection at maximum follow-up in the three tri-
als reporting cause of death (Barnes 1997 Keiding 1997 Angelico
1999) (RR 030 95 CI 001 to 712) 098 (0) versus 189
(11)) (Analysis 15) The only death due to acute rejection was
found in the placebo group of the Keiding 1997 trial
Number of liver retransplantations
Two trials (Fleckenstein 1998 Keiding 1997) including 132 liver-
transplanted patients reported the number of liver retransplan-
tations UDCA did not significantly reduce the risk of liver re-
transplantation at maximum follow-up (RR 076 95 CI 020
to 286) 368 (44) versus 464 (63)) (Analysis 16) In the
Keiding 1997 trial one patient in the UDCA group was retrans-
planted due to chronic rejection and four patients in the placebo
group were retransplanted either due to chronic rejection (three
cases) or acute rejection (one case) In the Fleckenstein 1998 trial
two patients in the UDCA group were retransplanted due to acute
rejection (one case) and chronic rejection (one case) respectively
Number of patients with acute cellular rejection
Seven trials reported the number of patients who had acute cellu-
lar rejection after liver transplantation Bile acids did not signifi-
cantly reduce the number of patients who experienced acute cel-
lular rejection (RR 089 95 CI 074 to 106) 93174(535)
versus 99165 (600)) There was no significant heterogeneity
(I2 = 0)
Six trials (Sama 1991 Koneru 1993 Pageaux 1995 Barnes 1997
10Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Keiding 1997 Fleckenstein 1998) compared UDCA with placebo
or no intervention and demonstrated that UDCA did not signifi-
cantly reduce the number of patients with acute cellular rejection
after liver transplantation (RR 089 95 CI 074 to 108 85
158 (538) versus 89148 (601)) Neither did the Angelico
1999 trial demonstrate significant reduction of the number of pa-
tients with acute cellular rejection with TUDCA (RR 085 95
CI 045 to 160) 816 (500) versus 1017 (588) (Analysis
17)
Subgroup analyses
Two trials (Koneru 1993 Keiding 1997) in which the patients
started bile acids intake less than three days after liver transplan-
tation did not demonstrate any significant reduction of the risk
of acute cellular rejection by bile acids (RR 084 95 CI 063 to
111) 3870 (543) versus 4164 (641) The other five tri-
als (Sama 1991 Pageaux 1995 Barnes 1997 Fleckenstein 1998
Angelico 1999) in which the patients were started on bile acid
intake three days or more after liver transplantation did not find
a significant reduction of the risk of acute cellular rejection by bile
acids (RR 092 95 CI 072 to 117) 55104 (529) versus 58
101 (574) (Analysis 18) There was no significant difference
between the two estimates
Bile acids did not significantly reduce the risk of acute cellular
rejection in the five trials (Koneru 1993 Pageaux 1995 Barnes
1997 Keiding 1997 Fleckenstein 1998) in which the patients
received treatment with bile acids less than six months (RR 087
95 CI 071 to 107) 72138 (522) versus 76128 (594)
Neither did bile acids in the two other trials (Sama 1991 Angelico
1999) in which the patients received bile acids for more than six
months (RR 094 95 CI 065 to 136) 2136 (583) versus
2337 (622) (Analysis 19) There were no significant difference
between the two estimates
Number of patients with chronic rejection
Three trials comparing UDCA versus placebo (Barnes 1997
Keiding 1997 Fleckenstein 1998) reported the number of patients
with chronic rejection after liver transplantation UDCA signifi-
cantly reduced the number of patients with chronic rejection in
the fixed-effect model analysis (RR 028 95 CI 008 to 095)
396 (31) versus 1088 (114) (Analysis 110) but not in the
random-effects model analysis (RR 030 95 CI 008 to 113) 3
96 (31) versus 1088 (114) There was no statistically signifi-
cant heterogeneity (I2 0) We performed trial sequential analysis
for the available data from three trials (Figure 3) with heterogene-
ity corrected required information size based on proportion of this
outcome of 12 in the control group a relative risk reduction of
50 in the intervention group at a type I error of 5 and a type
II error of 10 We obtained a required information size of 957
patients UDCA was not able to reach or break the trial sequential
monitoring boundary and only 183 out of 957 (19) patients
were randomised regarding this outcome
11Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Figure 3 Trial sequential analysis for the number of patients with chronic rejection at maximum follow-up
We calculated the heterogeneity-corrected required information size (HCRIS) based on a proportion of 12 of
the patients in the placebo group with chronic rejection at maximum follow-up a 50 risk ratio reduction in
the bile acid group an alpha of 5 a beta of 10 and a heterogeneity of 0 Only 184 patients have been
randomised reporting this outcome which is only 19 of the HCRIS of 957 patients The cumulative Z-score
crosses the conventional boundaries for P 005 but not the monitoring boundaries
Number of patients with steroid-resistant rejection
Four trials (Pageaux 1995 Barnes 1997 Keiding 1997
Fleckenstein 1998) reported the number of patients with steroid-
resistant rejection These trials demonstrated that UDCA did not
significantly reduce the number of patients with steroid-resistant
rejection when compared with placebo (22122 (18) versus 26
112 (232) (RR 077 95 CI 047 to 127) (Analysis 111)
There was no significant heterogeneity (I2 0)
Liver biochemistry
The Fleckenstein 1998 trial reported serum bilirubin levels after
a three-month-treatment period in 30 liver-transplanted patients
There was no statistically significant difference in serum bilirubin
levels between the UDCA group and the placebo group (MD 260
mgdl 95 CI -096 to 616 mgdl) (Analysis 112)
No data were available for other liver biochemical variables
Cost-effectiveness
One trial (Barnes 1997) with 52 liver-transplanted patients re-
ported the days of hospitalisation after liver transplantation
UDCA significantly decreased the number of days of hospitali-
sation when compared with placebo (MD -850 days 95 CI -
1667 to -033 days) (Analysis 113) We were not able to extract
other medical cost from the trials
Adverse events
Among all the included and excluded trials only four reported on
adverse events however adverse events only occurred in two of
the included trials (Barnes 1997 Keiding 1997) There were no
significant differences regarding adverse events (RR 088 95 CI
030 to 260) 6112 (54) versus 6105 (57) (Analysis 114)
In the Barnes 1997 trial diarrhoea was reported by two patients
(one in the UDCA group and one in the placebo group) In the
Keiding 1997 trial five UDCA patients and five placebo patients
stopped intake of the trial medicine because of diarrhoea or dif-
ficulties in swallowing the capsules The remaining included trial
by Angelico 1999 stated that no adverse events occurred during
the study period The excluded trial by Assy 2007 was the only
one reporting on a case of mild diarrhoea in one patient in the
12Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
intervention group No other excluded studies reported on adverse
events (see Table 1)
Quality of life
None of the included studies assessed quality of life as an outcome
Other subgroup analyses
We planned to perform subgroup analyses regarding the risk of
bias of trials the dosage of bile acid and any co-intervention
However none of the trials were considered to be of low risk of
bias they all used a similar dosage of bile acid and patients in all
trials received similar immunosuppressive treatment as co-inter-
ventions (steroids azathioprine and cyclosporine or tacrolimus)
after liver transplantation Therefore we were not able to perform
the planned subgroup analyses
Funnel plot asymmetry
We did not draw a funnel plot analysis due to the limited number
of trials included in the present review
D I S C U S S I O N
In the update of this review we included no new trials assessing
the use of bile acids for liver-transplanted patients The analyses
of the seven previously included trials showed that bile acids did
not significantly affect mortality acute cellular rejection steroid-
resistant rejection retransplantation or serum bilirubin Bile acids
might significantly decrease the length of hospital stay and the
number of patients with chronic rejection included in these tri-
als but more supportive evidence is needed The number of pa-
tients with chronic rejection was not significantly influenced by
bile acids when a random-effects model was used and length of
stay was assessed in one single trial Furthermore none of the trials
were considered to be of low risk of bias and few patients were en-
rolled Therefore our positive findings may be due to bias (Schulz
1995 Moher 1998 Kjaergard 2001 Wood 2008) or random er-
rors (Wetterslev 2008 Brok 2009 Thorlund 2009) On the other
hand we are not able to exclude type II errors (that is finding
no significant differences when in fact they exist) due to the low
number of participants Therefore this topic could be of potential
interest in future large randomised trials with adequate control of
bias
All-cause mortality at one year after liver transplantation is re-
ported to be about 20 (Thuluvath 2003) which we also ob-
served for the patients included in the present review According to
our subgroup analyses neither UDCA nor TUDCA significantly
decreased all-cause mortality We also performed a subgroup anal-
ysis regarding treatment duration but we were not able to find any
difference between short (less than six months) and long treatment
duration (six months or more) Thus bile acids do not seem to
have statistically significant effects in reducing all-cause mortal-
ity after liver transplantation We performed both worst-best-case
scenario and best-worst-case scenario analyses In the worst-best-
case scenario bile acids did not differ significantly from placebo or
no intervention regarding all-cause mortality However bile acids
significantly decreased all-cause mortality in the best-worst-case
scenario analysis However such an analysis is very extreme and
may not be realistic We have also found that UDCA may be able
to decrease the risk of chronic rejection in liver-transplanted pa-
tients but trial sequential analysis could not confirm this result
Due to a limited number of patients (Ioannidis 2001) we are not
able to exclude the possibility that it may be relevant to perform
placebo-controlled trials with low risk of bias on the use of bile
acids for liver-transplanted patients
We looked into the causes of deaths that were reported by the trials
and only one trial reported one death related to rejection At the
same time the number of retransplantations was 3 among 68 liver-
transplanted patients who received treatment with UDCA and 4
among 64 liver-transplanted patients who received treatment with
placebo We noticed that all patients in the included trials received
co-interventions of standard triple-drug regimens (steroids aza-
thioprine and cyclosporine or tacrolimus) which were able to
control the possible acute or chronic rejection and prevent deaths
due to allograft rejection (FK506 1994)
The assumption that UDCA might reduce the incidence of acute
graft rejection came from the findings that UDCA could regulate
major histocompatibility complex antigen expression in bile ducts
and liver endothelia and inhibit lymphocyte activity (Calmus
1990 Terasaki 1991 Perez 2009) However in the present review
bile acids did not significantly reduce the risk of acute cellular re-
jection in liver-transplanted patients Considering that acute cellu-
lar rejection is commonly found within a few days after liver trans-
plantation (Vierling 1992) some might argue that the adminis-
tration of bile acids was started too late to prevent acute cellular
rejection We performed subgroup analyses regarding the time bile
acids were started and no statistically significant difference was
found Furthermore bile acids were not able to decrease the risk
of steroid-resistant rejection Therefore the lack of effects of bile
acids does not seem to be due to a delayed start to bile acid ad-
ministration after liver transplantation However it is a possibility
that one should start bile acids intake before liver transplantation
A retrospective study found that rejection rates differed signifi-
cantly between patients with primary biliary cirrhosis treated with
or without UDCA before liver transplantation (Heathcote 1999)
One could argue whether UDCA-induced delay in transplantation
has an adverse effect on post-transplantation outcome Since we
did not find any prospective randomised clinical trials addressing
this issue further research might be needed Furthermore some
studies may provide an explanation why UDCA was not able to
prevent acute cellular rejection These studies found that UDCA
did not appear to change the expression of major histocompatibil-
ity complex class II antigens but rather major histocompatibility
complex class I antigens (Calmus 1990) The initial mechanism
of acute rejection is thought to be recognition of MHC class II
13Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
antigens by CD4+ T cells (Vierling 1992) Moreover the inhibi-
tion of the production of interleukin-2 by peripheral blood lym-
phocytes with UDCA (Heuman 1993) might be negated by the
immunosuppressive treatment after liver transplantation (van den
Berg 1998) so that UDCA is unable to demonstrate effects on
graft rejection In a recent study by Assy 2007 a significant re-
duction in the mean dose of immunosuppressive medications was
achieved in stable liver graft recipients treated with UDCA indi-
cating a possible influence of UDCA on rejection mechanisms
In accordance with previous systematic reviews (Chen 2003a
Chen 2007 Gong 2008) bile acids were not associated with the
occurrence of serious adverse events or any major occurrence of
adverse events
In summary our results do not support or refute the use of bile
acids (UDCA and TUDCA) additional to standard immunosup-
pressive treatment in liver-transplanted patients
A U T H O R S rsquo C O N C L U S I O N SImplications for practice
There seems to be no evidence to support or refute the use of bile
acids for liver-transplanted patients receiving standard immuno-
suppressive treatment
Implications for research
We need more randomised placebo-controlled clinical trials with
enough statistical power and low risk of bias to explore the poten-
tial effects of bile acids on chronic rejection and mortality in liver-
transplanted patients Such trials should also consider evaluation
of quality of life and length of hospitalisation Such trials may
consider starting bile acid and placebo interventions before liver
transplantation we were not able to identify any randomised trials
addressing this regimen Such trials ought to be reported accord-
ing to the CONSORT statement (wwwconsort-statementorg)
However before embarking on such trials the effects of bile acids
in other patient groups should be scrutinised as they may have
small or negative effects
A C K N O W L E D G E M E N T S
We thank all the patients and investigators who were involved in
the clinical trials mentioned in this review We thank Wendong
Chen for his work and contribution on the previous version of this
review We thank the staff of The Cochrane Hepato-Biliary Group
Editorial Team especially Dimitrinka Nikolova and Sarah Louise
Klingenberg for excellent collaboration and assistance during the
update of this review
Peer Reviewers Carlo Merkel Italy M Tomikawa Japan
Contact Editor Bodil Als-Nielsen Denmark
R E F E R E N C E S
References to studies included in this review
Angelico 1999 published data only
Angelico M Tisone G Baiocchi L Palmieri G Pisani F Negrini S
et alOne-year pilot study on tauroursodeoxycholic acid as an
adjuvant treatment after liver transplantation Italian Journal of
Gastroenterology and Hepatology 199931(6)462ndash8 [MEDLINE
10575563]
Barnes 1997 published data onlylowast Barnes D Talenti D Cammell G Goormastic M Farquhar L
Henderson M et alA randomized clinical trial of ursodeoxycholic
acid as adjuvant treatment to prevent liver transplant rejection
Hepatology 199726(4)853ndash7 [MEDLINE 9328304]
Barnes D Talenti D Goormastic M Farquhar L Cammell G
Henderson M et alUrsodeoxycholic acid (UDCA) reduces hepatic
allograft rejection after orthotopic liver transplantation (OLT) - a
prospective randomized placebo-controlled double-blind trial
Hepatology 199522149A
Fleckenstein 1998 published data only
Fleckenstein JF Paredes M Thuluvath PJ A prospective
randomized double-blind trial evaluating the efficacy of
ursodeoxycholic acid in prevention of liver transplant rejection
Liver Transplantation and Surgery 19984(4)276ndash9 [MEDLINE
9649640]
Keiding 1997 published data only
Keiding S Hockerstedt K Bjoro K Bondesen S Hjortrup A
Isoniemi H et alThe Nordic multicenter double-blind randomized
controlled trial of prophylactic ursodeoxycholic acid in liver
transplant patients Transplantation 199763(11)1591ndash4
[MEDLINE 9197351]
Koneru 1993 published data only
Koneru B Tint GS Wilson DJ Leevy CB Salen F Randomised
prospective trial of ursodeoxycholic acid in liver transplant
recipients Hepatology 199318336A
Pageaux 1995 published data only
Pageaux GP Blanc P Perrigault PF Navarro F Fabre JM Souche B
et alFailure of ursodeoxycholic acid to prevent acute cellular
rejection after liver transplantation Journal of Hepatology 199523
(2)119ndash22 [MEDLINE 7499781]
Sama 1991 published data only
Sama C Mazziotti A Grigioni W Morselli AM Chianura A
Stefanini GF et alUrsodeoxycholic acid administration does not
14Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
prevent rejection after OLT Journal of Hepatology 199113(Suppl
2)68
References to studies excluded from this review
Assy 2007 published data only
Assy N Adams PC Myers P Simon V Minuk GY Wall W et
alRandomized controlled trial of total immunosuppression
withdrawal in liver transplant recipients role of ursodeoxycholic
acid Transplantation 200783(12)1571ndash6 [MEDLINE
17589339]
Clavien 1996 published data only
Clavien PA Sharara AI Camargo CA Jr Harland RC Fitz JG
Evidence that ursodeoxycholic acid prevents steroid-resistant
rejection in adult liver transplantation Clinical Transplantation
199610(6 Pt 2)658ndash62 [MEDLINE 8996761]
Friman 1992 published data only
Friman S Persson H Schersten T Svanvik J Karlberg I Adjuvant
treatment with ursodeoxycholic acid reduces acute rejection after
liver transplantation Transplantation Proceedings 199224(1)
389ndash90 [MEDLINE 1539328]
Heathcote 1999 published data onlylowast Heathcote EJ Stone J Cauch-Dudek K Poupon R Chazouilleres
O Lindor KD et alEffect of pretransplantation ursodeoxycholic
acid therapy on the outcome of liver transplantation in patients
with primary biliary cirrhosis Liver Transplantation and Surgery
19995(4)269ndash74 [MEDLINE 10388499]
Henriksson 1991 published data only
Henriksson BA Persson H Friman S Wangberg B Svanvik J
Karlberg I Adjuvant ursodeoxycholic acid prevents acute rejection
in liver transplant recipients Transplantation Proceedings 199123
(3)1971 [MEDLINE 2063453]
Persson 1990 published data only
Persson H Friman S Schersten T Svanvik J Karlberg I
Ursodeoxycholic acid for prevention of acute rejection in liver
transplant recipients Lancet 1990336(8706)52ndash3 [MEDLINE
1973232]
Rafael 1995 published data only
Rafael E Duraj F Rudstrom H Wilczek H Ericzon B Effect of
ursodeoxycholic acid treatment for cholestasis in liver transplant
recipients Transplantation Proceedings 199527(6)3501ndash2
[MEDLINE 8540069]
Sama 1998 published data only
Sama C Morselli-Labate AM Grazi GL Mastroianni A Danesi G
Pianta P et alUrsodeoxycholic acid in liver transplantation effect
on cholestasis and rejection Gastroenterology 1998114(4 Suppl)
A1332
Additional references
Adams 1990
Adams DH Neuberger JM Patterns of graft rejection following
liver transplantation Journal of Hepatology 199010(1)113ndash9
[MEDLINE 2407770]
Al-Quaiz 1994
Al-Quaiz M OrsquoGrady J Tredger J Williams R Variable effect of
ursodeoxycholic acid on cyclosporin absorption after orthotopic
liver transplantation Transplant International 19947(3)190ndash4
[MEDLINE 8060468]
Armstrong 1982
Armstrong MJ Carey MC The hydrophobic-hydrophilic balance
of bile salt Inverse correlation between reverse phase high
performance liquid chromatographic mobilities and micellar
cholesterol-solubilizing capacities Journal of Lipid Research 1982
23(1)70ndash80 [MEDLINE 7057113]
Ascher 1988
Ascher NL Stock PG Baumgardner GL Payne WD Najarian JS
Infection and rejection of primary hepatic transplant in 93
consecutive patients treated with triple immunosuppressive therapy
Surgery Gynecology amp Obstetrics 1988167(6)474ndash84
[MEDLINE 3055368]
Brok 2008
Brok J Thorlund K Gluud C Wetterslev J Trial sequential
analysis reveals insufficient information size and potentially false
positive results in many meta-analyses Journal of Clinical
Epidemiology 200861(8)763ndash9 [MEDLINE 18411040]
Brok 2009
Brok J Thorlund K Wetterslev J Gluud C Apparently conclusive
meta-analysis may be inconclusive - Trial sequential analysis
adjustment of random error risk due to repetitive testing of
accumulating data in apparently conclusive neonatal meta-analysis
International Journal of Epidemiology 200938(1)298ndash303
[MEDLINE 18824466]
Calmus 1990
Calmus Y Gane P Rouger P Poupon R Hepatic expression of class
I and class II major histocompatibility complex molecules in
primary biliary cirrhosis effect of ursodeoxycholic acid Hepatology
199011(1)12ndash5 [MEDLINE 2403961]
Calmus 1992
Calmus Y Arvieux C Gane P Boucher E Nordlinger B Rouger P
et alCholestasis induces major histocompatibility complex class I
expression in hepatocytes Gastroenterology 1992102(4 Pt 1)
1371ndash7 [MEDLINE 1551542]
Chen 2003a
Chen W Gluud C Bile acids for primary sclerosing cholangitis
Cochrane Database of Systematic Reviews 2003 Issue 2 [DOI
10100214651858CD003626]
Chen 2007
Chen W Liu J Gluud C Bile acids for viral hepatitis Cochrane
Database of Systematic Reviews 2007 Issue 4 [DOI 101002
14651858CD003181pub2]
Cheng 2002
Cheng K Ashby D Smyth R Ursodeoxycholic acid for cystic
fibrosis-related liver disease Cochrane Database of Systematic
Reviews 2002 Issue 2 [DOI 10100214651858CD000222]
Corbani 2008
Corbani A Burroughs AK Intrahepatic cholestasis after liver
transplantation Clinics in Liver Disease 200812(1)111ndash29
[MEDLINE 18242500]
DeMets 1987
DeMets DL Methods for combining randomised clinical trials
strengths and limitations Statistics in Medicine 19876(3)341ndash50
[MEDLINE 3616287]
15Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
DerSimonian 1986
DerSimonian R Laird N Meta-analysis in clinical trials Controlled
Clinical Trials 19867(3)177ndash88 [MEDLINE 3802833]
Egger 1997
Egger M Davey Smith G Schneider M Minder C Bias in meta-
analysis detected by a simple graphical test BMJ (Clinical Research
Ed) 1997315(7109)629ndash34 [MEDLINE 9310563]
Ericzon 1990
Ericzon BG Eusufzai S Kubota K Einarsson K Angelin B
Characteristics of biliary lipid metabolism after liver
transplantation Hepatology 199012(5)1222ndash8 [MEDLINE
2227822]
FK506 1994
The US Multicenter FK506 Liver Study Group A comparison of
tacrolimus (FK506) and cyclosporine for immunosuppression in
liver transplantation New England Journal of Medicine 1994331
(17)1110ndash5 [MEDLINE 7523946]
Friman 1994
Friman S Svanvik J A possible role of ursodeoxycholic acid in liver
transplantation Scandinavian Journal of Gastroenterology 1994204
62ndash4 [MEDLINE 7824880]
Fuchs 1999
Fuchs M Stange EF Metabolism of bile acids In Johannes
Bircher Jean-Pierre Benhamou Neil McIntyre Mario Rizzetto
Juan Rodes editor(s) Oxford Textbook of Clinical Hepatology 2
Vol 1 Oxford Oxford University Press 1999223ndash56
Fusai 2006
Fusai G Dhaliwal P Rolando N Sabin CA Patch D Davidson BR
et alIncidence and risk factors for the development of prolonged
and severe intrahepatic cholestasis after liver transplantation Liver
Transplantation 200612(11)1626ndash33 [DOI 101002lt20870]
Gluud 2001
Gluud C Alcoholic hepatitis no glucocorticosteroids In
Leuschner U James OFW Dancygier H editor(s) Steatohepatitis
(NASH and ASH) Falk Symposium 121 Lancaster Kluwer
Academic Publisher 2001322ndash42
Gluud 2010
Gluud C Nikolova D Klingenberg SL Alexakis N Als-Nielsen B
Colli A et alCochrane Hepato-Biliary Group About The
Cochrane Collaboration (Cochrane Review Groups (CRGs))
2010 Issue 1 Art No LIVER
Gong 2008
Gong Y Huang ZB Christiansen E Gluud C Ursodeoxycholic
acid for primary biliary cirrhosis Cochrane Database of Systematic
Reviews 2008 Issue 3 [DOI 101002
14651858CD000551pub2]
Haddad 2006
Haddad EM McAlister VC Renouf E Malthaner R Kjaer MS
Gluud LL Cyclosporin versus tacrolimus for liver transplanted
patients Cochrane Database of Systematic Reviews 2006 Issue 4
[DOI 10100214651858CD005161pub2]
Heuman 1993
Heuman DM Hepatoprotective properties of ursodeoxycholic acid
Gastroenterology 1993104(6)1865ndash9 [MEDLINE 8500748]
Higgins 2008
Higgins PTJ Green S editors Cochrane Handbook for Systematic
Reviews of Interventions West Sussex England Wiley-Blackwell
2008
Hirschfield 2009
Hirschfield GM Gibbs P Griffiths WJH Adult liver
transplantation what non-specialists need to know BMJ (Clinical
Research Ed) 2009338(b1670)1321ndash7 [DOI 101136
bmjb1670]
Hussain 2002
Hussain HK Nghiem HV Imaging of hepatic transplantation
Clinics in Liver Disease 20026(1)247ndash70 [MEDLINE
11933592]
ICH-GCP 1997
International Conference on Harmonisation Expert Working
Group Code of Federal Regulations amp International Conference on
Harmonization Guidelines Media Parexel Barnett 1997
Ioannidis 2001
Ioannidis JPA Lau J Evolution of treatment effects over time
Empirical insight from recursive cumulative meta analyses
Proceedings of the National Academy of Sciences 200198(3)831ndash6
IWP 1995
International Working Party Terminology for hepatic allograft
rejection Hepatology 199522(2)648ndash54 [MEDLINE 7635435]
Kjaergard 2001
Kjaergard LL Villumsen J Gluud C Reported methodological
quality and discrepancies between large and small randomised trials
in meta-analyses Annals of Internal Medicine 2001135(11)982ndash9
[MEDLINE 11730399]
Klintmalm 1989
Klintmalm GB Nery JR Husberg BS Gonwa TA Tillery GW
Rejection in liver transplantation Hepatology 198910(6)978ndash85
[MEDLINE 2583691]
Knechtle 2009
Knechtle SJ Kwun J Unique aspects of rejection and tolerance in
liver transplantation Seminars in Liver Disease 200929(1)91ndash101
[MEDLINE 19235662]
Krams 1993
Krams SM Ascher NL Martinez OM New immunologic insights
into mechanisms of allograft rejection Gastroenterology Clinics of
North America 199318(2)374ndash7 [MEDLINE 8509176]
Lan 1983
Lan KKG DeMets DL Discrete sequential boundaries for clinical
trials Biometrika 198370659ndash63
Merion 1989
Merion RM Gorski DH Burtch GD Turcotte JG Colletti LM
Campbell DA Jr Bile refeeding after liver transplantation and
avoidance of intravenous cyclosporine Surgery 1989106(4)
604ndash9 [MEDLINE 2799635]
Moher 1998
Moher D Pham B Jones A Cook DJ Jadad AR Moher M et
alDoes quality of reports of randomised trials affect estimates of
intervention efficacy reported in meta-analyses Lancet 1998352
(9128)609ndash13 [MEDLINE 9746022]
16Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Neuberger 1999
Neuberger J Incidence timing and risk factors for acute and
chronic rejection Liver Transplantation and Surgery 19995(4 Suppl
1)S30ndashS36 [MEDLINE 10431015]
Okolicsanyi 1986
Okolicsanyi L Lirussi F Strazzabosco M Jemmolo RM Orlando R
Nassuato G et alThe effect of drugs on bile flow and composition
An overview Drugs 198631(5)430ndash48 [MEDLINE 2872047]
Palmer 1972
Palmer RH Bile acids liver injury and liver disease Archives of
Internal Medicine 1972130(4)606ndash17 [MEDLINE 4627840]
Perez 2009
Perez MJ Briz O Bile-acid-induced cell injury and protection
World Journal of Gastroenterology 200915(14)1677ndash89
[MEDLINE 19360911]
Pogue 1997
Pogue JM Yusuf S Cumulating evidence from randomized trials
Utilizing sequential monitoring boundaries for cumulative meta-
analysis Controlled Clinical Trials 199718(6)580ndash93
[MEDLINE 9408720]
Pogue 1998
Pogue J Yusuf S Overcoming the limitations of current meta-
analysis of randomised controlled trials Lancet 1998351(9095)
45ndash52 [MEDLINE 9433436]
RevMan 2008
The Nordic Cochrane Centre The Cochrane Collaboration
Review Manager (RevMan) 50 Copenhagen The Nordic
Cochrane Centre The Cochrane Collaboration 2008
Royle 2003
Royle P Milne R Literature searching for randomized controlled
trials used in Cochrane reviews rapid versus exhaustive searches
International Journal of Technology Assessment in Health Care 2003
19(4)591ndash603
Schulz 1995
Schulz KF Chalmers I Hayer R Altman D Empirical evidence of
bias JAMA 1995273(5)408ndash12 [MEDLINE 7823387]
Sharara 1995
Sharara AI Camargo CA Clavien PA Ursodeoxycholic acid
prevents steroid resistant rejection in liver transplant recipients
Gastroenterology 1995108A1168
Sholmerich 1984
Sholmerich J Becher MS Schmidt KH Schubert R Kremer B
Felhaus S et alInfluence of hydroxylation and conjugation of bile
salts on their membrane damaging properties Hepatology 19844
(4)661ndash7 [MEDLINE 6745854]
Soderdahl 1998
Soderdahl G Nowak G Duraj F Wang FH Einarsson C Ericzon
BG Ursodeoxycholic acid increased bile flow and affects bile
composition in the early postoperative phase following liver
transplantation Transplantation International 199811(Suppl 1)
S231ndashS238 [MEDLINE 9664985]
Terasaki 1991
Terasaki S Nakanuma Y Ogino H Unoura M Kobayashi K
Hepatocellular and biliary expression of HLA antigens in primary
biliary cirrhosis before and after ursodeoxycholic acid therapy
American Journal of Gastroenterology 199186(9)1194ndash9
[MEDLINE 1882800]
Thalheimer 2002
Thalheimer U Capra F Liver transplantation making the best out
of what we have Digestive Diseases and Sciences 200247(5)
945ndash53 [MEDLINE 12018919]
Thorlund 2009
Thorlund K Devereaux PJ Wetterslev J Guyatt G Ioannidis JP
Thabane L et alCan trial sequential monitoring boundaries reduce
spurious inferences from meta-analyses International Journal of
Epidemiology 200938(1)276ndash86 [MEDLINE 18824467]
Thuluvath 2003
Thuluvath PJ Yoo HY Thompson RE A model to predict survival
at one month one year and five years after liver transplantation
based on pretransplant clinical characteristics Liver Transplantation
20039(5)527ndash32 [MEDLINE 12740799]
van den Berg 1998
van den Berg AP Twilhaar WN Mesander G van Son WJ van der
Bij W Klompmaker IJ et alQuantitation of immunosuppression
by flow cytometric measurement of the capacity of T cells for
interleukin-2 production Transplantation 199865(8)1066ndash71
[MEDLINE 9583867]
Vierling 1992
Vierling J Immunologic mechanisms of hepatic allograft rejection
Seminars in Liver Disease 199212(1)16ndash27 [MEDLINE
1570548]
Wetterslev 2008
Wetterslev J Thorlund K Brok J Gluud C Trial sequential
analysis may establish when firm evidence is reached in cumulative
meta-analysis Journal of Clinical Epidemiology 200861(1)64ndash75
[MEDLINE 18083463]
Wiesner 1992
Wiesner RH Acute cellular rejection following liver
transplantation incidence risk factors and outcome in the
NIDDK Liver Transplant Database (LTD) study Gastroenterology
1992102A910
Wood 2008
Wood L Egger M Gluud LL Schulz KF Juni P Altman DG et
alEmpirical evidence of bias in treatment effect estimates in
controlled trials with different interventions and outcomes meta-
epidemiological study BMJ (Clinical Research Ed) 2008336
(7644)601ndash5 [MEDLINE 18316340]
Yoshikawa 1998
Yoshikawa M Matsui Y Kawamoto H Toyohara M Matsumura
K Yamao J et alIntragastric administration of ursodeoxycholic
acid suppresses immunoglobulin secretion by lymphocytes from
liver but not from peripheral blood spleen or Peyerrsquos patches in
mice International Journal of Immunopharmacology 199820(1-3)
29ndash38 [MEDLINE 9717080]
References to other published versions of this review
17Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Chen 2003b
Chen W Gluud C Bile acids for liver transplanted patients
Cochrane Database of Systematic Reviews 2005 Issue 3 [DOI
10100214651858CD005442]lowast Indicates the major publication for the study
18Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
C H A R A C T E R I S T I C S O F S T U D I E S
Characteristics of included studies [ordered by study ID]
Angelico 1999
Methods Study design open-label randomised one-year pilot study
Participants Country Italy
Publication language English
Inclusion criteria
- patients who underwent liver transplantation from April 1994 to December 1994
Exclusion criteria
- not mentioned
Participants
Two patients in TUDCA group and two patients in control group were excluded from
the basic information of participants by the study due to withdrawal
- TUDCA group (n = 14)
Mean age (years +- SD)
467 +- 84
Ratio of sex (malefemale) 122
Origins of liver diseases
hepatitis C cirrhosis (9) hepatitis B cirrhosis (2) hepatitis B and C cirrhosis (1) cryp-
togenic cirrhosis (2) alcoholic cirrhosis (0) Wilson cirrhosis (0)
- Control group (n = 15)
Mean age (years +- SD)
474 +- 74
Ratio of sex (malefemale) 123
Origins of liver diseases
hepatitis C cirrhosis (7) hepatitis B cirrhosis (2) hepatitis B and C cirrhosis (2) cryp-
togenic cirrhosis (2) alcoholic cirrhosis (1) Wilson cirrhosis (1)
Interventions TUDCA group
- Dose 500 mgday in two divided doses
- Route orally
- Duration the treatment was started on day 5 after transplantation and continued for
one year
Control group
- no treatment
Co-interventions all patients received standard triple-drug regimens (steroids azathio-
prine and cyclosporine or tacrolimus)
Outcomes All cause mortality
Number of patients with rejection after liver transplantation
Notes Letter was sent to the authors in September 2009 A reply with additional information
was received shortly after
Risk of bias
19Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Angelico 1999 (Continued)
Item Authorsrsquo judgement Description
Adequate sequence generation Yes Computer generated table
Allocation concealment Unclear No information provided
Blinding No Not performed
Incomplete outcome data addressed
All outcomes
Yes Withdrawal two patients from the
TUDCA group and two patients from the
placebo group Three of them died due to
transplant non-function in the first postop-
erative week and one patient was regrafted
due to thrombosis of hepatic artery
Free of selective reporting Unclear Post-transplant cholestasis and liver bio-
chemistry specified as outcomes Differ-
ence reported as not significant but no ac-
tual data given
Sample size calculation No Not reported
Intention-to-treat analysis No Not stated and not used
Baseline imbalance Unclear Not enough information provided
Early stopping of trial Unclear Not enough information provided
Barnes 1997
Methods Study design randomised placebo-controlled double-blind trial
Participants Country United States
Publication language English
Inclusion criteria
- patients aged 18 years or older who underwent liver transplantation at the Cleveland
Clinic Foundation from April 1992 through June of 1994
Exclusion criteria
- patients who were found to have cancer at surgically resected margins of the biliary
tree
- patents who underwent retransplantation
Participants
- UDCA group (n = 28)
Mean age (years +- SD)
505 +- 116
Ratio of sex (malefemale) 1810
Child class A 7
20Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Barnes 1997 (Continued)
B 13
and C 8
Origins of liver diseases Laennecrsquos cirrhosis 4
PBC 3
cryptogenic cirrhosis 6
hepatitis Ccirrhosis 4
hepatitis Bcirrhosis 3
autoimmune hepatitis with cirrhosis 3
PSC 2
other 3
- Placebo group (n = 24)
Mean age (years +- SD)
507 +- 93
Ratio of sex (malefemale) 159
Child class A 6
B 14
and C 4
Origins of liver diseases Laennecrsquos cirrhosis 9
PBC 5
cryptogenic cirrhosis 1
hepatitis Ccirrhosis 1
hepatitis Bcirrhosis 1
autoimmune hepatitis with cirrhosis 1
PSC 2
other 4
Interventions UDCA group
- Dose 10-15 mgkg body weightday in divided doses
- Route orally
- Duration immediately after intestinal transit recovery usually between postoperative
days three and five and continue for three months
Placebo group
- identical-appearing capsules administered in the same quantity and manner
Co-interventions all patients received standard triple-drug regimens (steroids azathio-
prine and cyclosporine or tacrolimus)
Outcomes All cause mortality
Number of patients with acute cellular rejection
Number of patients with chronic rejection
Number of patients with steroid-resistant rejection
Number of days of hospitalisation
Adverse events
Notes Letter was sent to the authors in September 2009 A reply with additional information
was received shortly after
Risk of bias
Item Authorsrsquo judgement Description
21Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Barnes 1997 (Continued)
Adequate sequence generation Yes Computer generated table
Allocation concealment Unclear No information provided
Blinding Yes Quote ldquorandomised to receive either
UDCA or an identical placebo capsulerdquo
Incomplete outcome data addressed
All outcomes
Yes Mean follow-up time 18 months Ten pa-
tients withdrawn from study 6 in UDCA
group and 4 in placebo group Reasons
for withdrawal were reported Four patients
died in the placebo group
Free of selective reporting Yes All expected outcomes reported
Sample size calculation Unclear The trial reported the method of sample
size calculation but the actual number of
patients needed was not reported
Intention-to-treat analysis Yes Stated and used
Baseline imbalance Unclear Not enough information provided
Early stopping of trial Unclear The number of patients needed to gain the
actual power was not reported Whether
the trial was terminated early is not clear
Fleckenstein 1998
Methods Study design prospective randomised double-blind trial
Participants Country United States
Publication language English
Inclusion criteria
- patients who underwent liver transplantation at the Johns Hopkins Hospital
Exclusion criteria
- patients who were under 18 years old undergoing repeat transplantation had primary
graft nonfunction or refused consent
Participants
- UDCA group (n = 14)
Mean age (years +- SD)
443 +- 127
Ratio of sex (malefemale) 68
Origins of liver diseases hepatitis C 6
alcohol 2
autoimmune 1
PBC 2
22Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Fleckenstein 1998 (Continued)
PSC 1
autoimmune cholangiopathy 1
hepatitis B 1
- Placebo group (n = 16)
Mean age (years +- SD)
496 +- 109
Ratio of sex (malefemale) 124
Origins of liver diseases hepatitis C 3
alcohol 3
autoimmune 3
PBC 1
PSC 2
cryptogenic 2
hepatitis B 1
alpha1-antitrypsin deficiency 1
Interventions UDCA group
- Dose 15 mgkg body weightday in divided doses
- Route orally
- Duration immediately after intestinal transit recovery usually between postoperative
days three and five and continue for three months
Placebo group
- Identical-appearing capsules administered in the same quantity and manner
Co-interventions all patients received standard triple-drug regimens (steroids azathio-
prine and cyclosporine or tacrolimus)
Outcomes All cause mortality
Number with retransplantation
Number of patients with acute cellular rejection
Number of patients with chronic rejection
Serum bilirubin levels at the end of treatment
Notes Follow-up time nine months
Letter was sent to the authors in September 2009 No reply was received
Risk of bias
Item Authorsrsquo judgement Description
Adequate sequence generation Unclear No information provided
Allocation concealment Unclear No information provided
Blinding Yes Method of blinding not described but
probably adequate
Incomplete outcome data addressed
All outcomes
Yes Withdrawal one patient from the UDCA
group and two patients from the placebo
group because of capsule size
23Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Fleckenstein 1998 (Continued)
Free of selective reporting Unclear Outcomes were not completely described
Sample size calculation No Not reported
Intention-to-treat analysis Yes Quote ldquoThree patients withdrew after in-
clusionThey were included in the statis-
tical analysisrdquo
Baseline imbalance Unclear Not enough information provided
Early stopping of trial Unclear Not enough information provided
Keiding 1997
Methods Study design prospective randomised placebo-controlled multicenter study
Participants Country Denmark Finland Norway and Sweden
Publication language English
Inclusion criteria
- patients who underwent liver transplantation in Denmark Finland Norway and Swe-
den from September 1 1992 to May 31 1994
Exclusion criteria
- patients with malignant diseases
Participants
The age of the children ranged from 0 to 13 years (median 15) and the age of adults
ranged from 14 to 59 years old (median 44) MaleFemale ratio was 96 for children and
4344 for adults
- UDCA group (n = 54)
Origins of liver diseases
paracetamol intoxication 1 hepatitis B 1 autoimmune hepatitis 0 biliary atresia 2
metabolic diseases 7 neonatal hepatitis 2 PBC 13 post hepatitis cirrhosis 8 PSC 3
cryptogenic cirrhosis 7 alcoholic cirrhosis 2 other reasons 8
- Placebo group (n = 48)
Origins of liver diseases paracetamol intoxication 1 hepatitis B 0 autoimmune hepatitis
1 biliary atresia 3 metabolic diseases 11 neonatal hepatitis 0 PBC 7 post hepatitis
cirrhosis 5 PSC 7 cryptogenic cirrhosis 2 alcoholic cirrhosis 6 other reasons 5
Interventions UDCA group
- Dose 15 mgkg body weightday in two or three divided doses
- Route orally
- Duration immediately after intestinal transit recovery usually between postoperative
days three and five and continue for three months
Placebo group
- Identical-appearing capsules administered in the same quantity and manner
Co-interventions all patients received standard triple-drug regimens (steroids azathio-
prine and cyclosporine or tacrolimus)
24Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Keiding 1997 (Continued)
Outcomes All cause mortality
Number of deaths related to rejection
Number of patients with acute cellular rejection
Number of patients with chronic rejection
Number of patients with steroid-resistant rejection
Adverse events
Notes Letter was sent to the authors in September 2009 No reply was received
Risk of bias
Item Authorsrsquo judgement Description
Adequate sequence generation Unclear Patients were randomised at a ratio of 11
Allocation concealment Yes Quote ldquo The allocation was performed in
blocks of 10 patients using the sealed serial
envelope methodrdquo
Blinding Yes Quote ldquoThe UDCA and the placebo cap-
sules had identical appearance and tasterdquo
Incomplete outcome data addressed
All outcomes
Yes Follow-up time 12 months Five UDCA
patients and five placebo patients withdrew
from study Reasons were reported
Free of selective reporting Unclear Insufficient information
Sample size calculation Yes Performed and allowed for a difference in
the incidence of at least one episode of
acute rejection of 50 between the treat-
ment and placebo groups with 90 statisti-
cal power and a significance level of P value
less than 005 The calculated sample size
was 80 patients
Intention-to-treat analysis Yes Stated and used
Baseline imbalance Yes The study seems to be free of baseline im-
balance
Early stopping of trial Yes Study attained the pre-specified sample
size
25Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Koneru 1993
Methods Study design randomised controlled trial
Participants Country United States
Publication language English
Inclusion criteria
- patients who underwent liver transplantation
Exclusion criteria
- not mentioned
Participants
- UDCA group (n = 16)
Mean age (years +- SD)
no information
Ratio of sex (malefemale) no information
Origins of liver diseases
no information
- Control group (n = 16)
Mean age (years +- SD)
no information
Ratio of sex (malefemale) no information
Origins of liver diseases
no information
Interventions UDCA group
- Dose 900 mgday
- Route orally
- Duration immediately after intestinal transit recovery usually between postoperative
days three and five and continue for three months
Control group
- no treatment
Co-interventions all patients received standard triple-drug regimens (steroids azathio-
prine and cyclosporine)
Outcomes Number of patients with retransplantation due to rejection
Number of patients with rejection episodes
Notes Abstract
Letter was sent to the authors in September 2009 No reply was received
Risk of bias
Item Authorsrsquo judgement Description
Adequate sequence generation Unclear No information provided
Allocation concealment Unclear No information provided
Blinding No Not performed
26Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Koneru 1993 (Continued)
Incomplete outcome data addressed
All outcomes
Unclear The study gives the impression that there
were no withdrawals but this was not ex-
plicitly stated
Free of selective reporting Unclear Insufficient information provided
Sample size calculation No Not performed
Intention-to-treat analysis Unclear No information provided
Baseline imbalance Unclear Not enough information provided
Early stopping of trial Unclear Not enough information provided
Pageaux 1995
Methods Study design double-blind randomised study
Participants Country France
Publication language English
Inclusion criteria
- patients who underwent liver transplantation
Exclusion criteria
- not mentioned
Participants
- UDCA group (n=26)
Mean age (years +- SD)
47 +- 10
Ratio of sex (malefemale) 179
Origins of liver diseases alcoholic cirrhosis 14
post-hepatic B cirrhosis 2
post-hepatitis C cirrhosis 4
PBC 2
liver cancer 2
fulminant hepatitis 1
miscellaneous 1
- Placebo group (n = 24)
Mean age (years +- SD)
51+- 9
Ratio of sex (malefemale) 159
Origins of liver diseases alcoholic cirrhosis 10
post-hepatic B cirrhosis 0
post-hepatic C cirrhosis 6
PBC 3
liver cancer 4
fulminant hepatitis 0
miscellaneous 1
27Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Pageaux 1995 (Continued)
Interventions UDCA group
- Dose 600 mgday in three divided doses
- Route orally
- Duration immediately after intestinal transit recovery usually between postoperative
days three and five and continue for two months
Placebo group
- identical-appearing capsules administered in the same quantity and manner
Co-interventions all patients received standard triple-drug regimens (steroids azathio-
prine and cyclosporine or tacrolimus)
Outcomes Number of patients with acute cellular rejection
Number of patients with steroid-resistant rejection
Notes Letter was sent to the authors in September 2009 No reply was received
Risk of bias
Item Authorsrsquo judgement Description
Adequate sequence generation Unclear No information provided
Allocation concealment Unclear No information provided
Blinding Unclear Method of blinding not described
Incomplete outcome data addressed
All outcomes
Yes Five patients died from non-immunologi-
cal causes before the end of the first month
and were excluded from the study Reasons
were reported
Free of selective reporting Unclear Not enough information provided
Sample size calculation No Not performed
Intention-to-treat analysis No Not stated and not used
Baseline imbalance Unclear Not enough information provided
Early stopping of trial Unclear Not enough information provided
Sama 1991
Methods Study design randomised controlled trial
Participants Country Italy
Publication language English
Inclusion criteria
28Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Sama 1991 (Continued)
- patients who underwent liver transplantation
Exclusion criteria
- not mentioned
Participants
- UDCA group (n = 20)
Mean age (years +- SD)
no information
Ratio of sex (malefemale) no information
Origins of liver diseases
no information
- Control group (n = 20)
Mean age (years +- SD)
no information
Ratio of sex (malefemale) no information
Origins of liver diseases
no information
Interventions UDCA group
- Dose 600 mgday in two divided doses
- Route orally
- Duration immediately after intestinal transit recovery usually between postoperative
day five and day seven and continue for six months
Control group
- no treatment
Co-interventions all patients received standard immunosuppressive treatment (steroids
and cyclosporine)
Outcomes All cause mortality
Number of patients with acute cellular rejection
Notes Abstract
Letter was sent to the authors in September 2009 No reply was received
Risk of bias
Item Authorsrsquo judgement Description
Adequate sequence generation Unclear A randomisation list was performed before
patients were admitted to the trial (infor-
mation from principal author)
Allocation concealment Unclear No information provided
Blinding Unclear The principle author provided information
that the study was made according to a
single-blind randomised protocol The pri-
mary outcome was the occurrence of biopsy
proven rejection episodes The pathologists
were blind but the patients were not
29Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Sama 1991 (Continued)
Incomplete outcome data addressed
All outcomes
Unclear Five patients from the UDCA group and
six patients from the placebo group were
excluded Reasons for exclusion were not
fully stated
Free of selective reporting No Data about survival of patients were not
adequately reported
Sample size calculation No Not performed
Intention-to-treat analysis No Not stated and not used
Baseline imbalance Unclear Basic characteristics of patients not re-
ported
Early stopping of trial Unclear Not enough information provided
UDCA = ursodeoxycholic acid
TUDCA = tauroursodeoxycholic acid
PBC = primary biliary cirrhosis
PSC = primary sclerosing cholangitis
OKT3 = anti-CD3 monoclonal antibody
Characteristics of excluded studies [ordered by study ID]
Assy 2007 A randomised controlled trial that included only recipients of liver transplantation with stable graft function and
no episodes of rejection for at least 2 years that were then offered total immunosuppression withdrawal Fourteen
patients received UDCA (15 mgkg body weightday) and 12 received placebo Rejection occurred in 43 and
75 of patients respectively (no significant difference) None developed chronic rejection After follow-up two
patients were free of immunosuppression 80 were steroid free and 50 were able to reduce their dose of
cyclosporine
Clavien 1996 Case series Fifty consecutive liver-transplanted patients were treated with a standard cyclosporine immunosup-
pressive regimen Twenty three of the 43 survivors developed an episode of rejection and UDCA (10 mgkg
weightday) was initiated Only one patient had a second episode of rejection
Friman 1992 Observational study Thirty-three liver-transplanted patients received 10 mg UDCAkg body weightday for
median of 10 months (range four to 21 months) Eight historical liver-transplanted patients served as control
group The rejection incidence was significantly lower in the patients who received the treatment with UDCA
Biochemistry one month after transplantation demonstrated significantly lower average values of aminotrans-
ferases and alkaline phosphatases in patients treated with UDCA than in the control group
30Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
Heathcote 1999 Observational study From 1987 to 1996 37 UDCA treated and 53 placebo treated patients with primary biliary
cirrhosis were referred for transplantation Posttransplantation survival rates at one month were 939 in the
UDCA group and 884 in the placebo group and one year survival rates were 903 and 784 respectively
(no significant differences) However rejection (type not defined - a secondary outcome measure) occurred
significantly less often in the UDCA group (429) than in placebo group (688)
Henriksson 1991 Observational study All patients in this study were given sequential quadruple immunosuppression with anti-
lymphocyte globulin azathioprine steroids and cyclosporine All patients with primary graft function (n = 11)
were treated with 10 mg UDCAkg body weightday starting during the first postoperative week Patients who
received liver transplantation in the first 6 months of 1989 (n = 8) served as controls In the control group one
patient died after 9 months with chronic graft dysfunction and six patients had rejection episodes during the
first postoperative month All patients in the UDCA group were alive without rejection episodes
Persson 1990 Observational study All 11 adult patients transplanted between August 1989 and January 1990 with primary
graft function were treated with 10 mg UDCA kg body weightday Eight patients transplanted during the first
half of 1989 served as control UDCA was started during the first postoperative week and the treatment was
continued for six months All patients in the UDCA treated group survived with satisfactory graft function In
the control group six patients had at least one rejection episode needing treatment during the first postoperative
month
Rafael 1995 Observational study Seventeen patients who underwent liver transplantation between February 1990 and April
1993 and developed biliary complications after transplantation were retrospectively analysed regarding treatment
with UDCA UDCA was given in a dose of 500 to 1000 mgday Ten patients were treated for at least one year while
seven patients were treated for 14 to 250 days UDCA significantly improved gammaglutamyl transpeptidase in
liver graft recipients with biliary complications There was also a trend towards improvement in serum bilirubin
and alanine transaminase values
Sama 1998 Observational study Thirty-four patients who underwent liver transplantation between January 1995 and June
1996 were included in the study Seventeen were treated with UDCA 10 mgkg body weightday during 6
months while 17 served as controls on the basis of having undergone liver transplantation closest to UDCA
patients A significant decrease in serum bilirubin levels was observed in UDCA patients There was a significantly
higher incidence of recurrent hepatitis in the control group
UDCA ursodeoxycholic acid
31Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
D A T A A N D A N A L Y S E S
Comparison 1 Bile acids for liver-transplanted patients
Outcome or subgroup titleNo of
studies
No of
participants Statistical method Effect size
1 All-cause mortality at maximum
follow-up
5 257 Risk Ratio (M-H Fixed 95 CI) 085 [053 136]
11 UDCA versus placebo or
no treatment
4 224 Risk Ratio (M-H Fixed 95 CI) 080 [049 130]
12 TUDCA versus no
treatment
1 33 Risk Ratio (M-H Fixed 95 CI) 159 [030 833]
2 All-cause mortality worst-best
case and best-worst case
scenarios
5 Risk Ratio (M-H Fixed 95 CI) Subtotals only
21 Worst-best case scenario 5 257 Risk Ratio (M-H Fixed 95 CI) 130 [086 196]
22 Best-worst case scenario 5 257 Risk Ratio (M-H Fixed 95 CI) 058 [038 090]
3 Subgroup analyses all-cause
mortality at maximum
follow-up according to time of
start of bile acids
5 257 Risk Ratio (M-H Fixed 95 CI) 085 [053 136]
31 Less than three days after
transplantation
1 102 Risk Ratio (M-H Fixed 95 CI) 124 [061 254]
32 Three days or more after
transplantation
4 155 Risk Ratio (M-H Fixed 95 CI) 063 [033 120]
4 Subgroup analyses all cause
mortality at maximum
follow-up according to
treatment duration
5 257 Risk Ratio (M-H Fixed 95 CI) 085 [053 136]
41 Less than six months 3 184 Risk Ratio (M-H Fixed 95 CI) 078 [045 138]
42 Six months or more 2 73 Risk Ratio (M-H Fixed 95 CI) 102 [043 240]
5 Number of deaths related
to rejection at maximum
follow-up
1 102 Risk Ratio (M-H Fixed 95 CI) 030 [001 712]
51 UDCA versus placebo 1 102 Risk Ratio (M-H Fixed 95 CI) 030 [001 712]
6 Number of retransplantations at
maximum follow-up
2 132 Risk Ratio (M-H Fixed 95 CI) 076 [020 286]
7 Number of patients with acute
cellular rejection at maximum
follow-up
7 339 Risk Ratio (M-H Fixed 95 CI) 089 [074 106]
71 UDCA versus placebo or
no treatment
6 306 Risk Ratio (M-H Fixed 95 CI) 089 [074 108]
72 TUDCA versus no
treatment
1 33 Risk Ratio (M-H Fixed 95 CI) 085 [045 160]
8 Subgroup analysis number of
patients with acute cellular
rejection according to time of
start of bile acid
7 339 Risk Ratio (M-H Fixed 95 CI) 089 [074 106]
32Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
81 Less than three days after
transplantation
2 134 Risk Ratio (M-H Fixed 95 CI) 084 [063 111]
82 Three days or more after
liver transplantation
5 205 Risk Ratio (M-H Fixed 95 CI) 092 [072 117]
9 Subgroup analysis number
of patients with acute
cellular rejection according to
treatment duration
7 339 Risk Ratio (M-H Fixed 95 CI) 089 [074 106]
91 Less than six months 5 266 Risk Ratio (M-H Fixed 95 CI) 087 [071 107]
92 Six months or more 2 73 Risk Ratio (M-H Fixed 95 CI) 094 [065 136]
10 Number of patients with
chronic rejection at maximum
follow-up
3 184 Risk Ratio (M-H Fixed 95 CI) 028 [008 095]
11 Number of patients with
steroid-resistant rejection at
maximum follow-up
4 234 Risk Ratio (M-H Fixed 95 CI) 077 [047 127]
12 Serum bilirubin (mgdl) at the
end of treatment
1 30 Mean Difference (IV Fixed 95 CI) 26 [-096 616]
13 Number of days of
hospitalisation after liver
transplantation
1 52 Mean Difference (IV Fixed 95 CI) -85 [-1667 -033]
14 Adverse events 3 187 Risk Ratio (M-H Fixed 95 CI) 088 [030 260]
Analysis 11 Comparison 1 Bile acids for liver-transplanted patients Outcome 1 All-cause mortality at
maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 1 All-cause mortality at maximum follow-up
Study or subgroup Favours bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 UDCA versus placebo or no treatment
Barnes 1997 228 724 253 024 [ 006 107 ]
Fleckenstein 1998 214 416 125 057 [ 012 266 ]
Keiding 1997 1454 1048 355 124 [ 061 254 ]
Sama 1991 520 620 201 083 [ 030 229 ]
Subtotal (95 CI) 116 108 935 080 [ 049 130 ]
Total events 23 (Favours bile acids) 27 (Control)
Heterogeneity Chi2 = 416 df = 3 (P = 025) I2 =28
Test for overall effect Z = 091 (P = 036)
01 02 05 1 2 5 10
Favours bile acids Favours control
(Continued )
33Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Favours bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
2 TUDCA versus no treatment
Angelico 1999 316 217 65 159 [ 030 833 ]
Subtotal (95 CI) 16 17 65 159 [ 030 833 ]
Total events 3 (Favours bile acids) 2 (Control)
Heterogeneity not applicable
Test for overall effect Z = 055 (P = 058)
Total (95 CI) 132 125 1000 085 [ 053 136 ]
Total events 26 (Favours bile acids) 29 (Control)
Heterogeneity Chi2 = 466 df = 4 (P = 032) I2 =14
Test for overall effect Z = 069 (P = 049)
01 02 05 1 2 5 10
Favours bile acids Favours control
Analysis 12 Comparison 1 Bile acids for liver-transplanted patients Outcome 2 All-cause mortality worst-
best case and best-worst case scenarios
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 2 All-cause mortality worst-best case and best-worst case scenarios
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 Worst-best case scenario
Angelico 1999 516 217 65 266 [ 060 1180 ]
Barnes 1997 828 724 253 098 [ 042 230 ]
Fleckenstein 1998 314 416 125 086 [ 023 319 ]
Keiding 1997 1954 1048 355 169 [ 087 327 ]
Sama 1991 520 620 201 083 [ 030 229 ]
Subtotal (95 CI) 132 125 1000 130 [ 086 196 ]
Total events 40 (Bile acids) 29 (Control)
Heterogeneity Chi2 = 303 df = 4 (P = 055) I2 =00
Test for overall effect Z = 123 (P = 022)
2 Best-worst case scenario
005 02 1 5 20
Favours bile acids Favours control
(Continued )
34Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Angelico 1999 316 417 90 080 [ 021 302 ]
Barnes 1997 228 1124 274 016 [ 004 063 ]
Fleckenstein 1998 214 616 130 038 [ 009 159 ]
Keiding 1997 1454 1548 368 083 [ 045 154 ]
Sama 1991 520 620 139 083 [ 030 229 ]
Subtotal (95 CI) 132 125 1000 058 [ 038 090 ]
Total events 26 (Bile acids) 42 (Control)
Heterogeneity Chi2 = 567 df = 4 (P = 023) I2 =29
Test for overall effect Z = 247 (P = 0014)
005 02 1 5 20
Favours bile acids Favours control
Analysis 13 Comparison 1 Bile acids for liver-transplanted patients Outcome 3 Subgroup analyses all-
cause mortality at maximum follow-up according to time of start of bile acids
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 3 Subgroup analyses all-cause mortality at maximum follow-up according to time of start of bile acids
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 Less than three days after transplantation
Keiding 1997 1454 1048 355 124 [ 061 254 ]
Subtotal (95 CI) 54 48 355 124 [ 061 254 ]
Total events 14 (Bile acids) 10 (Control)
Heterogeneity not applicable
Test for overall effect Z = 060 (P = 055)
2 Three days or more after transplantation
Angelico 1999 316 217 65 159 [ 030 833 ]
Barnes 1997 228 724 253 024 [ 006 107 ]
Fleckenstein 1998 214 416 125 057 [ 012 266 ]
Sama 1991 520 620 201 083 [ 030 229 ]
005 02 1 5 20
Favours bile acids Favours control
(Continued )
35Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Subtotal (95 CI) 78 77 645 063 [ 033 120 ]
Total events 12 (Bile acids) 19 (Control)
Heterogeneity Chi2 = 310 df = 3 (P = 038) I2 =3
Test for overall effect Z = 141 (P = 016)
Total (95 CI) 132 125 1000 085 [ 053 136 ]
Total events 26 (Bile acids) 29 (Control)
Heterogeneity Chi2 = 466 df = 4 (P = 032) I2 =14
Test for overall effect Z = 069 (P = 049)
005 02 1 5 20
Favours bile acids Favours control
Analysis 14 Comparison 1 Bile acids for liver-transplanted patients Outcome 4 Subgroup analyses all
cause mortality at maximum follow-up according to treatment duration
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 4 Subgroup analyses all cause mortality at maximum follow-up according to treatment duration
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 Less than six months
Barnes 1997 228 724 253 024 [ 006 107 ]
Fleckenstein 1998 214 416 125 057 [ 012 266 ]
Keiding 1997 1454 1048 355 124 [ 061 254 ]
Subtotal (95 CI) 96 88 734 078 [ 045 138 ]
Total events 18 (Bile acids) 21 (Control)
Heterogeneity Chi2 = 417 df = 2 (P = 012) I2 =52
Test for overall effect Z = 084 (P = 040)
2 Six months or more
Angelico 1999 316 217 65 159 [ 030 833 ]
Sama 1991 520 620 201 083 [ 030 229 ]
Subtotal (95 CI) 36 37 266 102 [ 043 240 ]
Total events 8 (Bile acids) 8 (Control)
Heterogeneity Chi2 = 043 df = 1 (P = 051) I2 =00
005 02 1 5 20
Favours bile acids Favours control
(Continued )
36Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Test for overall effect Z = 004 (P = 097)
Total (95 CI) 132 125 1000 085 [ 053 136 ]
Total events 26 (Bile acids) 29 (Control)
Heterogeneity Chi2 = 466 df = 4 (P = 032) I2 =14
Test for overall effect Z = 069 (P = 049)
005 02 1 5 20
Favours bile acids Favours control
Analysis 15 Comparison 1 Bile acids for liver-transplanted patients Outcome 5 Number of deaths related
to rejection at maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 5 Number of deaths related to rejection at maximum follow-up
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 UDCA versus placebo
Keiding 1997 054 148 1000 030 [ 001 712 ]
Total (95 CI) 54 48 1000 030 [ 001 712 ]
Total events 0 (Bile acids) 1 (Control)
Heterogeneity not applicable
Test for overall effect Z = 075 (P = 045)
0001 001 01 1 10 100 1000
Favours bile acids Favours control
37Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 16 Comparison 1 Bile acids for liver-transplanted patients Outcome 6 Number of
retransplantations at maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 6 Number of retransplantations at maximum follow-up
Study or subgroup Bile acids Placebo Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Fleckenstein 1998 214 016 100 567 [ 029 10891 ]
Keiding 1997 154 448 900 022 [ 003 192 ]
Total (95 CI) 68 64 1000 076 [ 020 286 ]
Total events 3 (Bile acids) 4 (Placebo)
Heterogeneity Chi2 = 303 df = 1 (P = 008) I2 =67
Test for overall effect Z = 040 (P = 069)
0001 001 01 1 10 100 1000
Favours bile acids Favours placebo
Analysis 17 Comparison 1 Bile acids for liver-transplanted patients Outcome 7 Number of patients with
acute cellular rejection at maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 7 Number of patients with acute cellular rejection at maximum follow-up
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 UDCA versus placebo or no treatment
Barnes 1997 1728 1724 180 086 [ 058 127 ]
Fleckenstein 1998 814 916 83 102 [ 054 190 ]
Keiding 1997 3554 3248 333 097 [ 073 129 ]
Koneru 1993 316 916 89 033 [ 011 101 ]
Pageaux 1995 926 924 92 092 [ 044 193 ]
Sama 1991 1320 1320 128 100 [ 063 158 ]
Subtotal (95 CI) 158 148 905 089 [ 074 108 ]
01 02 05 1 2 5 10
Favours bile acids Favours control
(Continued )
38Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Total events 85 (Bile acids) 89 (Control)
Heterogeneity Chi2 = 387 df = 5 (P = 057) I2 =00
Test for overall effect Z = 120 (P = 023)
2 TUDCA versus no treatment
Angelico 1999 816 1017 95 085 [ 045 160 ]
Subtotal (95 CI) 16 17 95 085 [ 045 160 ]
Total events 8 (Bile acids) 10 (Control)
Heterogeneity not applicable
Test for overall effect Z = 050 (P = 061)
Total (95 CI) 174 165 1000 089 [ 074 106 ]
Total events 93 (Bile acids) 99 (Control)
Heterogeneity Chi2 = 392 df = 6 (P = 069) I2 =00
Test for overall effect Z = 130 (P = 019)
01 02 05 1 2 5 10
Favours bile acids Favours control
Analysis 18 Comparison 1 Bile acids for liver-transplanted patients Outcome 8 Subgroup analysis
number of patients with acute cellular rejection according to time of start of bile acid
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 8 Subgroup analysis number of patients with acute cellular rejection according to time of start of bile acid
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 Less than three days after transplantation
Keiding 1997 3554 3248 333 097 [ 073 129 ]
Koneru 1993 316 916 89 033 [ 011 101 ]
Subtotal (95 CI) 70 64 422 084 [ 063 111 ]
Total events 38 (Bile acids) 41 (Control)
Heterogeneity Chi2 = 374 df = 1 (P = 005) I2 =73
Test for overall effect Z = 124 (P = 022)
2 Three days or more after liver transplantation
Angelico 1999 816 1017 95 085 [ 045 160 ]
01 02 05 1 2 5 10
Favours bile acids Favours control
(Continued )
39Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Barnes 1997 1728 1724 180 086 [ 058 127 ]
Fleckenstein 1998 814 916 83 102 [ 054 190 ]
Pageaux 1995 926 924 92 092 [ 044 193 ]
Sama 1991 1320 1320 128 100 [ 063 158 ]
Subtotal (95 CI) 104 101 578 092 [ 072 117 ]
Total events 55 (Bile acids) 58 (Control)
Heterogeneity Chi2 = 041 df = 4 (P = 098) I2 =00
Test for overall effect Z = 067 (P = 050)
Total (95 CI) 174 165 1000 089 [ 074 106 ]
Total events 93 (Bile acids) 99 (Control)
Heterogeneity Chi2 = 392 df = 6 (P = 069) I2 =00
Test for overall effect Z = 130 (P = 019)
01 02 05 1 2 5 10
Favours bile acids Favours control
40Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 19 Comparison 1 Bile acids for liver-transplanted patients Outcome 9 Subgroup analysis
number of patients with acute cellular rejection according to treatment duration
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 9 Subgroup analysis number of patients with acute cellular rejection according to treatment duration
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 Less than six months
Barnes 1997 1728 1724 180 086 [ 058 127 ]
Fleckenstein 1998 814 916 83 102 [ 054 190 ]
Keiding 1997 3554 3248 333 097 [ 073 129 ]
Koneru 1993 316 916 89 033 [ 011 101 ]
Pageaux 1995 926 924 92 092 [ 044 193 ]
Subtotal (95 CI) 138 128 777 087 [ 071 107 ]
Total events 72 (Bile acids) 76 (Control)
Heterogeneity Chi2 = 374 df = 4 (P = 044) I2 =00
Test for overall effect Z = 129 (P = 020)
2 Six months or more
Angelico 1999 816 1017 95 085 [ 045 160 ]
Sama 1991 1320 1320 128 100 [ 063 158 ]
Subtotal (95 CI) 36 37 223 094 [ 065 136 ]
Total events 21 (Bile acids) 23 (Control)
Heterogeneity Chi2 = 017 df = 1 (P = 068) I2 =00
Test for overall effect Z = 035 (P = 073)
Total (95 CI) 174 165 1000 089 [ 074 106 ]
Total events 93 (Bile acids) 99 (Control)
Heterogeneity Chi2 = 392 df = 6 (P = 069) I2 =00
Test for overall effect Z = 130 (P = 019)
01 02 05 1 2 5 10
Favours bile acids Favours control
41Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 110 Comparison 1 Bile acids for liver-transplanted patients Outcome 10 Number of patients
with chronic rejection at maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 10 Number of patients with chronic rejection at maximum follow-up
Study or subgroup Bile acids Placebo Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Barnes 1997 128 624 611 014 [ 002 110 ]
Fleckenstein 1998 114 116 88 114 [ 008 1663 ]
Keiding 1997 154 348 300 030 [ 003 275 ]
Total (95 CI) 96 88 1000 028 [ 008 095 ]
Total events 3 (Bile acids) 10 (Placebo)
Heterogeneity Chi2 = 148 df = 2 (P = 048) I2 =00
Test for overall effect Z = 204 (P = 0041)
0001 001 01 1 10 100 1000
Favours bile acids Favours placebo
Analysis 111 Comparison 1 Bile acids for liver-transplanted patients Outcome 11 Number of patients
with steroid-resistant rejection at maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 11 Number of patients with steroid-resistant rejection at maximum follow-up
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Barnes 1997 328 724 277 037 [ 011 127 ]
Fleckenstein 1998 314 316 103 114 [ 027 478 ]
Keiding 1997 1454 1548 583 083 [ 045 154 ]
Pageaux 1995 226 124 38 185 [ 018 1908 ]
Total (95 CI) 122 112 1000 077 [ 047 127 ]
Total events 22 (Bile acids) 26 (Control)
Heterogeneity Chi2 = 226 df = 3 (P = 052) I2 =00
Test for overall effect Z = 102 (P = 031)
001 01 1 10 100
Favours bile acids Favours placebo
42Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 112 Comparison 1 Bile acids for liver-transplanted patients Outcome 12 Serum bilirubin (mgdl)
at the end of treatment
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 12 Serum bilirubin (mgdl) at the end of treatment
Study or subgroup Bile acids Placebo Mean Difference Weight Mean Difference
N Mean(SD) N Mean(SD) IVFixed95 CI IVFixed95 CI
Fleckenstein 1998 14 319 (68) 16 059 (022) 1000 260 [ -096 616 ]
Total (95 CI) 14 16 1000 260 [ -096 616 ]
Heterogeneity not applicable
Test for overall effect Z = 143 (P = 015)
-10 -5 0 5 10
Favours bile acids Favours placebo
Analysis 113 Comparison 1 Bile acids for liver-transplanted patients Outcome 13 Number of days of
hospitalisation after liver transplantation
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 13 Number of days of hospitalisation after liver transplantation
Study or subgroup Bile acids Placebo Mean Difference Weight Mean Difference
N Mean(SD) N Mean(SD) IVFixed95 CI IVFixed95 CI
Barnes 1997 28 25 (17) 24 335 (13) 1000 -850 [ -1667 -033 ]
Total (95 CI) 28 24 1000 -850 [ -1667 -033 ]
Heterogeneity not applicable
Test for overall effect Z = 204 (P = 0041)
-100 -50 0 50 100
Favours bile acids Favours placebo
43Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 114 Comparison 1 Bile acids for liver-transplanted patients Outcome 14 Adverse events
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 14 Adverse events
Study or subgroup Bile acids Placebo Risk Ratio Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Angelico 1999 016 017 00 [ 00 00 ]
Barnes 1997 128 124 086 [ 006 1298 ]
Keiding 1997 554 548 089 [ 027 288 ]
Total (95 CI) 98 89 088 [ 030 260 ]
Total events 6 (Bile acids) 6 (Placebo)
Heterogeneity Chi2 = 000 df = 1 (P = 098) I2 =00
Test for overall effect Z = 022 (P = 082)
001 01 1 10 100
Favours bile acids Favours placebo
A P P E N D I C E S
Appendix 1 Search strategies
Data Base Date of Search Search Strategy
The Cochrane Hepato-Biliary Group Con-
trolled Trials Register
September 2009 1 rsquoliver transplantationrsquo and rsquochenodeoxy-
cholicrsquo
2 rsquoliver transplantationrsquo and rsquocholicrsquo
3 rsquoliver transplantationrsquo and rsquodeoxycholicrsquo
4 rsquoliver transplantationrsquo and rsquoglycochen-
odeoxycholicrsquo
5 rsquoliver transplantationrsquo and rsquoglycocholicrsquo
6 rsquoliver transplantationrsquo and rsquoglycodeoxy-
cholicrsquo
7 rsquoliver transplantationrsquo and rsquoglycolitho-
cholicrsquo
8 rsquoliver transplantationrsquo and rsquohyodeoxy-
cholicrsquo
9 rsquoliver transplantationrsquo and rsquolithocholicrsquo
10 rsquoliver transplantationrsquo and rsquotaurochen-
odeoxycholicrsquo
44Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
11 rsquoliver transplantationrsquo and rsquotauro-
cholicrsquo
12 rsquoliver transplantationrsquo and rsquotaurodehy-
drocholicrsquo
13 rsquoliver transplantationrsquo and rsquotau-
rodeoxycholicrsquo
14 rsquoliver transplantationrsquo and rsquotauroglyco-
cholicrsquo
15 rsquoliver transplantationrsquo and rsquotaurolitho-
cholicrsquo
16 rsquoliver transplantationrsquo and rsquotaurosel-
cholicrsquo
17 rsquoliver transplantationrsquo and rsquotaurourso-
cholicrsquo
18 rsquoliver transplantationrsquo and rsquotaurour-
sodeoxycholicrsquo
19 rsquoliver transplantationrsquo and rsquoursocholicrsquo
20 rsquoliver transplantationrsquo and rsquoursodeoxy-
cholicrsquo
The Cochrane Central Register of Con-
trolled Trials in The Cochrane Library
Issue 3 2009 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
6 3 or 4
7 5 and 6
MEDLINE September 2009 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
45Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
6 3 or 4
7 5 and 6
8 RANDOMIZED-CONTROLLED-
TRIAL ME
9 RANDOM
10 8 or 9
11 7 and 10
EMBASE September 2009 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
6 3 or 4
7 5 and 6
8 RANDOMIZED-CONTROLLED-
TRIAL ME
9 RANDOM
10 8 or 9
11 7 and 10
46Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
Science Citation Index Expanded September 2009 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
6 3 or 4
7 5 and 6
8 RANDOMIZED-CONTROLLED-
TRIAL ME
9 RANDOM
10 8 or 9
11 7 and 10
The Chinese Biomedical Database Searched from January 1980 to April 2002 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
47Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
6 3 or 4
7 5 and 6
8 RANDOMIZED-CONTROLLED-
TRIAL ME
9 RANDOM
10 8 or 9
11 7 and 10
W H A T rsquo S N E W
Last assessed as up-to-date 8 February 2010
18 September 2009 New citation required but conclusions have not
changed
This review is an updated version of a review that was
published for the first time in Issue 3 2005 of TheCochrane Library by Chen 2003b
18 September 2009 New search has been performed No new studies fulfilled the inclusion criteria
H I S T O R Y
Protocol first published Issue 3 2003
Review first published Issue 3 2005
C O N T R I B U T I O N S O F A U T H O R S
GP and VG independently performed searches of relevant databases GP validated the search selected trials for inclusion contacted
the authors of the trials performed data extraction and data analysis and drafted the systematic review VG revised the review update
CG and DS revised the review update solved discrepancies of data extraction validated data analyses and provided consultation
D E C L A R A T I O N S O F I N T E R E S T
None known
48Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
S O U R C E S O F S U P P O R T
Internal sources
bull Copenhagen Trial Unit Denmark
External sources
bull Danish Medical Research Councilrsquos Grant on Getting Research into Practice (GRIP) Denmark
D I F F E R E N C E S B E T W E E N P R O T O C O L A N D R E V I E W
We assessed the risk of bias in the included studies for another four domains that were added to the review protocol (incomplete
outcome data selective outcome reporting baseline imbalance and early stopping of trial) In general the text of the risk of bias
domains were updated following Higgins 2008 Trials were considered at low risk of bias when judged as adequate in all domains
Quasi-randomised studies observational and case-control studies were included for the report of adverse events
We performed trial sequential analysis for outcomes demonstrating a statistically significant result
I N D E X T E R M S
Medical Subject Headings (MeSH)
lowastLiver Transplantation Cholagogues and Choleretics [lowasttherapeutic use] Graft Rejection [lowastprevention amp control] Randomized Con-
trolled Trials as Topic Taurochenodeoxycholic Acid [lowasttherapeutic use] Ursodeoxycholic Acid [lowasttherapeutic use]
MeSH check words
Humans
49Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
T A B L E O F C O N T E N T S
1HEADER
1ABSTRACT
2PLAIN LANGUAGE SUMMARY
2BACKGROUND
3OBJECTIVES
3METHODS
6RESULTS
Figure 1 8
Figure 2 9
Figure 3 12
13DISCUSSION
14AUTHORSrsquo CONCLUSIONS
14ACKNOWLEDGEMENTS
14REFERENCES
18CHARACTERISTICS OF STUDIES
32DATA AND ANALYSES
Analysis 11 Comparison 1 Bile acids for liver-transplanted patients Outcome 1 All-cause mortality at maximum follow-
up 33
Analysis 12 Comparison 1 Bile acids for liver-transplanted patients Outcome 2 All-cause mortality worst-best case and
best-worst case scenarios 34
Analysis 13 Comparison 1 Bile acids for liver-transplanted patients Outcome 3 Subgroup analyses all-cause mortality at
maximum follow-up according to time of start of bile acids 35
Analysis 14 Comparison 1 Bile acids for liver-transplanted patients Outcome 4 Subgroup analyses all cause mortality at
maximum follow-up according to treatment duration 36
Analysis 15 Comparison 1 Bile acids for liver-transplanted patients Outcome 5 Number of deaths related to rejection at
maximum follow-up 37
Analysis 16 Comparison 1 Bile acids for liver-transplanted patients Outcome 6 Number of retransplantations at maximum
follow-up 38
Analysis 17 Comparison 1 Bile acids for liver-transplanted patients Outcome 7 Number of patients with acute cellular
rejection at maximum follow-up 38
Analysis 18 Comparison 1 Bile acids for liver-transplanted patients Outcome 8 Subgroup analysis number of patients
with acute cellular rejection according to time of start of bile acid 39
Analysis 19 Comparison 1 Bile acids for liver-transplanted patients Outcome 9 Subgroup analysis number of patients
with acute cellular rejection according to treatment duration 41
Analysis 110 Comparison 1 Bile acids for liver-transplanted patients Outcome 10 Number of patients with chronic
rejection at maximum follow-up 42
Analysis 111 Comparison 1 Bile acids for liver-transplanted patients Outcome 11 Number of patients with steroid-
resistant rejection at maximum follow-up 42
Analysis 112 Comparison 1 Bile acids for liver-transplanted patients Outcome 12 Serum bilirubin (mgdl) at the end of
treatment 43
Analysis 113 Comparison 1 Bile acids for liver-transplanted patients Outcome 13 Number of days of hospitalisation after
liver transplantation 43
Analysis 114 Comparison 1 Bile acids for liver-transplanted patients Outcome 14 Adverse events 44
44APPENDICES
48WHATrsquoS NEW
48HISTORY
48CONTRIBUTIONS OF AUTHORS
48DECLARATIONS OF INTEREST
48SOURCES OF SUPPORT
49DIFFERENCES BETWEEN PROTOCOL AND REVIEW
49INDEX TERMS
iBile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
[Intervention Review]
Bile acids for liver-transplanted patients
Goran Poropat1 Vanja Giljaca1 Davor Stimac1 Christian Gluud2
1Department of Gastroenterology Clinical Hospital Centre Rijeka Rijeka Croatia 2Cochrane Hepato-Biliary Group Copenhagen
Trial Unit Centre for Clinical Intervention Research Department 3344 Rigshospitalet Copenhagen University Hospital Copenhagen
Denmark
Contact address Goran Poropat Department of Gastroenterology Clinical Hospital Centre Rijeka Kresimirova 42 Rijeka 51000
Croatia goran_poropatyahoocom
Editorial group Cochrane Hepato-Biliary Group
Publication status and date New search for studies and content updated (no change to conclusions) published in Issue 3 2010
Review content assessed as up-to-date 8 February 2010
Citation Poropat G Giljaca V Stimac D Gluud C Bile acids for liver-transplanted patients Cochrane Database of Systematic Reviews2010 Issue 3 Art No CD005442 DOI 10100214651858CD005442pub2
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
A B S T R A C T
Background
Liver transplantation has become a widely accepted form of treatment for numerous end-stage liver diseases Bile acids may decrease
allograft rejection after liver transplantation by changing the expression of major histocompatibility complex class molecules in bile
duct epithelium and central vein endothelium
Objectives
To assess the beneficial and harmful effects of bile acids for liver-transplanted patients
Search strategy
We performed searches of The Cochrane Hepato-Biliary Group Controlled Trials Register The Cochrane Central Register of ControlledTrials in The Cochrane Library MEDLINE EMBASE and Science Citation Expanded to September 2009
Selection criteria
Randomised clinical trials comparing any dose of bile acids or duration of treatment in liver-transplanted patients versus placebo no
intervention or another intervention We included randomised clinical trials irrespective of blinding language and publication status
Data collection and analysis
Two review authors extracted and checked data independently We evaluated the risk of bias of the trials from the method of allocation
sequence generation allocation concealment blinding outcome data analysis outcome data reporting and other potential sources
of bias We used the intention-to-treat principle to perform meta-analyses and presented the outcomes as relative risks (RR) or mean
differences (MD) both with 95 confidence intervals (CI)
Main results
The updated search resulted in no new trials meeting the inclusion criteria of this review thus leaving it to the seven already included
randomised trials (six evaluating ursodeoxycholic acid versus placebo or no intervention and one evaluating tauro-ursodeoxycholic
acid versus no intervention) enrolling a total of 335 participants The administration of bile acids began one day or more after liver
transplantation All patients received the standard triple-drug immunosuppressive regimen (steroids azathioprine and cyclosporine or
tacrolimus) to suppress the allograft rejection response after liver transplantation Bile acids compared with placebo or no intervention
1Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
did not significantly change all-cause mortality (RR 085 95 CI 053 to 136) mortality related to allograft rejection (RR 030
95 CI 001 to 712) retransplantation (RR 076 95 CI 020 to 286) acute cellular rejection or number of patients with steroid-
resistant rejection Bile acids significantly reduced the number of patients who had chronic rejection in a fixed-effect model but not in
a random-effects model meta-analysis Bile acids were safe and well tolerated by liver-transplanted patients However this observation
is based on data analysis from three trials with only 187 patients
Authorsrsquo conclusions
We did not find evidence to support or refute bile acids for liver-transplanted patients Further randomised trials are necessary before
bile acids can be recommended to liver-transplanted patients
P L A I N L A N G U A G E S U M M A R Y
Bile acids for liver-transplanted patients
Liver transplantation is a major surgical procedure that has been practiced for more than forty years and has nowadays become a
generally accepted treatment option in patients with end-stage liver disease The most common cause for liver transplantation in adults
is cirrhosis caused by various types of liver injuries such as infections (hepatitis B and C) alcohol autoimmune liver diseases early-
stage liver cancer metabolic and hereditary disorders but also diseases of unknown aetiology All transplant recipients need lifetime
immunosuppressive therapy to prevent transplant rejection
Bile acids are being used for a variety of chronic liver diseases mainly primary biliary cirrhosis and primary sclerosing cholangitis
However their mechanisms of action and beneficial and harmful effects are poorly understood This has led to the idea of the potential
use of bile acids to prevent rejection in liver-transplanted patients
Results of the seven randomised clinical trials included in the review in which patients received standard immunosuppressive treatment
(steroids azathioprine and cyclosporine or tacrolimus) with or without bile acids after liver transplantation did not show any significant
effects of bile acids on all-cause mortality mortality related to rejection acute cellular rejection steroid resistant rejection or need for
retransplantation One analysis suggested that bile acids might beneficially influence number of patients with chronic rejection but was
contradicted by the analyses The evidence that the use of ursodeoxycholic acid might have beneficial effects on chronic rejection and
length of hospitalisation is weak as it is produced from trials with high risk of bias and insufficient number of included patients That
bile acids seemed well tolerated with no reports of serious adverse events is good knowledge but much more research is needed before
their use is acquitted None of the randomised clinical trials assessed the effects of bile acids on quality of life or cost-effectiveness
B A C K G R O U N D
Liver transplantation has become a widely accepted treatment
for numerous end-stage liver diseases (Hussain 2002 Thalheimer
2002) Previous studies report an incidence of acute cellular rejec-
tion to range from 50 to 80 in adult recipients (Ascher 1988
Klintmalm 1989 Adams 1990 Wiesner 1992 FK506 1994)
However recent data suggest that the proportion of patients with
rejection is currently down to 30 (Hirschfield 2009 Knechtle
2009) Despite advances in immunosuppressive treatment and
care-quality of liver-transplanted patients allograft rejection is still
a major problem in the post-transplantation period
Acute cellular rejection usually occurs within the first 15 to 30 days
after transplantation even if immunosuppression is achieved with
tacrolimus or cyclosporine (FK506 1994 Haddad 2006 Corbani
2008) The cellular mechanisms of acute liver allograft rejection
are not completely understood (Krams 1993) Initiation of al-
lograft rejection is thought to involve the recognition of donor
class II major histocompatibility complex alloantigens by recipient
CD4+ T cells (Vierling 1992) Activated CD4+ T cells produce
cytokines that induce lymphocyte proliferation and the matura-
tion of CD8+ cytotoxic T cells which are specific for donor class I
major histocompatibility complex antigens (Calmus 1990) Both
the bile duct epithelium and central vein endothelium are rich in
class I and class II major histocompatibility complex antigens dur-
ing rejection whereas hepatocytes display a relative paucity of class
I antigens and virtually no class II antigen (Vierling 1992) There-
2Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
fore the bile duct epithelium and central vein endothelium are
the primary targets attacked by cytotoxic T cells during rejection
Impairment of the bile flow in the grafted liver may also cause re-
jection (Ericzon 1990) Mild cholestasis is a common finding after
liver transplantation and its association with clinically significant
pathology is unlikely Nevertheless severe cholestasis should be
treated as a potential cause of allograft rejection (Corbani 2008)
In the study by Fusai 2006 the development of cholestasis was sig-
nificantly related to prolonged warm ischaemia of the liver trans-
plant Cholestasis can induce hyper-expression of major histocom-
patibility complex class I molecules by hepatocytes and thereby
lymphocyte CD8+-dependent cytotoxicity (Calmus 1992)
Bile acids include chenodeoxycholic acid deoxycholic acid litho-
cholic acid and ursodeoxycholic acid (UDCA) (Fuchs 1999)
In the course of cholestasis intrahepatic accumulation of chen-
odeoxycholic acid and deoxycholic acid is thought to induce liver
damage (Palmer 1972) In fact the direct damage of membrane
phospholipids and cholesterol components caused by the deter-
gent-like properties of hydrophobic bile acids results in hepato-
cyte necrosis (Sholmerich 1984 Perez 2009) It is also suggested
that oxidative stress induced by hydrophobic bile acids plays an
important role in liver damage during cholestasis These effects
can be prevented by the addition of UDCA which modifies the
bile acid pool resulting in an increase of the hydrophilic frac-
tion and stabilisation of the cell membranes (Armstrong 1982
Perez 2009) Several studies on animal models showed evidence
of potential immunomodulatory beneficial effects of UDCA and
tauro-ursodeoxycholic acid (TUDCA) by suppressing cytokine
and immunoglobulin production and T-cell mediated cytotoxic-
ity (Yoshikawa 1998) In the study by Calmus 1990 it has been
observed that UDCA down-regulates the expression of abnormal
major histocompatibility complex class I molecules in periportal
hepatocytes in patients with primary biliary cirrhosis Treatment
with UDCA has been reported to have potential beneficial ef-
fects in various cholestatic liver conditions including primary bil-
iary cirrhosis (Gong 2008) primary sclerosing cholangitis (Chen
2003a) and cystic fibrosis (Cheng 2002)
It has previously been suggested that UDCA and perhaps tauro-
UDCA (TUDCA) may reduce the incidence of acute rejection
and steroid-resistant rejection in liver-transplanted patients when
administered with combination of immunosuppressive treatment
There are several potential mechanisms by which UDCA may in-
hibit allograft rejection in liver transplant recipients (Okolicsanyi
1986 Merion 1989 Calmus 1990 Terasaki 1991 Heuman 1993
Al-Quaiz 1994 Friman 1994 Soderdahl 1998 Yoshikawa 1998
Assy 2007 Perez 2009) However most of these studies included
a relatively small number of patients were not randomised and
often did not include histological information (Persson 1990
Friman 1992 Koneru 1993 Sharara 1995)
The previous version of this review by Chen 2003b stated that
there was no convincing beneficial effects from the use of bile acids
in liver-transplanted patients the risk of bias in the seven included
trials was high The review also found that there was a low occur-
rence of adverse events and hence the use of bile acids could be
considered safe It should be noted however that this observation
is based on reports from four trials with few patients We have
been unable to identify any other meta-analyses or systematic re-
views either This review represents an update of the Chen 2003b
Cochrane hepato-Biliary Group review
O B J E C T I V E S
To evaluate the beneficial and harmful effects of bile acids for liver-
transplanted patients by comparing bile acids versus placebo no
intervention or another intervention in randomised clinical trials
M E T H O D S
Criteria for considering studies for this review
Types of studies
We included randomised clinical trials irrespective of blinding
publication status year of publication or language We assessed
both included and excluded studies for the report of adverse events
We listed all studies reporting on adverse events in an additional
table (Table 1) However only data from the included trials were
used in the statistical analysis
Table 1 Adverse events
Study Pts in experimental
group
Patients in control
group
AE in experimental
group
AE in control group Authorrsquos conclusion
Barnes 1997 28 24 Diarrhoea (1 pt) Diarrhoea (1 pt) Adverse
reactions attributable
to study medication
were rare
3Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Table 1 Adverse events (Continued)
Keiding 1997 54 48 Diarrhoea and diffi-
culties in swallowing
capsules (5 pts)
Diarrhoea and diffi-
culties in swallowing
capsules (5 pts)
No other presumed
drug-induced side ef-
fects were observed
Angelico 1999 16 17 No AE No AE TUDCA administra-
tion was well tol-
erated in all pa-
tients and no drug-
related side effects
were recorded
Assy 2007 14 12 Mild diarrhoea (1 pt) No AE No dose reduction
was required
pt(s) = patient(s)
AE = adverse events
Types of participants
Patients who underwent liver transplantation
Types of interventions
Any dose of a bile acid or duration of treatment versus placebo
no intervention or another intervention
We allowed co-interventions if received equally by the intervention
groups within a trial
Types of outcome measures
The primary outcome measures were
1 All-cause mortality
2 Death due to allograft rejection (acute cellular rejection or
chronic rejection or liver retransplantation because of rejection)
Acute cellular rejection was diagnosed by the combination of ab-
normal liver biochemical variables (bilirubin aspartate transam-
inase alanine transaminase alkaline phosphatases andor gam-
maglutamyl transpeptidase) clinical signs such as fever and liver
histological changes including mononuclear portal inflammation
bile duct damage and subendothelial inflammation of portal or
terminal hepatic veins (IWP 1995) Chronic rejection was charac-
terised by liver histological changes including the progressive loss
of interlobular bile ducts and arteriopathy characterised by foam
cell infiltration of the arterial intima
The secondary outcome measures were
3 Number of patients who experienced rejection - irrespective of
the type acute cellular rejection chronic rejection or both types
of rejections
4 Number of patients with acute cellular rejection
5 Number of patients with chronic rejection
6 Number of patients with steroid-resistant rejection
7 Biochemical responses serum activities of alkaline phos-
phatases gammaglutamyl transpeptidase alanine aminotrans-
ferase and aspartate aminotransferase and serum bilirubin con-
centration andor number of patients with abnormal liver bio-
chemical variables mentioned above
8 Adverse events Adverse events were defined as any untoward
medical occurrence not necessarily having a causal relationship
with the treatment but resulting in a dose reduction or discontin-
uation of treatment (ICH-GCP 1997)
9 Quality of life
10 Cost-effectiveness
Search methods for identification of studies
We performed searches of The Cochrane Hepato-Biliary GroupControlled Trials Register (September 2009)(Gluud 2010) and TheCochrane Central Register of Controlled Trials (CENTRAL) in TheCochrane Library (Issue 3 2009) by combining the terms rsquoliverrsquo
and rsquotransplantationrsquo with the individual bile acid name (litho-
cholic acid chenodeoxycholic acid ursodeoxycholic acid deoxy-
cholic acid dehydrocholic acid and tauro-ursodeoxycholic acid)
We searched MEDLINE (January 1966 to September 2009) EM-BASE (January 1980 to September 2009) and Science Citation In-dex Expanded (1945 to September 2009) by using the terms rsquoliverrsquo
4Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
and rsquotransplantationrsquo in combination with the bile acids mentioned
above (Royle 2003) The search strategies with the time span of
the searches are given in Appendix 1 We contacted the Chinese
Cochrane Centre regarding the search of The Chinese BiomedicalDatabase and received a reply that they are unable to help us with
this search Therefore the latter database could not be included
in the search strategy of this update
Further trials were identified by reading the reference lists of the
identified studies We wrote to the principal authors of the reports
of the identified randomised clinical trials in September 2009 and
enquired about additional trials which they might know of The
first team of authors had also written to pharmaceutical companies
involved in the production of bile acids to obtain information on
published or unpublished randomised clinical trials in 2002 but
no information had been received at that time
Data collection and analysis
The update of this review was conducted according to the proto-
col previously published in The Cochrane Library (Chen 2003b)
and following the recommendations given by the Cochrane Hand-book for Systematic Reviews of Interventions (Higgins 2008) and the
Cochrane Hepato-Biliary Group Module (Gluud 2010)
Trial identification
Identified trials were listed and the two review authors evaluated
whether the trials fulfilled the inclusion criteria Excluded trials
were listed with the reasons for exclusion
Data extraction
GP and VG extracted the data independently and disagreements
were resolved by discussion or by CG We extracted the following
characteristics from each trial primary author number of patients
randomised patient inclusion and exclusion criteria methodolog-
ical quality follow-up (number and reasons for withdrawal) sam-
ple size calculation intention-to-treat analysis intervention reg-
imens mean age proportion of males and females aetiology of
liver disease origin of allograft matching criteria between donor
and recipient time to follow-up number of outcomes and num-
ber and type of adverse events in both the intervention and the
control groups Additional information was sought by correspon-
dence with the principal investigator or co-investigators of the trial
in cases where the relevant data were not published
Assessment of risk of bias
Risk of bias was defined as the confidence that the study design and
reporting restricted bias in the intervention comparison (Schulz
1995 Moher 1998 Kjaergard 2001 Wood 2008) Due to the risk
of overestimation of intervention effects in randomised trials with
unclear or inadequate components we assessed the risk of bias by
separate domains
Allocation sequence generation
bull Adequate if the allocation sequence was generated by a
computer or random number table Drawing of lots tossing of a
coin shuffling of cards or throwing dice was considered as
adequate if a person who was not otherwise involved in the
recruitment of participants performed the procedure
bull Unclear if the trial was described as randomised but the
method used for the allocation sequence generation was not
described
bull Inadequate if a system involving dates names or
admittance numbers were used for the allocation of patients
Such quasi-randomised studies were excluded
Allocation concealment
bull Adequate if the allocation of patients involved a central
independent unit on-site locked computer identically appearing
numbered drug bottles or containers prepared by an
independent pharmacist or investigator or serially numbered
sealed and opaque envelopes
bull Unclear if the trial was described as randomised but the
method used to conceal the allocation was not described
bull Inadequate if the allocation sequence was known to the
investigators who assigned participants or if the study was quasi-
randomised The latter studies were excluded
Blinding
bull Adequate the trial was described as blinded the parties that
were blinded and the method of blinding was described so that
knowledge of allocation was adequately prevented during the
trial
bull Unclear the trial was described as double blind but the
method of blinding was not described so that knowledge of
allocation was possible during the trial
bull Not performed the trial was not blinded so that the
allocation was known during the trial
Incomplete outcome data
bull Adequate if the numbers and reasons for dropouts and
withdrawals in all intervention groups were described or if it was
specified that there were no dropouts or withdrawals
bull Unclear if the report gave the impression that there had
been no dropouts or withdrawals but this was not specifically
stated
bull Inadequate if the number or reasons for dropouts and
withdrawals were not described
Selective outcome reporting
bull Adequate if study protocol is available and all pre-specified
outcomes are reported in the manuscript or if the study protocol
is not available but it is clear that the report includes all expected
outcomes
bull Unclear if there are no sufficient information to permit
judgement
bull Inadequate if not all of the pre-specified outcomes were
reported andor were reported incompletely or one or more
reported outcomes were not pre-specified
Baseline imbalance
5Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
bull Adequate if there is no baseline imbalance in the main
characteristics
bull Unclear if there is no sufficient information to assess
baseline characteristics
bull Inadequate if there was a baseline imbalance due to chance
or due to imbalanced exclusion after randomisation
Early stopping
bull Adequate if sample size calculation was reported and the
trial was not stopped or the trial was stopped early by formal
stopping rules at a point where the likelihood of observing an
extreme intervention effect due to chance was low
bull Unclear if sample size calculation was not reported and it is
not clear whether the trial was stopped early or not
bull Inadequate if the trial was stopped early due to informal
stopping rules or the trial was stopped early by a formal stopping
rule at a point where the likelihood of observing an extreme
intervention effect due to chance was high
Furthermore we registered whether the randomised clinical trials
had used an intention-to-treat analysis (Gluud 2001) and had
calculated a sample size estimate
Statistical methods
We performed the analyses in RevMan 5 (RevMan 2008) Anal-
yses included all patients irrespective of compliance or follow-up
according to the intention-to-treat principle and using the last
reported observed response (rsquocarry forwardrsquo) Regarding death
both a worst-best-case scenario analysis considering all dropped-
out patients in the bile acid group as dead and the dropped-out
patients in the control group as alive and a best-worst-case sce-
nario analysis considering all dropped-out patients in the bile acid
group as alive and the dropped-out patients in the control group as
dead were performed Both a random-effects model (DerSimonian
1986) and a fixed-effect model (DeMets 1987) were used The re-
sults of the fixed-effect model were reported if there were no differ-
ences between the results produced by the two models otherwise
we reported the results produced by both models We presented
binary outcome measures as relative risks (RR) with 95 confi-
dence intervals (CI) and continuous outcome measures as mean
differences (MD) with 95 CI
The risk of type I errors increases in single trials with interim anal-
yses To avoid type I errors group sequential monitoring bound-
aries (Lan 1983) can be performed when deciding to terminate the
trial earlier than planned This requires analyses at different time
intervals to record when the P-value has become sufficiently small
that is when the cumulative Z-curve will cross the monitoring
boundaries Sequential monitoring boundaries the so called rsquotrial
sequential monitoring boundariesrsquo can also be applied to meta-
analyses In a trial sequential analysis (TSA) every trial that is
added in a cumulative meta-analysis is regarded as an interim meta-
analysis and the information it adds on helps on deciding if more
trials need to be included
The interpretation of the TSA is as follows if the cumulative Z-
curve has crossed the boundary a sufficient level of evidence is
reached and no further trials may be needed If the Z-curve has
not crossed the boundary then the evidence is insufficient in order
to reach a conclusion To construct the trial sequential monitor-
ing boundaries information size is needed It is calculated as the
minimum number of participants needed in a well-powered single
trial (Pogue 1997 Pogue 1998 Brok 2008 Wetterslev 2008) We
applied TSA since it prevents an increase of the risk of type I error
due to sparse and multiple updating in a cumulative meta-analysis
and provides us with important information in order to estimate
the level of evidence of the experimental intervention Addition-
ally TSA provides us with important information regarding the
need for additional trials and the required information size We
applied trial sequential monitoring boundaries according to an in-
formation size suggested by the trials with low risk of bias and a
50 relative risk reduction (RRR)
Subgroup analyses
We planned to perform the following subgroup analyses on the
main outcome measures (all-cause mortality and number of pa-
tients with acute rejection)
1 Risk of bias of the trials comparing the intervention effect for
trials with low risk of bias components to the intervention effect
in trials with unclear or high risk of bias components
2 Dose and duration of treatment with bile acids comparing the
intervention effect in trials administrating bile acid at or above the
median dose multiplied by duration to the intervention effect of
trials administrating bile acid at less than the median dose multi-
plied by duration
3 Time between transplantation and the start of bile acids com-
paring the intervention effect of trials having less than three days
between transplantation and starting bile acid intake to the inter-
vention effect of trials with a duration of three days or more be-
tween transplantation and the start of bile acid intake (Neuberger
1999)
4 Co-interventions comparing the intervention effect of trials
with co-interventions to the intervention effect of trials without
co-interventions
Funnel plot analysis
We planned to explore bias by funnel plot analysis (Egger 1997)
R E S U L T S
Description of studies
See Characteristics of included studies Characteristics of excluded
studies
The performed electronic searches resulted in a total of 378 ref-
erences We excluded 362 duplicates or irrelevant references by
reading abstracts We excluded eight of the 16 further assessed ref-
erences because they were observational studies case series or ran-
6Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
domised clinical trials with a different reason for exclusion They
are listed under rsquoCharacteristic of excluded studiesrsquo with reasons
for exclusion Seven references already included in the previous
version of this review and one new reference referring to an al-
ready included trial (Barnes 1997) were included in this review
We were not able to identify more trials by reading the reference
lists of the identified studies contacting the principle authors of
the identified trials or approaching pharmaceutical companies for
unpublished trials
Seven publications included in the review (five full publications
and two abstracts) were randomised clinical trials that reported
the random allocation of liver-transplanted patients into groups
receiving bile acid placebo or no treatment We listed these trials
in the table of Characteristics of included studies All seven trials
were published in English Three randomised clinical trials were
from the United States (Koneru 1993 Barnes 1997 Fleckenstein
1998) two from Italy (Sama 1991 Angelico 1999) one from
France (Pageaux 1995) and one from Denmark (Keiding 1997)
Patients
In the included trials all patients received blood group-compatible
grafts The median size of the seven trials was 40 patients (range
29 to 102 patients) In total 335 patients were randomised
Five trials were published as full publications (Pageaux 1995
Barnes 1997 Keiding 1997 Fleckenstein 1998 Angelico 1999)
which allowed us to extract detailed information on 263 of the
patients The mean age of the patients ranged from 44 to 51 years
One trial (Keiding 1997) also enrolled children ranging in age
from 0 to 13 years (median 15 years) The male to female ratio in
these five trials was 159104 The diseases that led to liver trans-
plantation were alcoholic cirrhosis in 51 patients (194) cirrho-
sis caused by chronic hepatitis C in 40 patients (152) primary
biliary cirrhosis in 36 patients (137) cryptogenic cirrhosis in
22 patients (84) metabolic diseases in 19 patients (72) pri-
mary sclerosing cholangitis in 17 patients (65) non-specified
post-hepatitis cirrhosis in 17 patients (65) cirrhosis caused by
chronic hepatitis B in 13 patients (49) 9 with autoimmune
hepatitis and cirrhosis (34) six with liver cancer (23) five
with biliary atresia (19) and 28 with other diseases (106)
Only one trial reported the severity of liver function according to
the Child-Pugh class (Barnes 1997)
Bile acids and collateral interventions
Six trials (Sama 1991 Koneru 1993 Pageaux 1995 Barnes
1997 Keiding 1997 Fleckenstein 1998) compared UDCA versus
placebo or no intervention One trial (Angelico 1999) compared
TUDCA versus no intervention Bile acid treatment began one
day after transplantation in the Keiding 1997 trial three days after
transplantation in the Koneru 1993 trial three or five days in the
Fleckenstein 1998 and Pageaux 1995 trials five days after trans-
plantation in the Barnes 1997 and Angelico 1999 trials and five
or seven days after transplantation in the Sama 1991 trial
Patients received UCDA (10 to 15 mgkg body weightday) for
two months in the Pageaux 1995 trial for three months in the
Koneru 1993 Barnes 1997 Keiding 1997 and Fleckenstein 1998
trials and for six months in the Sama 1991 trial In the Barnes
1997 trial patients were followed up for 18 months Patients in the
Fleckenstein 1998 trial and the Keiding 1997 trial were followed
up for nine months There was no post-treatment follow-up in
three trials (Sama 1991 Koneru 1993 Pageaux 1995) Patients
received TUDCA (500 mgday) for one year and no follow-up
was conducted in the Angelico 1999 trial
In addition to the bile acids or control intervention all patients
in the seven trials received standard triple-drug regimens (steroids
azathioprine and cyclosporine or tacrolimus) The patients who
had steroid-resistant rejection received treatment with immuno-
suppressive antibodies (OKT3)
Outcome measures
The outcome measures reported by most trials were all-cause mor-
tality and acute cellular rejection Three trials reported on death
related to rejection (Barnes 1997 Keiding 1997 Angelico 1999)
two trials reported the number of patients who received retrans-
plantation due to rejection (Keiding 1997 Fleckenstein 1998)
three trials reported the number of patients with chronic rejection
(Barnes 1997 Keiding 1997 Fleckenstein 1998) and four trials
reported the number of patients with steroid-resistant rejection
(Pageaux 1995 Barnes 1997 Keiding 1997 Fleckenstein 1998)
Four trials had adverse events as outcome measures (Barnes 1997
Keiding 1997 Fleckenstein 1998 Angelico 1999) Serum biliru-
bin level was only reported by the Fleckenstein 1998 trial No tri-
als provided data on other liver biochemical parameters quality
of life or cost-effectiveness
Risk of bias in included studies
Two trials reported adequate allocation sequence generation by
using computer-generated random tables (Barnes 1997 Angelico
1999) One trial (Keiding 1997) reported adequate allocation con-
cealment by using sealed serially numbered envelopes Three tri-
als (Barnes 1997 Keiding 1997 Fleckenstein 1998) reported ad-
equate blinding by using placebo with an identical appearance
and taste Five trials (Pageaux 1995 Barnes 1997 Keiding 1997
Fleckenstein 1998 Angelico 1999) reported adequate description
of incomplete outcome data by the number of withdrawals the
reasons for withdrawal or no patients dropped out The trial by
Keiding 1997 is the only one free of selective reporting since all
the pre-specified outcomes were fairly reported Two trials (Barnes
1997 Keiding 1997) performed sample-size calculations Only
the trial by Keiding 1997 seemed to be free of baseline imbalance
and it is the only trial achieving the calculated sample size and
therefore probably the only that was not terminated early Other
trials did not perform sample size calculation or the authors did
not report whether the calculated sample size was achieved The
lack of this information made it unclear for us to judge whether
7Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
a trial was terminated early that is before an adequate number
of patients was included in the trial Three trials (Barnes 1997
Keiding 1997 Fleckenstein 1998) stated that intention-to-treat
analyses were used (Figure 1 Figure 2)
Figure 1 Methodological quality graph review authorsrsquo judgements about each methodological quality
item presented as percentages across all included studies
8Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Figure 2 Methodological quality summary review authorsrsquo judgements about each methodological quality
item for each included study
9Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Following the assessment of risk of bias domains none of the seven
trials were considered to have low risk of bias that is having all
the nine domains for risk of bias assessed as adequate
Effects of interventions
We were able to include seven randomised clinical trials in this
review Six trials with 306 liver-transplanted patients compared
ursodeoxycholic acid (UDCA) with placebo or no intervention
and one trial with 29 liver-transplanted patients compared tauro-
UDCA (TUDCA) with no intervention
All-cause mortality
Five trials including 257 liver-transplanted patients reported on
all-cause mortality at the end of treatment or at maximum follow-
up Bile acids did not significantly reduce all-cause mortality (RR
085 95 CI 053 to 136) there were 26 deaths among 132
patients treated with bile acids (197) versus 29 deaths among
125 patients in the control groups (232) (Analysis 11) There
was no statistically significant heterogeneity (I2 = 141)
Four trials (Sama 1991 Barnes 1997 Keiding 1997 Fleckenstein
1998) showed that UDCA did not significantly reduce all-cause
mortality (RR 080 95 CI 049 to 130) 23 deaths among 116
patients treated with UCDA (198) versus 27 deaths among
108 patients in the control groups (250) The Angelico 1999
trial demonstrated that TUDCA was not able to reduce all-cause
mortality (RR 159 95 CI 030 to 833) there were 3 deaths
among 16 patients (188) versus 2 deaths among 17 patients
(118)
The Fleckenstein 1998 trial and the Sama 1991 trial did not report
the causes of deaths In the three other trials the deaths were
considered to be caused by infections (n = 11) hepatic failure (n =
7) abdominal bleeding (n = 3) renal failure (n = 2) multiple organ
failure (n = 2) hepatitis B virus fibrosis (n = 2) acute rejection
(n = 1) hepatic artery thrombosis (n = 1) encephalitis (n = 1)
lymphoproliferative disorder (n = 1) cerebral haemorrhage (n =
1) or other reasons (n = 6)
Worst-best case and best-worst case scenario analyses
In the worst-best case scenario analysis bile acids did not signif-
icantly reduce all-cause mortality when compared with placebo
or no intervention (RR 130 95 CI 086 to 196) 40 deaths
among 132 patients on bile acids (303) versus 29 deaths among
125 patients in the control groups (232) However all-cause
mortality was significantly reduced by bile acids in the best-worst
case scenario analysis (RR 058 95 CI 038 to 090) 26 deaths
among 132 patients (197) versus 42 deaths among 125 patients
in the control groups (336) (Analysis 12)
Subgroup analyses
We performed subgroup analyses regarding the time that bile acid
intake was started The Keiding 1997 trial started bile acid intake
less than three days after liver transplantation and demonstrated
no significant effect of UDCA on all-cause mortality (RR 124
95 CI 061 to 254) 14 deaths out of 54 patients (259)
versus 10 out of 48 control patients (208) The same effect
was noticed in the four other trials (Sama 1991 Barnes 1997
Fleckenstein 1998 Angelico 1999) which started bile acids three
days or more after liver transplantation (RR 063 95 CI 033
to 120) 12 deaths among 78 patients (154) versus 9 deaths
among 77 control patients (247) (Analysis 13) There were no
statistically significant differences between the two estimates
We also performed subgroup analyses regarding the duration of
bile acid treatment Bile acids were administrated for less than six
months in three trials (Barnes 1997 Keiding 1997 Fleckenstein
1998) and were not able to significantly decrease all-cause mor-
tality (RR 078 95 CI 045 to 138) 18 deaths in a group of
96 treated patients (188) versus 21 deaths among 88 control
patients (239) In the other two trials (Sama 1991 Angelico
1999) patients were treated with bile acids for six months or more
The treatment did not show statistically significant decrease in all-
cause mortality (RR 102 95 CI 043 to 24) 8 deaths in a
group of 36 treated patients (222) versus 8 deaths in a group
of 37 control patients (216) (Analysis 14) There were no sta-
tistically significant differences between the two estimates
Mortality related to allograft rejection
We did not find statistically significant reduction in mortality re-
lated to allograft rejection at maximum follow-up in the three tri-
als reporting cause of death (Barnes 1997 Keiding 1997 Angelico
1999) (RR 030 95 CI 001 to 712) 098 (0) versus 189
(11)) (Analysis 15) The only death due to acute rejection was
found in the placebo group of the Keiding 1997 trial
Number of liver retransplantations
Two trials (Fleckenstein 1998 Keiding 1997) including 132 liver-
transplanted patients reported the number of liver retransplan-
tations UDCA did not significantly reduce the risk of liver re-
transplantation at maximum follow-up (RR 076 95 CI 020
to 286) 368 (44) versus 464 (63)) (Analysis 16) In the
Keiding 1997 trial one patient in the UDCA group was retrans-
planted due to chronic rejection and four patients in the placebo
group were retransplanted either due to chronic rejection (three
cases) or acute rejection (one case) In the Fleckenstein 1998 trial
two patients in the UDCA group were retransplanted due to acute
rejection (one case) and chronic rejection (one case) respectively
Number of patients with acute cellular rejection
Seven trials reported the number of patients who had acute cellu-
lar rejection after liver transplantation Bile acids did not signifi-
cantly reduce the number of patients who experienced acute cel-
lular rejection (RR 089 95 CI 074 to 106) 93174(535)
versus 99165 (600)) There was no significant heterogeneity
(I2 = 0)
Six trials (Sama 1991 Koneru 1993 Pageaux 1995 Barnes 1997
10Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Keiding 1997 Fleckenstein 1998) compared UDCA with placebo
or no intervention and demonstrated that UDCA did not signifi-
cantly reduce the number of patients with acute cellular rejection
after liver transplantation (RR 089 95 CI 074 to 108 85
158 (538) versus 89148 (601)) Neither did the Angelico
1999 trial demonstrate significant reduction of the number of pa-
tients with acute cellular rejection with TUDCA (RR 085 95
CI 045 to 160) 816 (500) versus 1017 (588) (Analysis
17)
Subgroup analyses
Two trials (Koneru 1993 Keiding 1997) in which the patients
started bile acids intake less than three days after liver transplan-
tation did not demonstrate any significant reduction of the risk
of acute cellular rejection by bile acids (RR 084 95 CI 063 to
111) 3870 (543) versus 4164 (641) The other five tri-
als (Sama 1991 Pageaux 1995 Barnes 1997 Fleckenstein 1998
Angelico 1999) in which the patients were started on bile acid
intake three days or more after liver transplantation did not find
a significant reduction of the risk of acute cellular rejection by bile
acids (RR 092 95 CI 072 to 117) 55104 (529) versus 58
101 (574) (Analysis 18) There was no significant difference
between the two estimates
Bile acids did not significantly reduce the risk of acute cellular
rejection in the five trials (Koneru 1993 Pageaux 1995 Barnes
1997 Keiding 1997 Fleckenstein 1998) in which the patients
received treatment with bile acids less than six months (RR 087
95 CI 071 to 107) 72138 (522) versus 76128 (594)
Neither did bile acids in the two other trials (Sama 1991 Angelico
1999) in which the patients received bile acids for more than six
months (RR 094 95 CI 065 to 136) 2136 (583) versus
2337 (622) (Analysis 19) There were no significant difference
between the two estimates
Number of patients with chronic rejection
Three trials comparing UDCA versus placebo (Barnes 1997
Keiding 1997 Fleckenstein 1998) reported the number of patients
with chronic rejection after liver transplantation UDCA signifi-
cantly reduced the number of patients with chronic rejection in
the fixed-effect model analysis (RR 028 95 CI 008 to 095)
396 (31) versus 1088 (114) (Analysis 110) but not in the
random-effects model analysis (RR 030 95 CI 008 to 113) 3
96 (31) versus 1088 (114) There was no statistically signifi-
cant heterogeneity (I2 0) We performed trial sequential analysis
for the available data from three trials (Figure 3) with heterogene-
ity corrected required information size based on proportion of this
outcome of 12 in the control group a relative risk reduction of
50 in the intervention group at a type I error of 5 and a type
II error of 10 We obtained a required information size of 957
patients UDCA was not able to reach or break the trial sequential
monitoring boundary and only 183 out of 957 (19) patients
were randomised regarding this outcome
11Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Figure 3 Trial sequential analysis for the number of patients with chronic rejection at maximum follow-up
We calculated the heterogeneity-corrected required information size (HCRIS) based on a proportion of 12 of
the patients in the placebo group with chronic rejection at maximum follow-up a 50 risk ratio reduction in
the bile acid group an alpha of 5 a beta of 10 and a heterogeneity of 0 Only 184 patients have been
randomised reporting this outcome which is only 19 of the HCRIS of 957 patients The cumulative Z-score
crosses the conventional boundaries for P 005 but not the monitoring boundaries
Number of patients with steroid-resistant rejection
Four trials (Pageaux 1995 Barnes 1997 Keiding 1997
Fleckenstein 1998) reported the number of patients with steroid-
resistant rejection These trials demonstrated that UDCA did not
significantly reduce the number of patients with steroid-resistant
rejection when compared with placebo (22122 (18) versus 26
112 (232) (RR 077 95 CI 047 to 127) (Analysis 111)
There was no significant heterogeneity (I2 0)
Liver biochemistry
The Fleckenstein 1998 trial reported serum bilirubin levels after
a three-month-treatment period in 30 liver-transplanted patients
There was no statistically significant difference in serum bilirubin
levels between the UDCA group and the placebo group (MD 260
mgdl 95 CI -096 to 616 mgdl) (Analysis 112)
No data were available for other liver biochemical variables
Cost-effectiveness
One trial (Barnes 1997) with 52 liver-transplanted patients re-
ported the days of hospitalisation after liver transplantation
UDCA significantly decreased the number of days of hospitali-
sation when compared with placebo (MD -850 days 95 CI -
1667 to -033 days) (Analysis 113) We were not able to extract
other medical cost from the trials
Adverse events
Among all the included and excluded trials only four reported on
adverse events however adverse events only occurred in two of
the included trials (Barnes 1997 Keiding 1997) There were no
significant differences regarding adverse events (RR 088 95 CI
030 to 260) 6112 (54) versus 6105 (57) (Analysis 114)
In the Barnes 1997 trial diarrhoea was reported by two patients
(one in the UDCA group and one in the placebo group) In the
Keiding 1997 trial five UDCA patients and five placebo patients
stopped intake of the trial medicine because of diarrhoea or dif-
ficulties in swallowing the capsules The remaining included trial
by Angelico 1999 stated that no adverse events occurred during
the study period The excluded trial by Assy 2007 was the only
one reporting on a case of mild diarrhoea in one patient in the
12Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
intervention group No other excluded studies reported on adverse
events (see Table 1)
Quality of life
None of the included studies assessed quality of life as an outcome
Other subgroup analyses
We planned to perform subgroup analyses regarding the risk of
bias of trials the dosage of bile acid and any co-intervention
However none of the trials were considered to be of low risk of
bias they all used a similar dosage of bile acid and patients in all
trials received similar immunosuppressive treatment as co-inter-
ventions (steroids azathioprine and cyclosporine or tacrolimus)
after liver transplantation Therefore we were not able to perform
the planned subgroup analyses
Funnel plot asymmetry
We did not draw a funnel plot analysis due to the limited number
of trials included in the present review
D I S C U S S I O N
In the update of this review we included no new trials assessing
the use of bile acids for liver-transplanted patients The analyses
of the seven previously included trials showed that bile acids did
not significantly affect mortality acute cellular rejection steroid-
resistant rejection retransplantation or serum bilirubin Bile acids
might significantly decrease the length of hospital stay and the
number of patients with chronic rejection included in these tri-
als but more supportive evidence is needed The number of pa-
tients with chronic rejection was not significantly influenced by
bile acids when a random-effects model was used and length of
stay was assessed in one single trial Furthermore none of the trials
were considered to be of low risk of bias and few patients were en-
rolled Therefore our positive findings may be due to bias (Schulz
1995 Moher 1998 Kjaergard 2001 Wood 2008) or random er-
rors (Wetterslev 2008 Brok 2009 Thorlund 2009) On the other
hand we are not able to exclude type II errors (that is finding
no significant differences when in fact they exist) due to the low
number of participants Therefore this topic could be of potential
interest in future large randomised trials with adequate control of
bias
All-cause mortality at one year after liver transplantation is re-
ported to be about 20 (Thuluvath 2003) which we also ob-
served for the patients included in the present review According to
our subgroup analyses neither UDCA nor TUDCA significantly
decreased all-cause mortality We also performed a subgroup anal-
ysis regarding treatment duration but we were not able to find any
difference between short (less than six months) and long treatment
duration (six months or more) Thus bile acids do not seem to
have statistically significant effects in reducing all-cause mortal-
ity after liver transplantation We performed both worst-best-case
scenario and best-worst-case scenario analyses In the worst-best-
case scenario bile acids did not differ significantly from placebo or
no intervention regarding all-cause mortality However bile acids
significantly decreased all-cause mortality in the best-worst-case
scenario analysis However such an analysis is very extreme and
may not be realistic We have also found that UDCA may be able
to decrease the risk of chronic rejection in liver-transplanted pa-
tients but trial sequential analysis could not confirm this result
Due to a limited number of patients (Ioannidis 2001) we are not
able to exclude the possibility that it may be relevant to perform
placebo-controlled trials with low risk of bias on the use of bile
acids for liver-transplanted patients
We looked into the causes of deaths that were reported by the trials
and only one trial reported one death related to rejection At the
same time the number of retransplantations was 3 among 68 liver-
transplanted patients who received treatment with UDCA and 4
among 64 liver-transplanted patients who received treatment with
placebo We noticed that all patients in the included trials received
co-interventions of standard triple-drug regimens (steroids aza-
thioprine and cyclosporine or tacrolimus) which were able to
control the possible acute or chronic rejection and prevent deaths
due to allograft rejection (FK506 1994)
The assumption that UDCA might reduce the incidence of acute
graft rejection came from the findings that UDCA could regulate
major histocompatibility complex antigen expression in bile ducts
and liver endothelia and inhibit lymphocyte activity (Calmus
1990 Terasaki 1991 Perez 2009) However in the present review
bile acids did not significantly reduce the risk of acute cellular re-
jection in liver-transplanted patients Considering that acute cellu-
lar rejection is commonly found within a few days after liver trans-
plantation (Vierling 1992) some might argue that the adminis-
tration of bile acids was started too late to prevent acute cellular
rejection We performed subgroup analyses regarding the time bile
acids were started and no statistically significant difference was
found Furthermore bile acids were not able to decrease the risk
of steroid-resistant rejection Therefore the lack of effects of bile
acids does not seem to be due to a delayed start to bile acid ad-
ministration after liver transplantation However it is a possibility
that one should start bile acids intake before liver transplantation
A retrospective study found that rejection rates differed signifi-
cantly between patients with primary biliary cirrhosis treated with
or without UDCA before liver transplantation (Heathcote 1999)
One could argue whether UDCA-induced delay in transplantation
has an adverse effect on post-transplantation outcome Since we
did not find any prospective randomised clinical trials addressing
this issue further research might be needed Furthermore some
studies may provide an explanation why UDCA was not able to
prevent acute cellular rejection These studies found that UDCA
did not appear to change the expression of major histocompatibil-
ity complex class II antigens but rather major histocompatibility
complex class I antigens (Calmus 1990) The initial mechanism
of acute rejection is thought to be recognition of MHC class II
13Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
antigens by CD4+ T cells (Vierling 1992) Moreover the inhibi-
tion of the production of interleukin-2 by peripheral blood lym-
phocytes with UDCA (Heuman 1993) might be negated by the
immunosuppressive treatment after liver transplantation (van den
Berg 1998) so that UDCA is unable to demonstrate effects on
graft rejection In a recent study by Assy 2007 a significant re-
duction in the mean dose of immunosuppressive medications was
achieved in stable liver graft recipients treated with UDCA indi-
cating a possible influence of UDCA on rejection mechanisms
In accordance with previous systematic reviews (Chen 2003a
Chen 2007 Gong 2008) bile acids were not associated with the
occurrence of serious adverse events or any major occurrence of
adverse events
In summary our results do not support or refute the use of bile
acids (UDCA and TUDCA) additional to standard immunosup-
pressive treatment in liver-transplanted patients
A U T H O R S rsquo C O N C L U S I O N SImplications for practice
There seems to be no evidence to support or refute the use of bile
acids for liver-transplanted patients receiving standard immuno-
suppressive treatment
Implications for research
We need more randomised placebo-controlled clinical trials with
enough statistical power and low risk of bias to explore the poten-
tial effects of bile acids on chronic rejection and mortality in liver-
transplanted patients Such trials should also consider evaluation
of quality of life and length of hospitalisation Such trials may
consider starting bile acid and placebo interventions before liver
transplantation we were not able to identify any randomised trials
addressing this regimen Such trials ought to be reported accord-
ing to the CONSORT statement (wwwconsort-statementorg)
However before embarking on such trials the effects of bile acids
in other patient groups should be scrutinised as they may have
small or negative effects
A C K N O W L E D G E M E N T S
We thank all the patients and investigators who were involved in
the clinical trials mentioned in this review We thank Wendong
Chen for his work and contribution on the previous version of this
review We thank the staff of The Cochrane Hepato-Biliary Group
Editorial Team especially Dimitrinka Nikolova and Sarah Louise
Klingenberg for excellent collaboration and assistance during the
update of this review
Peer Reviewers Carlo Merkel Italy M Tomikawa Japan
Contact Editor Bodil Als-Nielsen Denmark
R E F E R E N C E S
References to studies included in this review
Angelico 1999 published data only
Angelico M Tisone G Baiocchi L Palmieri G Pisani F Negrini S
et alOne-year pilot study on tauroursodeoxycholic acid as an
adjuvant treatment after liver transplantation Italian Journal of
Gastroenterology and Hepatology 199931(6)462ndash8 [MEDLINE
10575563]
Barnes 1997 published data onlylowast Barnes D Talenti D Cammell G Goormastic M Farquhar L
Henderson M et alA randomized clinical trial of ursodeoxycholic
acid as adjuvant treatment to prevent liver transplant rejection
Hepatology 199726(4)853ndash7 [MEDLINE 9328304]
Barnes D Talenti D Goormastic M Farquhar L Cammell G
Henderson M et alUrsodeoxycholic acid (UDCA) reduces hepatic
allograft rejection after orthotopic liver transplantation (OLT) - a
prospective randomized placebo-controlled double-blind trial
Hepatology 199522149A
Fleckenstein 1998 published data only
Fleckenstein JF Paredes M Thuluvath PJ A prospective
randomized double-blind trial evaluating the efficacy of
ursodeoxycholic acid in prevention of liver transplant rejection
Liver Transplantation and Surgery 19984(4)276ndash9 [MEDLINE
9649640]
Keiding 1997 published data only
Keiding S Hockerstedt K Bjoro K Bondesen S Hjortrup A
Isoniemi H et alThe Nordic multicenter double-blind randomized
controlled trial of prophylactic ursodeoxycholic acid in liver
transplant patients Transplantation 199763(11)1591ndash4
[MEDLINE 9197351]
Koneru 1993 published data only
Koneru B Tint GS Wilson DJ Leevy CB Salen F Randomised
prospective trial of ursodeoxycholic acid in liver transplant
recipients Hepatology 199318336A
Pageaux 1995 published data only
Pageaux GP Blanc P Perrigault PF Navarro F Fabre JM Souche B
et alFailure of ursodeoxycholic acid to prevent acute cellular
rejection after liver transplantation Journal of Hepatology 199523
(2)119ndash22 [MEDLINE 7499781]
Sama 1991 published data only
Sama C Mazziotti A Grigioni W Morselli AM Chianura A
Stefanini GF et alUrsodeoxycholic acid administration does not
14Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
prevent rejection after OLT Journal of Hepatology 199113(Suppl
2)68
References to studies excluded from this review
Assy 2007 published data only
Assy N Adams PC Myers P Simon V Minuk GY Wall W et
alRandomized controlled trial of total immunosuppression
withdrawal in liver transplant recipients role of ursodeoxycholic
acid Transplantation 200783(12)1571ndash6 [MEDLINE
17589339]
Clavien 1996 published data only
Clavien PA Sharara AI Camargo CA Jr Harland RC Fitz JG
Evidence that ursodeoxycholic acid prevents steroid-resistant
rejection in adult liver transplantation Clinical Transplantation
199610(6 Pt 2)658ndash62 [MEDLINE 8996761]
Friman 1992 published data only
Friman S Persson H Schersten T Svanvik J Karlberg I Adjuvant
treatment with ursodeoxycholic acid reduces acute rejection after
liver transplantation Transplantation Proceedings 199224(1)
389ndash90 [MEDLINE 1539328]
Heathcote 1999 published data onlylowast Heathcote EJ Stone J Cauch-Dudek K Poupon R Chazouilleres
O Lindor KD et alEffect of pretransplantation ursodeoxycholic
acid therapy on the outcome of liver transplantation in patients
with primary biliary cirrhosis Liver Transplantation and Surgery
19995(4)269ndash74 [MEDLINE 10388499]
Henriksson 1991 published data only
Henriksson BA Persson H Friman S Wangberg B Svanvik J
Karlberg I Adjuvant ursodeoxycholic acid prevents acute rejection
in liver transplant recipients Transplantation Proceedings 199123
(3)1971 [MEDLINE 2063453]
Persson 1990 published data only
Persson H Friman S Schersten T Svanvik J Karlberg I
Ursodeoxycholic acid for prevention of acute rejection in liver
transplant recipients Lancet 1990336(8706)52ndash3 [MEDLINE
1973232]
Rafael 1995 published data only
Rafael E Duraj F Rudstrom H Wilczek H Ericzon B Effect of
ursodeoxycholic acid treatment for cholestasis in liver transplant
recipients Transplantation Proceedings 199527(6)3501ndash2
[MEDLINE 8540069]
Sama 1998 published data only
Sama C Morselli-Labate AM Grazi GL Mastroianni A Danesi G
Pianta P et alUrsodeoxycholic acid in liver transplantation effect
on cholestasis and rejection Gastroenterology 1998114(4 Suppl)
A1332
Additional references
Adams 1990
Adams DH Neuberger JM Patterns of graft rejection following
liver transplantation Journal of Hepatology 199010(1)113ndash9
[MEDLINE 2407770]
Al-Quaiz 1994
Al-Quaiz M OrsquoGrady J Tredger J Williams R Variable effect of
ursodeoxycholic acid on cyclosporin absorption after orthotopic
liver transplantation Transplant International 19947(3)190ndash4
[MEDLINE 8060468]
Armstrong 1982
Armstrong MJ Carey MC The hydrophobic-hydrophilic balance
of bile salt Inverse correlation between reverse phase high
performance liquid chromatographic mobilities and micellar
cholesterol-solubilizing capacities Journal of Lipid Research 1982
23(1)70ndash80 [MEDLINE 7057113]
Ascher 1988
Ascher NL Stock PG Baumgardner GL Payne WD Najarian JS
Infection and rejection of primary hepatic transplant in 93
consecutive patients treated with triple immunosuppressive therapy
Surgery Gynecology amp Obstetrics 1988167(6)474ndash84
[MEDLINE 3055368]
Brok 2008
Brok J Thorlund K Gluud C Wetterslev J Trial sequential
analysis reveals insufficient information size and potentially false
positive results in many meta-analyses Journal of Clinical
Epidemiology 200861(8)763ndash9 [MEDLINE 18411040]
Brok 2009
Brok J Thorlund K Wetterslev J Gluud C Apparently conclusive
meta-analysis may be inconclusive - Trial sequential analysis
adjustment of random error risk due to repetitive testing of
accumulating data in apparently conclusive neonatal meta-analysis
International Journal of Epidemiology 200938(1)298ndash303
[MEDLINE 18824466]
Calmus 1990
Calmus Y Gane P Rouger P Poupon R Hepatic expression of class
I and class II major histocompatibility complex molecules in
primary biliary cirrhosis effect of ursodeoxycholic acid Hepatology
199011(1)12ndash5 [MEDLINE 2403961]
Calmus 1992
Calmus Y Arvieux C Gane P Boucher E Nordlinger B Rouger P
et alCholestasis induces major histocompatibility complex class I
expression in hepatocytes Gastroenterology 1992102(4 Pt 1)
1371ndash7 [MEDLINE 1551542]
Chen 2003a
Chen W Gluud C Bile acids for primary sclerosing cholangitis
Cochrane Database of Systematic Reviews 2003 Issue 2 [DOI
10100214651858CD003626]
Chen 2007
Chen W Liu J Gluud C Bile acids for viral hepatitis Cochrane
Database of Systematic Reviews 2007 Issue 4 [DOI 101002
14651858CD003181pub2]
Cheng 2002
Cheng K Ashby D Smyth R Ursodeoxycholic acid for cystic
fibrosis-related liver disease Cochrane Database of Systematic
Reviews 2002 Issue 2 [DOI 10100214651858CD000222]
Corbani 2008
Corbani A Burroughs AK Intrahepatic cholestasis after liver
transplantation Clinics in Liver Disease 200812(1)111ndash29
[MEDLINE 18242500]
DeMets 1987
DeMets DL Methods for combining randomised clinical trials
strengths and limitations Statistics in Medicine 19876(3)341ndash50
[MEDLINE 3616287]
15Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
DerSimonian 1986
DerSimonian R Laird N Meta-analysis in clinical trials Controlled
Clinical Trials 19867(3)177ndash88 [MEDLINE 3802833]
Egger 1997
Egger M Davey Smith G Schneider M Minder C Bias in meta-
analysis detected by a simple graphical test BMJ (Clinical Research
Ed) 1997315(7109)629ndash34 [MEDLINE 9310563]
Ericzon 1990
Ericzon BG Eusufzai S Kubota K Einarsson K Angelin B
Characteristics of biliary lipid metabolism after liver
transplantation Hepatology 199012(5)1222ndash8 [MEDLINE
2227822]
FK506 1994
The US Multicenter FK506 Liver Study Group A comparison of
tacrolimus (FK506) and cyclosporine for immunosuppression in
liver transplantation New England Journal of Medicine 1994331
(17)1110ndash5 [MEDLINE 7523946]
Friman 1994
Friman S Svanvik J A possible role of ursodeoxycholic acid in liver
transplantation Scandinavian Journal of Gastroenterology 1994204
62ndash4 [MEDLINE 7824880]
Fuchs 1999
Fuchs M Stange EF Metabolism of bile acids In Johannes
Bircher Jean-Pierre Benhamou Neil McIntyre Mario Rizzetto
Juan Rodes editor(s) Oxford Textbook of Clinical Hepatology 2
Vol 1 Oxford Oxford University Press 1999223ndash56
Fusai 2006
Fusai G Dhaliwal P Rolando N Sabin CA Patch D Davidson BR
et alIncidence and risk factors for the development of prolonged
and severe intrahepatic cholestasis after liver transplantation Liver
Transplantation 200612(11)1626ndash33 [DOI 101002lt20870]
Gluud 2001
Gluud C Alcoholic hepatitis no glucocorticosteroids In
Leuschner U James OFW Dancygier H editor(s) Steatohepatitis
(NASH and ASH) Falk Symposium 121 Lancaster Kluwer
Academic Publisher 2001322ndash42
Gluud 2010
Gluud C Nikolova D Klingenberg SL Alexakis N Als-Nielsen B
Colli A et alCochrane Hepato-Biliary Group About The
Cochrane Collaboration (Cochrane Review Groups (CRGs))
2010 Issue 1 Art No LIVER
Gong 2008
Gong Y Huang ZB Christiansen E Gluud C Ursodeoxycholic
acid for primary biliary cirrhosis Cochrane Database of Systematic
Reviews 2008 Issue 3 [DOI 101002
14651858CD000551pub2]
Haddad 2006
Haddad EM McAlister VC Renouf E Malthaner R Kjaer MS
Gluud LL Cyclosporin versus tacrolimus for liver transplanted
patients Cochrane Database of Systematic Reviews 2006 Issue 4
[DOI 10100214651858CD005161pub2]
Heuman 1993
Heuman DM Hepatoprotective properties of ursodeoxycholic acid
Gastroenterology 1993104(6)1865ndash9 [MEDLINE 8500748]
Higgins 2008
Higgins PTJ Green S editors Cochrane Handbook for Systematic
Reviews of Interventions West Sussex England Wiley-Blackwell
2008
Hirschfield 2009
Hirschfield GM Gibbs P Griffiths WJH Adult liver
transplantation what non-specialists need to know BMJ (Clinical
Research Ed) 2009338(b1670)1321ndash7 [DOI 101136
bmjb1670]
Hussain 2002
Hussain HK Nghiem HV Imaging of hepatic transplantation
Clinics in Liver Disease 20026(1)247ndash70 [MEDLINE
11933592]
ICH-GCP 1997
International Conference on Harmonisation Expert Working
Group Code of Federal Regulations amp International Conference on
Harmonization Guidelines Media Parexel Barnett 1997
Ioannidis 2001
Ioannidis JPA Lau J Evolution of treatment effects over time
Empirical insight from recursive cumulative meta analyses
Proceedings of the National Academy of Sciences 200198(3)831ndash6
IWP 1995
International Working Party Terminology for hepatic allograft
rejection Hepatology 199522(2)648ndash54 [MEDLINE 7635435]
Kjaergard 2001
Kjaergard LL Villumsen J Gluud C Reported methodological
quality and discrepancies between large and small randomised trials
in meta-analyses Annals of Internal Medicine 2001135(11)982ndash9
[MEDLINE 11730399]
Klintmalm 1989
Klintmalm GB Nery JR Husberg BS Gonwa TA Tillery GW
Rejection in liver transplantation Hepatology 198910(6)978ndash85
[MEDLINE 2583691]
Knechtle 2009
Knechtle SJ Kwun J Unique aspects of rejection and tolerance in
liver transplantation Seminars in Liver Disease 200929(1)91ndash101
[MEDLINE 19235662]
Krams 1993
Krams SM Ascher NL Martinez OM New immunologic insights
into mechanisms of allograft rejection Gastroenterology Clinics of
North America 199318(2)374ndash7 [MEDLINE 8509176]
Lan 1983
Lan KKG DeMets DL Discrete sequential boundaries for clinical
trials Biometrika 198370659ndash63
Merion 1989
Merion RM Gorski DH Burtch GD Turcotte JG Colletti LM
Campbell DA Jr Bile refeeding after liver transplantation and
avoidance of intravenous cyclosporine Surgery 1989106(4)
604ndash9 [MEDLINE 2799635]
Moher 1998
Moher D Pham B Jones A Cook DJ Jadad AR Moher M et
alDoes quality of reports of randomised trials affect estimates of
intervention efficacy reported in meta-analyses Lancet 1998352
(9128)609ndash13 [MEDLINE 9746022]
16Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Neuberger 1999
Neuberger J Incidence timing and risk factors for acute and
chronic rejection Liver Transplantation and Surgery 19995(4 Suppl
1)S30ndashS36 [MEDLINE 10431015]
Okolicsanyi 1986
Okolicsanyi L Lirussi F Strazzabosco M Jemmolo RM Orlando R
Nassuato G et alThe effect of drugs on bile flow and composition
An overview Drugs 198631(5)430ndash48 [MEDLINE 2872047]
Palmer 1972
Palmer RH Bile acids liver injury and liver disease Archives of
Internal Medicine 1972130(4)606ndash17 [MEDLINE 4627840]
Perez 2009
Perez MJ Briz O Bile-acid-induced cell injury and protection
World Journal of Gastroenterology 200915(14)1677ndash89
[MEDLINE 19360911]
Pogue 1997
Pogue JM Yusuf S Cumulating evidence from randomized trials
Utilizing sequential monitoring boundaries for cumulative meta-
analysis Controlled Clinical Trials 199718(6)580ndash93
[MEDLINE 9408720]
Pogue 1998
Pogue J Yusuf S Overcoming the limitations of current meta-
analysis of randomised controlled trials Lancet 1998351(9095)
45ndash52 [MEDLINE 9433436]
RevMan 2008
The Nordic Cochrane Centre The Cochrane Collaboration
Review Manager (RevMan) 50 Copenhagen The Nordic
Cochrane Centre The Cochrane Collaboration 2008
Royle 2003
Royle P Milne R Literature searching for randomized controlled
trials used in Cochrane reviews rapid versus exhaustive searches
International Journal of Technology Assessment in Health Care 2003
19(4)591ndash603
Schulz 1995
Schulz KF Chalmers I Hayer R Altman D Empirical evidence of
bias JAMA 1995273(5)408ndash12 [MEDLINE 7823387]
Sharara 1995
Sharara AI Camargo CA Clavien PA Ursodeoxycholic acid
prevents steroid resistant rejection in liver transplant recipients
Gastroenterology 1995108A1168
Sholmerich 1984
Sholmerich J Becher MS Schmidt KH Schubert R Kremer B
Felhaus S et alInfluence of hydroxylation and conjugation of bile
salts on their membrane damaging properties Hepatology 19844
(4)661ndash7 [MEDLINE 6745854]
Soderdahl 1998
Soderdahl G Nowak G Duraj F Wang FH Einarsson C Ericzon
BG Ursodeoxycholic acid increased bile flow and affects bile
composition in the early postoperative phase following liver
transplantation Transplantation International 199811(Suppl 1)
S231ndashS238 [MEDLINE 9664985]
Terasaki 1991
Terasaki S Nakanuma Y Ogino H Unoura M Kobayashi K
Hepatocellular and biliary expression of HLA antigens in primary
biliary cirrhosis before and after ursodeoxycholic acid therapy
American Journal of Gastroenterology 199186(9)1194ndash9
[MEDLINE 1882800]
Thalheimer 2002
Thalheimer U Capra F Liver transplantation making the best out
of what we have Digestive Diseases and Sciences 200247(5)
945ndash53 [MEDLINE 12018919]
Thorlund 2009
Thorlund K Devereaux PJ Wetterslev J Guyatt G Ioannidis JP
Thabane L et alCan trial sequential monitoring boundaries reduce
spurious inferences from meta-analyses International Journal of
Epidemiology 200938(1)276ndash86 [MEDLINE 18824467]
Thuluvath 2003
Thuluvath PJ Yoo HY Thompson RE A model to predict survival
at one month one year and five years after liver transplantation
based on pretransplant clinical characteristics Liver Transplantation
20039(5)527ndash32 [MEDLINE 12740799]
van den Berg 1998
van den Berg AP Twilhaar WN Mesander G van Son WJ van der
Bij W Klompmaker IJ et alQuantitation of immunosuppression
by flow cytometric measurement of the capacity of T cells for
interleukin-2 production Transplantation 199865(8)1066ndash71
[MEDLINE 9583867]
Vierling 1992
Vierling J Immunologic mechanisms of hepatic allograft rejection
Seminars in Liver Disease 199212(1)16ndash27 [MEDLINE
1570548]
Wetterslev 2008
Wetterslev J Thorlund K Brok J Gluud C Trial sequential
analysis may establish when firm evidence is reached in cumulative
meta-analysis Journal of Clinical Epidemiology 200861(1)64ndash75
[MEDLINE 18083463]
Wiesner 1992
Wiesner RH Acute cellular rejection following liver
transplantation incidence risk factors and outcome in the
NIDDK Liver Transplant Database (LTD) study Gastroenterology
1992102A910
Wood 2008
Wood L Egger M Gluud LL Schulz KF Juni P Altman DG et
alEmpirical evidence of bias in treatment effect estimates in
controlled trials with different interventions and outcomes meta-
epidemiological study BMJ (Clinical Research Ed) 2008336
(7644)601ndash5 [MEDLINE 18316340]
Yoshikawa 1998
Yoshikawa M Matsui Y Kawamoto H Toyohara M Matsumura
K Yamao J et alIntragastric administration of ursodeoxycholic
acid suppresses immunoglobulin secretion by lymphocytes from
liver but not from peripheral blood spleen or Peyerrsquos patches in
mice International Journal of Immunopharmacology 199820(1-3)
29ndash38 [MEDLINE 9717080]
References to other published versions of this review
17Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Chen 2003b
Chen W Gluud C Bile acids for liver transplanted patients
Cochrane Database of Systematic Reviews 2005 Issue 3 [DOI
10100214651858CD005442]lowast Indicates the major publication for the study
18Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
C H A R A C T E R I S T I C S O F S T U D I E S
Characteristics of included studies [ordered by study ID]
Angelico 1999
Methods Study design open-label randomised one-year pilot study
Participants Country Italy
Publication language English
Inclusion criteria
- patients who underwent liver transplantation from April 1994 to December 1994
Exclusion criteria
- not mentioned
Participants
Two patients in TUDCA group and two patients in control group were excluded from
the basic information of participants by the study due to withdrawal
- TUDCA group (n = 14)
Mean age (years +- SD)
467 +- 84
Ratio of sex (malefemale) 122
Origins of liver diseases
hepatitis C cirrhosis (9) hepatitis B cirrhosis (2) hepatitis B and C cirrhosis (1) cryp-
togenic cirrhosis (2) alcoholic cirrhosis (0) Wilson cirrhosis (0)
- Control group (n = 15)
Mean age (years +- SD)
474 +- 74
Ratio of sex (malefemale) 123
Origins of liver diseases
hepatitis C cirrhosis (7) hepatitis B cirrhosis (2) hepatitis B and C cirrhosis (2) cryp-
togenic cirrhosis (2) alcoholic cirrhosis (1) Wilson cirrhosis (1)
Interventions TUDCA group
- Dose 500 mgday in two divided doses
- Route orally
- Duration the treatment was started on day 5 after transplantation and continued for
one year
Control group
- no treatment
Co-interventions all patients received standard triple-drug regimens (steroids azathio-
prine and cyclosporine or tacrolimus)
Outcomes All cause mortality
Number of patients with rejection after liver transplantation
Notes Letter was sent to the authors in September 2009 A reply with additional information
was received shortly after
Risk of bias
19Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Angelico 1999 (Continued)
Item Authorsrsquo judgement Description
Adequate sequence generation Yes Computer generated table
Allocation concealment Unclear No information provided
Blinding No Not performed
Incomplete outcome data addressed
All outcomes
Yes Withdrawal two patients from the
TUDCA group and two patients from the
placebo group Three of them died due to
transplant non-function in the first postop-
erative week and one patient was regrafted
due to thrombosis of hepatic artery
Free of selective reporting Unclear Post-transplant cholestasis and liver bio-
chemistry specified as outcomes Differ-
ence reported as not significant but no ac-
tual data given
Sample size calculation No Not reported
Intention-to-treat analysis No Not stated and not used
Baseline imbalance Unclear Not enough information provided
Early stopping of trial Unclear Not enough information provided
Barnes 1997
Methods Study design randomised placebo-controlled double-blind trial
Participants Country United States
Publication language English
Inclusion criteria
- patients aged 18 years or older who underwent liver transplantation at the Cleveland
Clinic Foundation from April 1992 through June of 1994
Exclusion criteria
- patients who were found to have cancer at surgically resected margins of the biliary
tree
- patents who underwent retransplantation
Participants
- UDCA group (n = 28)
Mean age (years +- SD)
505 +- 116
Ratio of sex (malefemale) 1810
Child class A 7
20Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Barnes 1997 (Continued)
B 13
and C 8
Origins of liver diseases Laennecrsquos cirrhosis 4
PBC 3
cryptogenic cirrhosis 6
hepatitis Ccirrhosis 4
hepatitis Bcirrhosis 3
autoimmune hepatitis with cirrhosis 3
PSC 2
other 3
- Placebo group (n = 24)
Mean age (years +- SD)
507 +- 93
Ratio of sex (malefemale) 159
Child class A 6
B 14
and C 4
Origins of liver diseases Laennecrsquos cirrhosis 9
PBC 5
cryptogenic cirrhosis 1
hepatitis Ccirrhosis 1
hepatitis Bcirrhosis 1
autoimmune hepatitis with cirrhosis 1
PSC 2
other 4
Interventions UDCA group
- Dose 10-15 mgkg body weightday in divided doses
- Route orally
- Duration immediately after intestinal transit recovery usually between postoperative
days three and five and continue for three months
Placebo group
- identical-appearing capsules administered in the same quantity and manner
Co-interventions all patients received standard triple-drug regimens (steroids azathio-
prine and cyclosporine or tacrolimus)
Outcomes All cause mortality
Number of patients with acute cellular rejection
Number of patients with chronic rejection
Number of patients with steroid-resistant rejection
Number of days of hospitalisation
Adverse events
Notes Letter was sent to the authors in September 2009 A reply with additional information
was received shortly after
Risk of bias
Item Authorsrsquo judgement Description
21Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Barnes 1997 (Continued)
Adequate sequence generation Yes Computer generated table
Allocation concealment Unclear No information provided
Blinding Yes Quote ldquorandomised to receive either
UDCA or an identical placebo capsulerdquo
Incomplete outcome data addressed
All outcomes
Yes Mean follow-up time 18 months Ten pa-
tients withdrawn from study 6 in UDCA
group and 4 in placebo group Reasons
for withdrawal were reported Four patients
died in the placebo group
Free of selective reporting Yes All expected outcomes reported
Sample size calculation Unclear The trial reported the method of sample
size calculation but the actual number of
patients needed was not reported
Intention-to-treat analysis Yes Stated and used
Baseline imbalance Unclear Not enough information provided
Early stopping of trial Unclear The number of patients needed to gain the
actual power was not reported Whether
the trial was terminated early is not clear
Fleckenstein 1998
Methods Study design prospective randomised double-blind trial
Participants Country United States
Publication language English
Inclusion criteria
- patients who underwent liver transplantation at the Johns Hopkins Hospital
Exclusion criteria
- patients who were under 18 years old undergoing repeat transplantation had primary
graft nonfunction or refused consent
Participants
- UDCA group (n = 14)
Mean age (years +- SD)
443 +- 127
Ratio of sex (malefemale) 68
Origins of liver diseases hepatitis C 6
alcohol 2
autoimmune 1
PBC 2
22Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Fleckenstein 1998 (Continued)
PSC 1
autoimmune cholangiopathy 1
hepatitis B 1
- Placebo group (n = 16)
Mean age (years +- SD)
496 +- 109
Ratio of sex (malefemale) 124
Origins of liver diseases hepatitis C 3
alcohol 3
autoimmune 3
PBC 1
PSC 2
cryptogenic 2
hepatitis B 1
alpha1-antitrypsin deficiency 1
Interventions UDCA group
- Dose 15 mgkg body weightday in divided doses
- Route orally
- Duration immediately after intestinal transit recovery usually between postoperative
days three and five and continue for three months
Placebo group
- Identical-appearing capsules administered in the same quantity and manner
Co-interventions all patients received standard triple-drug regimens (steroids azathio-
prine and cyclosporine or tacrolimus)
Outcomes All cause mortality
Number with retransplantation
Number of patients with acute cellular rejection
Number of patients with chronic rejection
Serum bilirubin levels at the end of treatment
Notes Follow-up time nine months
Letter was sent to the authors in September 2009 No reply was received
Risk of bias
Item Authorsrsquo judgement Description
Adequate sequence generation Unclear No information provided
Allocation concealment Unclear No information provided
Blinding Yes Method of blinding not described but
probably adequate
Incomplete outcome data addressed
All outcomes
Yes Withdrawal one patient from the UDCA
group and two patients from the placebo
group because of capsule size
23Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Fleckenstein 1998 (Continued)
Free of selective reporting Unclear Outcomes were not completely described
Sample size calculation No Not reported
Intention-to-treat analysis Yes Quote ldquoThree patients withdrew after in-
clusionThey were included in the statis-
tical analysisrdquo
Baseline imbalance Unclear Not enough information provided
Early stopping of trial Unclear Not enough information provided
Keiding 1997
Methods Study design prospective randomised placebo-controlled multicenter study
Participants Country Denmark Finland Norway and Sweden
Publication language English
Inclusion criteria
- patients who underwent liver transplantation in Denmark Finland Norway and Swe-
den from September 1 1992 to May 31 1994
Exclusion criteria
- patients with malignant diseases
Participants
The age of the children ranged from 0 to 13 years (median 15) and the age of adults
ranged from 14 to 59 years old (median 44) MaleFemale ratio was 96 for children and
4344 for adults
- UDCA group (n = 54)
Origins of liver diseases
paracetamol intoxication 1 hepatitis B 1 autoimmune hepatitis 0 biliary atresia 2
metabolic diseases 7 neonatal hepatitis 2 PBC 13 post hepatitis cirrhosis 8 PSC 3
cryptogenic cirrhosis 7 alcoholic cirrhosis 2 other reasons 8
- Placebo group (n = 48)
Origins of liver diseases paracetamol intoxication 1 hepatitis B 0 autoimmune hepatitis
1 biliary atresia 3 metabolic diseases 11 neonatal hepatitis 0 PBC 7 post hepatitis
cirrhosis 5 PSC 7 cryptogenic cirrhosis 2 alcoholic cirrhosis 6 other reasons 5
Interventions UDCA group
- Dose 15 mgkg body weightday in two or three divided doses
- Route orally
- Duration immediately after intestinal transit recovery usually between postoperative
days three and five and continue for three months
Placebo group
- Identical-appearing capsules administered in the same quantity and manner
Co-interventions all patients received standard triple-drug regimens (steroids azathio-
prine and cyclosporine or tacrolimus)
24Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Keiding 1997 (Continued)
Outcomes All cause mortality
Number of deaths related to rejection
Number of patients with acute cellular rejection
Number of patients with chronic rejection
Number of patients with steroid-resistant rejection
Adverse events
Notes Letter was sent to the authors in September 2009 No reply was received
Risk of bias
Item Authorsrsquo judgement Description
Adequate sequence generation Unclear Patients were randomised at a ratio of 11
Allocation concealment Yes Quote ldquo The allocation was performed in
blocks of 10 patients using the sealed serial
envelope methodrdquo
Blinding Yes Quote ldquoThe UDCA and the placebo cap-
sules had identical appearance and tasterdquo
Incomplete outcome data addressed
All outcomes
Yes Follow-up time 12 months Five UDCA
patients and five placebo patients withdrew
from study Reasons were reported
Free of selective reporting Unclear Insufficient information
Sample size calculation Yes Performed and allowed for a difference in
the incidence of at least one episode of
acute rejection of 50 between the treat-
ment and placebo groups with 90 statisti-
cal power and a significance level of P value
less than 005 The calculated sample size
was 80 patients
Intention-to-treat analysis Yes Stated and used
Baseline imbalance Yes The study seems to be free of baseline im-
balance
Early stopping of trial Yes Study attained the pre-specified sample
size
25Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Koneru 1993
Methods Study design randomised controlled trial
Participants Country United States
Publication language English
Inclusion criteria
- patients who underwent liver transplantation
Exclusion criteria
- not mentioned
Participants
- UDCA group (n = 16)
Mean age (years +- SD)
no information
Ratio of sex (malefemale) no information
Origins of liver diseases
no information
- Control group (n = 16)
Mean age (years +- SD)
no information
Ratio of sex (malefemale) no information
Origins of liver diseases
no information
Interventions UDCA group
- Dose 900 mgday
- Route orally
- Duration immediately after intestinal transit recovery usually between postoperative
days three and five and continue for three months
Control group
- no treatment
Co-interventions all patients received standard triple-drug regimens (steroids azathio-
prine and cyclosporine)
Outcomes Number of patients with retransplantation due to rejection
Number of patients with rejection episodes
Notes Abstract
Letter was sent to the authors in September 2009 No reply was received
Risk of bias
Item Authorsrsquo judgement Description
Adequate sequence generation Unclear No information provided
Allocation concealment Unclear No information provided
Blinding No Not performed
26Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Koneru 1993 (Continued)
Incomplete outcome data addressed
All outcomes
Unclear The study gives the impression that there
were no withdrawals but this was not ex-
plicitly stated
Free of selective reporting Unclear Insufficient information provided
Sample size calculation No Not performed
Intention-to-treat analysis Unclear No information provided
Baseline imbalance Unclear Not enough information provided
Early stopping of trial Unclear Not enough information provided
Pageaux 1995
Methods Study design double-blind randomised study
Participants Country France
Publication language English
Inclusion criteria
- patients who underwent liver transplantation
Exclusion criteria
- not mentioned
Participants
- UDCA group (n=26)
Mean age (years +- SD)
47 +- 10
Ratio of sex (malefemale) 179
Origins of liver diseases alcoholic cirrhosis 14
post-hepatic B cirrhosis 2
post-hepatitis C cirrhosis 4
PBC 2
liver cancer 2
fulminant hepatitis 1
miscellaneous 1
- Placebo group (n = 24)
Mean age (years +- SD)
51+- 9
Ratio of sex (malefemale) 159
Origins of liver diseases alcoholic cirrhosis 10
post-hepatic B cirrhosis 0
post-hepatic C cirrhosis 6
PBC 3
liver cancer 4
fulminant hepatitis 0
miscellaneous 1
27Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Pageaux 1995 (Continued)
Interventions UDCA group
- Dose 600 mgday in three divided doses
- Route orally
- Duration immediately after intestinal transit recovery usually between postoperative
days three and five and continue for two months
Placebo group
- identical-appearing capsules administered in the same quantity and manner
Co-interventions all patients received standard triple-drug regimens (steroids azathio-
prine and cyclosporine or tacrolimus)
Outcomes Number of patients with acute cellular rejection
Number of patients with steroid-resistant rejection
Notes Letter was sent to the authors in September 2009 No reply was received
Risk of bias
Item Authorsrsquo judgement Description
Adequate sequence generation Unclear No information provided
Allocation concealment Unclear No information provided
Blinding Unclear Method of blinding not described
Incomplete outcome data addressed
All outcomes
Yes Five patients died from non-immunologi-
cal causes before the end of the first month
and were excluded from the study Reasons
were reported
Free of selective reporting Unclear Not enough information provided
Sample size calculation No Not performed
Intention-to-treat analysis No Not stated and not used
Baseline imbalance Unclear Not enough information provided
Early stopping of trial Unclear Not enough information provided
Sama 1991
Methods Study design randomised controlled trial
Participants Country Italy
Publication language English
Inclusion criteria
28Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Sama 1991 (Continued)
- patients who underwent liver transplantation
Exclusion criteria
- not mentioned
Participants
- UDCA group (n = 20)
Mean age (years +- SD)
no information
Ratio of sex (malefemale) no information
Origins of liver diseases
no information
- Control group (n = 20)
Mean age (years +- SD)
no information
Ratio of sex (malefemale) no information
Origins of liver diseases
no information
Interventions UDCA group
- Dose 600 mgday in two divided doses
- Route orally
- Duration immediately after intestinal transit recovery usually between postoperative
day five and day seven and continue for six months
Control group
- no treatment
Co-interventions all patients received standard immunosuppressive treatment (steroids
and cyclosporine)
Outcomes All cause mortality
Number of patients with acute cellular rejection
Notes Abstract
Letter was sent to the authors in September 2009 No reply was received
Risk of bias
Item Authorsrsquo judgement Description
Adequate sequence generation Unclear A randomisation list was performed before
patients were admitted to the trial (infor-
mation from principal author)
Allocation concealment Unclear No information provided
Blinding Unclear The principle author provided information
that the study was made according to a
single-blind randomised protocol The pri-
mary outcome was the occurrence of biopsy
proven rejection episodes The pathologists
were blind but the patients were not
29Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Sama 1991 (Continued)
Incomplete outcome data addressed
All outcomes
Unclear Five patients from the UDCA group and
six patients from the placebo group were
excluded Reasons for exclusion were not
fully stated
Free of selective reporting No Data about survival of patients were not
adequately reported
Sample size calculation No Not performed
Intention-to-treat analysis No Not stated and not used
Baseline imbalance Unclear Basic characteristics of patients not re-
ported
Early stopping of trial Unclear Not enough information provided
UDCA = ursodeoxycholic acid
TUDCA = tauroursodeoxycholic acid
PBC = primary biliary cirrhosis
PSC = primary sclerosing cholangitis
OKT3 = anti-CD3 monoclonal antibody
Characteristics of excluded studies [ordered by study ID]
Assy 2007 A randomised controlled trial that included only recipients of liver transplantation with stable graft function and
no episodes of rejection for at least 2 years that were then offered total immunosuppression withdrawal Fourteen
patients received UDCA (15 mgkg body weightday) and 12 received placebo Rejection occurred in 43 and
75 of patients respectively (no significant difference) None developed chronic rejection After follow-up two
patients were free of immunosuppression 80 were steroid free and 50 were able to reduce their dose of
cyclosporine
Clavien 1996 Case series Fifty consecutive liver-transplanted patients were treated with a standard cyclosporine immunosup-
pressive regimen Twenty three of the 43 survivors developed an episode of rejection and UDCA (10 mgkg
weightday) was initiated Only one patient had a second episode of rejection
Friman 1992 Observational study Thirty-three liver-transplanted patients received 10 mg UDCAkg body weightday for
median of 10 months (range four to 21 months) Eight historical liver-transplanted patients served as control
group The rejection incidence was significantly lower in the patients who received the treatment with UDCA
Biochemistry one month after transplantation demonstrated significantly lower average values of aminotrans-
ferases and alkaline phosphatases in patients treated with UDCA than in the control group
30Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
Heathcote 1999 Observational study From 1987 to 1996 37 UDCA treated and 53 placebo treated patients with primary biliary
cirrhosis were referred for transplantation Posttransplantation survival rates at one month were 939 in the
UDCA group and 884 in the placebo group and one year survival rates were 903 and 784 respectively
(no significant differences) However rejection (type not defined - a secondary outcome measure) occurred
significantly less often in the UDCA group (429) than in placebo group (688)
Henriksson 1991 Observational study All patients in this study were given sequential quadruple immunosuppression with anti-
lymphocyte globulin azathioprine steroids and cyclosporine All patients with primary graft function (n = 11)
were treated with 10 mg UDCAkg body weightday starting during the first postoperative week Patients who
received liver transplantation in the first 6 months of 1989 (n = 8) served as controls In the control group one
patient died after 9 months with chronic graft dysfunction and six patients had rejection episodes during the
first postoperative month All patients in the UDCA group were alive without rejection episodes
Persson 1990 Observational study All 11 adult patients transplanted between August 1989 and January 1990 with primary
graft function were treated with 10 mg UDCA kg body weightday Eight patients transplanted during the first
half of 1989 served as control UDCA was started during the first postoperative week and the treatment was
continued for six months All patients in the UDCA treated group survived with satisfactory graft function In
the control group six patients had at least one rejection episode needing treatment during the first postoperative
month
Rafael 1995 Observational study Seventeen patients who underwent liver transplantation between February 1990 and April
1993 and developed biliary complications after transplantation were retrospectively analysed regarding treatment
with UDCA UDCA was given in a dose of 500 to 1000 mgday Ten patients were treated for at least one year while
seven patients were treated for 14 to 250 days UDCA significantly improved gammaglutamyl transpeptidase in
liver graft recipients with biliary complications There was also a trend towards improvement in serum bilirubin
and alanine transaminase values
Sama 1998 Observational study Thirty-four patients who underwent liver transplantation between January 1995 and June
1996 were included in the study Seventeen were treated with UDCA 10 mgkg body weightday during 6
months while 17 served as controls on the basis of having undergone liver transplantation closest to UDCA
patients A significant decrease in serum bilirubin levels was observed in UDCA patients There was a significantly
higher incidence of recurrent hepatitis in the control group
UDCA ursodeoxycholic acid
31Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
D A T A A N D A N A L Y S E S
Comparison 1 Bile acids for liver-transplanted patients
Outcome or subgroup titleNo of
studies
No of
participants Statistical method Effect size
1 All-cause mortality at maximum
follow-up
5 257 Risk Ratio (M-H Fixed 95 CI) 085 [053 136]
11 UDCA versus placebo or
no treatment
4 224 Risk Ratio (M-H Fixed 95 CI) 080 [049 130]
12 TUDCA versus no
treatment
1 33 Risk Ratio (M-H Fixed 95 CI) 159 [030 833]
2 All-cause mortality worst-best
case and best-worst case
scenarios
5 Risk Ratio (M-H Fixed 95 CI) Subtotals only
21 Worst-best case scenario 5 257 Risk Ratio (M-H Fixed 95 CI) 130 [086 196]
22 Best-worst case scenario 5 257 Risk Ratio (M-H Fixed 95 CI) 058 [038 090]
3 Subgroup analyses all-cause
mortality at maximum
follow-up according to time of
start of bile acids
5 257 Risk Ratio (M-H Fixed 95 CI) 085 [053 136]
31 Less than three days after
transplantation
1 102 Risk Ratio (M-H Fixed 95 CI) 124 [061 254]
32 Three days or more after
transplantation
4 155 Risk Ratio (M-H Fixed 95 CI) 063 [033 120]
4 Subgroup analyses all cause
mortality at maximum
follow-up according to
treatment duration
5 257 Risk Ratio (M-H Fixed 95 CI) 085 [053 136]
41 Less than six months 3 184 Risk Ratio (M-H Fixed 95 CI) 078 [045 138]
42 Six months or more 2 73 Risk Ratio (M-H Fixed 95 CI) 102 [043 240]
5 Number of deaths related
to rejection at maximum
follow-up
1 102 Risk Ratio (M-H Fixed 95 CI) 030 [001 712]
51 UDCA versus placebo 1 102 Risk Ratio (M-H Fixed 95 CI) 030 [001 712]
6 Number of retransplantations at
maximum follow-up
2 132 Risk Ratio (M-H Fixed 95 CI) 076 [020 286]
7 Number of patients with acute
cellular rejection at maximum
follow-up
7 339 Risk Ratio (M-H Fixed 95 CI) 089 [074 106]
71 UDCA versus placebo or
no treatment
6 306 Risk Ratio (M-H Fixed 95 CI) 089 [074 108]
72 TUDCA versus no
treatment
1 33 Risk Ratio (M-H Fixed 95 CI) 085 [045 160]
8 Subgroup analysis number of
patients with acute cellular
rejection according to time of
start of bile acid
7 339 Risk Ratio (M-H Fixed 95 CI) 089 [074 106]
32Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
81 Less than three days after
transplantation
2 134 Risk Ratio (M-H Fixed 95 CI) 084 [063 111]
82 Three days or more after
liver transplantation
5 205 Risk Ratio (M-H Fixed 95 CI) 092 [072 117]
9 Subgroup analysis number
of patients with acute
cellular rejection according to
treatment duration
7 339 Risk Ratio (M-H Fixed 95 CI) 089 [074 106]
91 Less than six months 5 266 Risk Ratio (M-H Fixed 95 CI) 087 [071 107]
92 Six months or more 2 73 Risk Ratio (M-H Fixed 95 CI) 094 [065 136]
10 Number of patients with
chronic rejection at maximum
follow-up
3 184 Risk Ratio (M-H Fixed 95 CI) 028 [008 095]
11 Number of patients with
steroid-resistant rejection at
maximum follow-up
4 234 Risk Ratio (M-H Fixed 95 CI) 077 [047 127]
12 Serum bilirubin (mgdl) at the
end of treatment
1 30 Mean Difference (IV Fixed 95 CI) 26 [-096 616]
13 Number of days of
hospitalisation after liver
transplantation
1 52 Mean Difference (IV Fixed 95 CI) -85 [-1667 -033]
14 Adverse events 3 187 Risk Ratio (M-H Fixed 95 CI) 088 [030 260]
Analysis 11 Comparison 1 Bile acids for liver-transplanted patients Outcome 1 All-cause mortality at
maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 1 All-cause mortality at maximum follow-up
Study or subgroup Favours bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 UDCA versus placebo or no treatment
Barnes 1997 228 724 253 024 [ 006 107 ]
Fleckenstein 1998 214 416 125 057 [ 012 266 ]
Keiding 1997 1454 1048 355 124 [ 061 254 ]
Sama 1991 520 620 201 083 [ 030 229 ]
Subtotal (95 CI) 116 108 935 080 [ 049 130 ]
Total events 23 (Favours bile acids) 27 (Control)
Heterogeneity Chi2 = 416 df = 3 (P = 025) I2 =28
Test for overall effect Z = 091 (P = 036)
01 02 05 1 2 5 10
Favours bile acids Favours control
(Continued )
33Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Favours bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
2 TUDCA versus no treatment
Angelico 1999 316 217 65 159 [ 030 833 ]
Subtotal (95 CI) 16 17 65 159 [ 030 833 ]
Total events 3 (Favours bile acids) 2 (Control)
Heterogeneity not applicable
Test for overall effect Z = 055 (P = 058)
Total (95 CI) 132 125 1000 085 [ 053 136 ]
Total events 26 (Favours bile acids) 29 (Control)
Heterogeneity Chi2 = 466 df = 4 (P = 032) I2 =14
Test for overall effect Z = 069 (P = 049)
01 02 05 1 2 5 10
Favours bile acids Favours control
Analysis 12 Comparison 1 Bile acids for liver-transplanted patients Outcome 2 All-cause mortality worst-
best case and best-worst case scenarios
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 2 All-cause mortality worst-best case and best-worst case scenarios
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 Worst-best case scenario
Angelico 1999 516 217 65 266 [ 060 1180 ]
Barnes 1997 828 724 253 098 [ 042 230 ]
Fleckenstein 1998 314 416 125 086 [ 023 319 ]
Keiding 1997 1954 1048 355 169 [ 087 327 ]
Sama 1991 520 620 201 083 [ 030 229 ]
Subtotal (95 CI) 132 125 1000 130 [ 086 196 ]
Total events 40 (Bile acids) 29 (Control)
Heterogeneity Chi2 = 303 df = 4 (P = 055) I2 =00
Test for overall effect Z = 123 (P = 022)
2 Best-worst case scenario
005 02 1 5 20
Favours bile acids Favours control
(Continued )
34Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Angelico 1999 316 417 90 080 [ 021 302 ]
Barnes 1997 228 1124 274 016 [ 004 063 ]
Fleckenstein 1998 214 616 130 038 [ 009 159 ]
Keiding 1997 1454 1548 368 083 [ 045 154 ]
Sama 1991 520 620 139 083 [ 030 229 ]
Subtotal (95 CI) 132 125 1000 058 [ 038 090 ]
Total events 26 (Bile acids) 42 (Control)
Heterogeneity Chi2 = 567 df = 4 (P = 023) I2 =29
Test for overall effect Z = 247 (P = 0014)
005 02 1 5 20
Favours bile acids Favours control
Analysis 13 Comparison 1 Bile acids for liver-transplanted patients Outcome 3 Subgroup analyses all-
cause mortality at maximum follow-up according to time of start of bile acids
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 3 Subgroup analyses all-cause mortality at maximum follow-up according to time of start of bile acids
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 Less than three days after transplantation
Keiding 1997 1454 1048 355 124 [ 061 254 ]
Subtotal (95 CI) 54 48 355 124 [ 061 254 ]
Total events 14 (Bile acids) 10 (Control)
Heterogeneity not applicable
Test for overall effect Z = 060 (P = 055)
2 Three days or more after transplantation
Angelico 1999 316 217 65 159 [ 030 833 ]
Barnes 1997 228 724 253 024 [ 006 107 ]
Fleckenstein 1998 214 416 125 057 [ 012 266 ]
Sama 1991 520 620 201 083 [ 030 229 ]
005 02 1 5 20
Favours bile acids Favours control
(Continued )
35Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Subtotal (95 CI) 78 77 645 063 [ 033 120 ]
Total events 12 (Bile acids) 19 (Control)
Heterogeneity Chi2 = 310 df = 3 (P = 038) I2 =3
Test for overall effect Z = 141 (P = 016)
Total (95 CI) 132 125 1000 085 [ 053 136 ]
Total events 26 (Bile acids) 29 (Control)
Heterogeneity Chi2 = 466 df = 4 (P = 032) I2 =14
Test for overall effect Z = 069 (P = 049)
005 02 1 5 20
Favours bile acids Favours control
Analysis 14 Comparison 1 Bile acids for liver-transplanted patients Outcome 4 Subgroup analyses all
cause mortality at maximum follow-up according to treatment duration
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 4 Subgroup analyses all cause mortality at maximum follow-up according to treatment duration
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 Less than six months
Barnes 1997 228 724 253 024 [ 006 107 ]
Fleckenstein 1998 214 416 125 057 [ 012 266 ]
Keiding 1997 1454 1048 355 124 [ 061 254 ]
Subtotal (95 CI) 96 88 734 078 [ 045 138 ]
Total events 18 (Bile acids) 21 (Control)
Heterogeneity Chi2 = 417 df = 2 (P = 012) I2 =52
Test for overall effect Z = 084 (P = 040)
2 Six months or more
Angelico 1999 316 217 65 159 [ 030 833 ]
Sama 1991 520 620 201 083 [ 030 229 ]
Subtotal (95 CI) 36 37 266 102 [ 043 240 ]
Total events 8 (Bile acids) 8 (Control)
Heterogeneity Chi2 = 043 df = 1 (P = 051) I2 =00
005 02 1 5 20
Favours bile acids Favours control
(Continued )
36Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Test for overall effect Z = 004 (P = 097)
Total (95 CI) 132 125 1000 085 [ 053 136 ]
Total events 26 (Bile acids) 29 (Control)
Heterogeneity Chi2 = 466 df = 4 (P = 032) I2 =14
Test for overall effect Z = 069 (P = 049)
005 02 1 5 20
Favours bile acids Favours control
Analysis 15 Comparison 1 Bile acids for liver-transplanted patients Outcome 5 Number of deaths related
to rejection at maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 5 Number of deaths related to rejection at maximum follow-up
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 UDCA versus placebo
Keiding 1997 054 148 1000 030 [ 001 712 ]
Total (95 CI) 54 48 1000 030 [ 001 712 ]
Total events 0 (Bile acids) 1 (Control)
Heterogeneity not applicable
Test for overall effect Z = 075 (P = 045)
0001 001 01 1 10 100 1000
Favours bile acids Favours control
37Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 16 Comparison 1 Bile acids for liver-transplanted patients Outcome 6 Number of
retransplantations at maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 6 Number of retransplantations at maximum follow-up
Study or subgroup Bile acids Placebo Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Fleckenstein 1998 214 016 100 567 [ 029 10891 ]
Keiding 1997 154 448 900 022 [ 003 192 ]
Total (95 CI) 68 64 1000 076 [ 020 286 ]
Total events 3 (Bile acids) 4 (Placebo)
Heterogeneity Chi2 = 303 df = 1 (P = 008) I2 =67
Test for overall effect Z = 040 (P = 069)
0001 001 01 1 10 100 1000
Favours bile acids Favours placebo
Analysis 17 Comparison 1 Bile acids for liver-transplanted patients Outcome 7 Number of patients with
acute cellular rejection at maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 7 Number of patients with acute cellular rejection at maximum follow-up
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 UDCA versus placebo or no treatment
Barnes 1997 1728 1724 180 086 [ 058 127 ]
Fleckenstein 1998 814 916 83 102 [ 054 190 ]
Keiding 1997 3554 3248 333 097 [ 073 129 ]
Koneru 1993 316 916 89 033 [ 011 101 ]
Pageaux 1995 926 924 92 092 [ 044 193 ]
Sama 1991 1320 1320 128 100 [ 063 158 ]
Subtotal (95 CI) 158 148 905 089 [ 074 108 ]
01 02 05 1 2 5 10
Favours bile acids Favours control
(Continued )
38Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Total events 85 (Bile acids) 89 (Control)
Heterogeneity Chi2 = 387 df = 5 (P = 057) I2 =00
Test for overall effect Z = 120 (P = 023)
2 TUDCA versus no treatment
Angelico 1999 816 1017 95 085 [ 045 160 ]
Subtotal (95 CI) 16 17 95 085 [ 045 160 ]
Total events 8 (Bile acids) 10 (Control)
Heterogeneity not applicable
Test for overall effect Z = 050 (P = 061)
Total (95 CI) 174 165 1000 089 [ 074 106 ]
Total events 93 (Bile acids) 99 (Control)
Heterogeneity Chi2 = 392 df = 6 (P = 069) I2 =00
Test for overall effect Z = 130 (P = 019)
01 02 05 1 2 5 10
Favours bile acids Favours control
Analysis 18 Comparison 1 Bile acids for liver-transplanted patients Outcome 8 Subgroup analysis
number of patients with acute cellular rejection according to time of start of bile acid
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 8 Subgroup analysis number of patients with acute cellular rejection according to time of start of bile acid
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 Less than three days after transplantation
Keiding 1997 3554 3248 333 097 [ 073 129 ]
Koneru 1993 316 916 89 033 [ 011 101 ]
Subtotal (95 CI) 70 64 422 084 [ 063 111 ]
Total events 38 (Bile acids) 41 (Control)
Heterogeneity Chi2 = 374 df = 1 (P = 005) I2 =73
Test for overall effect Z = 124 (P = 022)
2 Three days or more after liver transplantation
Angelico 1999 816 1017 95 085 [ 045 160 ]
01 02 05 1 2 5 10
Favours bile acids Favours control
(Continued )
39Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Barnes 1997 1728 1724 180 086 [ 058 127 ]
Fleckenstein 1998 814 916 83 102 [ 054 190 ]
Pageaux 1995 926 924 92 092 [ 044 193 ]
Sama 1991 1320 1320 128 100 [ 063 158 ]
Subtotal (95 CI) 104 101 578 092 [ 072 117 ]
Total events 55 (Bile acids) 58 (Control)
Heterogeneity Chi2 = 041 df = 4 (P = 098) I2 =00
Test for overall effect Z = 067 (P = 050)
Total (95 CI) 174 165 1000 089 [ 074 106 ]
Total events 93 (Bile acids) 99 (Control)
Heterogeneity Chi2 = 392 df = 6 (P = 069) I2 =00
Test for overall effect Z = 130 (P = 019)
01 02 05 1 2 5 10
Favours bile acids Favours control
40Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 19 Comparison 1 Bile acids for liver-transplanted patients Outcome 9 Subgroup analysis
number of patients with acute cellular rejection according to treatment duration
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 9 Subgroup analysis number of patients with acute cellular rejection according to treatment duration
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 Less than six months
Barnes 1997 1728 1724 180 086 [ 058 127 ]
Fleckenstein 1998 814 916 83 102 [ 054 190 ]
Keiding 1997 3554 3248 333 097 [ 073 129 ]
Koneru 1993 316 916 89 033 [ 011 101 ]
Pageaux 1995 926 924 92 092 [ 044 193 ]
Subtotal (95 CI) 138 128 777 087 [ 071 107 ]
Total events 72 (Bile acids) 76 (Control)
Heterogeneity Chi2 = 374 df = 4 (P = 044) I2 =00
Test for overall effect Z = 129 (P = 020)
2 Six months or more
Angelico 1999 816 1017 95 085 [ 045 160 ]
Sama 1991 1320 1320 128 100 [ 063 158 ]
Subtotal (95 CI) 36 37 223 094 [ 065 136 ]
Total events 21 (Bile acids) 23 (Control)
Heterogeneity Chi2 = 017 df = 1 (P = 068) I2 =00
Test for overall effect Z = 035 (P = 073)
Total (95 CI) 174 165 1000 089 [ 074 106 ]
Total events 93 (Bile acids) 99 (Control)
Heterogeneity Chi2 = 392 df = 6 (P = 069) I2 =00
Test for overall effect Z = 130 (P = 019)
01 02 05 1 2 5 10
Favours bile acids Favours control
41Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 110 Comparison 1 Bile acids for liver-transplanted patients Outcome 10 Number of patients
with chronic rejection at maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 10 Number of patients with chronic rejection at maximum follow-up
Study or subgroup Bile acids Placebo Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Barnes 1997 128 624 611 014 [ 002 110 ]
Fleckenstein 1998 114 116 88 114 [ 008 1663 ]
Keiding 1997 154 348 300 030 [ 003 275 ]
Total (95 CI) 96 88 1000 028 [ 008 095 ]
Total events 3 (Bile acids) 10 (Placebo)
Heterogeneity Chi2 = 148 df = 2 (P = 048) I2 =00
Test for overall effect Z = 204 (P = 0041)
0001 001 01 1 10 100 1000
Favours bile acids Favours placebo
Analysis 111 Comparison 1 Bile acids for liver-transplanted patients Outcome 11 Number of patients
with steroid-resistant rejection at maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 11 Number of patients with steroid-resistant rejection at maximum follow-up
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Barnes 1997 328 724 277 037 [ 011 127 ]
Fleckenstein 1998 314 316 103 114 [ 027 478 ]
Keiding 1997 1454 1548 583 083 [ 045 154 ]
Pageaux 1995 226 124 38 185 [ 018 1908 ]
Total (95 CI) 122 112 1000 077 [ 047 127 ]
Total events 22 (Bile acids) 26 (Control)
Heterogeneity Chi2 = 226 df = 3 (P = 052) I2 =00
Test for overall effect Z = 102 (P = 031)
001 01 1 10 100
Favours bile acids Favours placebo
42Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 112 Comparison 1 Bile acids for liver-transplanted patients Outcome 12 Serum bilirubin (mgdl)
at the end of treatment
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 12 Serum bilirubin (mgdl) at the end of treatment
Study or subgroup Bile acids Placebo Mean Difference Weight Mean Difference
N Mean(SD) N Mean(SD) IVFixed95 CI IVFixed95 CI
Fleckenstein 1998 14 319 (68) 16 059 (022) 1000 260 [ -096 616 ]
Total (95 CI) 14 16 1000 260 [ -096 616 ]
Heterogeneity not applicable
Test for overall effect Z = 143 (P = 015)
-10 -5 0 5 10
Favours bile acids Favours placebo
Analysis 113 Comparison 1 Bile acids for liver-transplanted patients Outcome 13 Number of days of
hospitalisation after liver transplantation
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 13 Number of days of hospitalisation after liver transplantation
Study or subgroup Bile acids Placebo Mean Difference Weight Mean Difference
N Mean(SD) N Mean(SD) IVFixed95 CI IVFixed95 CI
Barnes 1997 28 25 (17) 24 335 (13) 1000 -850 [ -1667 -033 ]
Total (95 CI) 28 24 1000 -850 [ -1667 -033 ]
Heterogeneity not applicable
Test for overall effect Z = 204 (P = 0041)
-100 -50 0 50 100
Favours bile acids Favours placebo
43Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 114 Comparison 1 Bile acids for liver-transplanted patients Outcome 14 Adverse events
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 14 Adverse events
Study or subgroup Bile acids Placebo Risk Ratio Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Angelico 1999 016 017 00 [ 00 00 ]
Barnes 1997 128 124 086 [ 006 1298 ]
Keiding 1997 554 548 089 [ 027 288 ]
Total (95 CI) 98 89 088 [ 030 260 ]
Total events 6 (Bile acids) 6 (Placebo)
Heterogeneity Chi2 = 000 df = 1 (P = 098) I2 =00
Test for overall effect Z = 022 (P = 082)
001 01 1 10 100
Favours bile acids Favours placebo
A P P E N D I C E S
Appendix 1 Search strategies
Data Base Date of Search Search Strategy
The Cochrane Hepato-Biliary Group Con-
trolled Trials Register
September 2009 1 rsquoliver transplantationrsquo and rsquochenodeoxy-
cholicrsquo
2 rsquoliver transplantationrsquo and rsquocholicrsquo
3 rsquoliver transplantationrsquo and rsquodeoxycholicrsquo
4 rsquoliver transplantationrsquo and rsquoglycochen-
odeoxycholicrsquo
5 rsquoliver transplantationrsquo and rsquoglycocholicrsquo
6 rsquoliver transplantationrsquo and rsquoglycodeoxy-
cholicrsquo
7 rsquoliver transplantationrsquo and rsquoglycolitho-
cholicrsquo
8 rsquoliver transplantationrsquo and rsquohyodeoxy-
cholicrsquo
9 rsquoliver transplantationrsquo and rsquolithocholicrsquo
10 rsquoliver transplantationrsquo and rsquotaurochen-
odeoxycholicrsquo
44Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
11 rsquoliver transplantationrsquo and rsquotauro-
cholicrsquo
12 rsquoliver transplantationrsquo and rsquotaurodehy-
drocholicrsquo
13 rsquoliver transplantationrsquo and rsquotau-
rodeoxycholicrsquo
14 rsquoliver transplantationrsquo and rsquotauroglyco-
cholicrsquo
15 rsquoliver transplantationrsquo and rsquotaurolitho-
cholicrsquo
16 rsquoliver transplantationrsquo and rsquotaurosel-
cholicrsquo
17 rsquoliver transplantationrsquo and rsquotaurourso-
cholicrsquo
18 rsquoliver transplantationrsquo and rsquotaurour-
sodeoxycholicrsquo
19 rsquoliver transplantationrsquo and rsquoursocholicrsquo
20 rsquoliver transplantationrsquo and rsquoursodeoxy-
cholicrsquo
The Cochrane Central Register of Con-
trolled Trials in The Cochrane Library
Issue 3 2009 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
6 3 or 4
7 5 and 6
MEDLINE September 2009 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
45Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
6 3 or 4
7 5 and 6
8 RANDOMIZED-CONTROLLED-
TRIAL ME
9 RANDOM
10 8 or 9
11 7 and 10
EMBASE September 2009 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
6 3 or 4
7 5 and 6
8 RANDOMIZED-CONTROLLED-
TRIAL ME
9 RANDOM
10 8 or 9
11 7 and 10
46Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
Science Citation Index Expanded September 2009 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
6 3 or 4
7 5 and 6
8 RANDOMIZED-CONTROLLED-
TRIAL ME
9 RANDOM
10 8 or 9
11 7 and 10
The Chinese Biomedical Database Searched from January 1980 to April 2002 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
47Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
6 3 or 4
7 5 and 6
8 RANDOMIZED-CONTROLLED-
TRIAL ME
9 RANDOM
10 8 or 9
11 7 and 10
W H A T rsquo S N E W
Last assessed as up-to-date 8 February 2010
18 September 2009 New citation required but conclusions have not
changed
This review is an updated version of a review that was
published for the first time in Issue 3 2005 of TheCochrane Library by Chen 2003b
18 September 2009 New search has been performed No new studies fulfilled the inclusion criteria
H I S T O R Y
Protocol first published Issue 3 2003
Review first published Issue 3 2005
C O N T R I B U T I O N S O F A U T H O R S
GP and VG independently performed searches of relevant databases GP validated the search selected trials for inclusion contacted
the authors of the trials performed data extraction and data analysis and drafted the systematic review VG revised the review update
CG and DS revised the review update solved discrepancies of data extraction validated data analyses and provided consultation
D E C L A R A T I O N S O F I N T E R E S T
None known
48Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
S O U R C E S O F S U P P O R T
Internal sources
bull Copenhagen Trial Unit Denmark
External sources
bull Danish Medical Research Councilrsquos Grant on Getting Research into Practice (GRIP) Denmark
D I F F E R E N C E S B E T W E E N P R O T O C O L A N D R E V I E W
We assessed the risk of bias in the included studies for another four domains that were added to the review protocol (incomplete
outcome data selective outcome reporting baseline imbalance and early stopping of trial) In general the text of the risk of bias
domains were updated following Higgins 2008 Trials were considered at low risk of bias when judged as adequate in all domains
Quasi-randomised studies observational and case-control studies were included for the report of adverse events
We performed trial sequential analysis for outcomes demonstrating a statistically significant result
I N D E X T E R M S
Medical Subject Headings (MeSH)
lowastLiver Transplantation Cholagogues and Choleretics [lowasttherapeutic use] Graft Rejection [lowastprevention amp control] Randomized Con-
trolled Trials as Topic Taurochenodeoxycholic Acid [lowasttherapeutic use] Ursodeoxycholic Acid [lowasttherapeutic use]
MeSH check words
Humans
49Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
[Intervention Review]
Bile acids for liver-transplanted patients
Goran Poropat1 Vanja Giljaca1 Davor Stimac1 Christian Gluud2
1Department of Gastroenterology Clinical Hospital Centre Rijeka Rijeka Croatia 2Cochrane Hepato-Biliary Group Copenhagen
Trial Unit Centre for Clinical Intervention Research Department 3344 Rigshospitalet Copenhagen University Hospital Copenhagen
Denmark
Contact address Goran Poropat Department of Gastroenterology Clinical Hospital Centre Rijeka Kresimirova 42 Rijeka 51000
Croatia goran_poropatyahoocom
Editorial group Cochrane Hepato-Biliary Group
Publication status and date New search for studies and content updated (no change to conclusions) published in Issue 3 2010
Review content assessed as up-to-date 8 February 2010
Citation Poropat G Giljaca V Stimac D Gluud C Bile acids for liver-transplanted patients Cochrane Database of Systematic Reviews2010 Issue 3 Art No CD005442 DOI 10100214651858CD005442pub2
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
A B S T R A C T
Background
Liver transplantation has become a widely accepted form of treatment for numerous end-stage liver diseases Bile acids may decrease
allograft rejection after liver transplantation by changing the expression of major histocompatibility complex class molecules in bile
duct epithelium and central vein endothelium
Objectives
To assess the beneficial and harmful effects of bile acids for liver-transplanted patients
Search strategy
We performed searches of The Cochrane Hepato-Biliary Group Controlled Trials Register The Cochrane Central Register of ControlledTrials in The Cochrane Library MEDLINE EMBASE and Science Citation Expanded to September 2009
Selection criteria
Randomised clinical trials comparing any dose of bile acids or duration of treatment in liver-transplanted patients versus placebo no
intervention or another intervention We included randomised clinical trials irrespective of blinding language and publication status
Data collection and analysis
Two review authors extracted and checked data independently We evaluated the risk of bias of the trials from the method of allocation
sequence generation allocation concealment blinding outcome data analysis outcome data reporting and other potential sources
of bias We used the intention-to-treat principle to perform meta-analyses and presented the outcomes as relative risks (RR) or mean
differences (MD) both with 95 confidence intervals (CI)
Main results
The updated search resulted in no new trials meeting the inclusion criteria of this review thus leaving it to the seven already included
randomised trials (six evaluating ursodeoxycholic acid versus placebo or no intervention and one evaluating tauro-ursodeoxycholic
acid versus no intervention) enrolling a total of 335 participants The administration of bile acids began one day or more after liver
transplantation All patients received the standard triple-drug immunosuppressive regimen (steroids azathioprine and cyclosporine or
tacrolimus) to suppress the allograft rejection response after liver transplantation Bile acids compared with placebo or no intervention
1Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
did not significantly change all-cause mortality (RR 085 95 CI 053 to 136) mortality related to allograft rejection (RR 030
95 CI 001 to 712) retransplantation (RR 076 95 CI 020 to 286) acute cellular rejection or number of patients with steroid-
resistant rejection Bile acids significantly reduced the number of patients who had chronic rejection in a fixed-effect model but not in
a random-effects model meta-analysis Bile acids were safe and well tolerated by liver-transplanted patients However this observation
is based on data analysis from three trials with only 187 patients
Authorsrsquo conclusions
We did not find evidence to support or refute bile acids for liver-transplanted patients Further randomised trials are necessary before
bile acids can be recommended to liver-transplanted patients
P L A I N L A N G U A G E S U M M A R Y
Bile acids for liver-transplanted patients
Liver transplantation is a major surgical procedure that has been practiced for more than forty years and has nowadays become a
generally accepted treatment option in patients with end-stage liver disease The most common cause for liver transplantation in adults
is cirrhosis caused by various types of liver injuries such as infections (hepatitis B and C) alcohol autoimmune liver diseases early-
stage liver cancer metabolic and hereditary disorders but also diseases of unknown aetiology All transplant recipients need lifetime
immunosuppressive therapy to prevent transplant rejection
Bile acids are being used for a variety of chronic liver diseases mainly primary biliary cirrhosis and primary sclerosing cholangitis
However their mechanisms of action and beneficial and harmful effects are poorly understood This has led to the idea of the potential
use of bile acids to prevent rejection in liver-transplanted patients
Results of the seven randomised clinical trials included in the review in which patients received standard immunosuppressive treatment
(steroids azathioprine and cyclosporine or tacrolimus) with or without bile acids after liver transplantation did not show any significant
effects of bile acids on all-cause mortality mortality related to rejection acute cellular rejection steroid resistant rejection or need for
retransplantation One analysis suggested that bile acids might beneficially influence number of patients with chronic rejection but was
contradicted by the analyses The evidence that the use of ursodeoxycholic acid might have beneficial effects on chronic rejection and
length of hospitalisation is weak as it is produced from trials with high risk of bias and insufficient number of included patients That
bile acids seemed well tolerated with no reports of serious adverse events is good knowledge but much more research is needed before
their use is acquitted None of the randomised clinical trials assessed the effects of bile acids on quality of life or cost-effectiveness
B A C K G R O U N D
Liver transplantation has become a widely accepted treatment
for numerous end-stage liver diseases (Hussain 2002 Thalheimer
2002) Previous studies report an incidence of acute cellular rejec-
tion to range from 50 to 80 in adult recipients (Ascher 1988
Klintmalm 1989 Adams 1990 Wiesner 1992 FK506 1994)
However recent data suggest that the proportion of patients with
rejection is currently down to 30 (Hirschfield 2009 Knechtle
2009) Despite advances in immunosuppressive treatment and
care-quality of liver-transplanted patients allograft rejection is still
a major problem in the post-transplantation period
Acute cellular rejection usually occurs within the first 15 to 30 days
after transplantation even if immunosuppression is achieved with
tacrolimus or cyclosporine (FK506 1994 Haddad 2006 Corbani
2008) The cellular mechanisms of acute liver allograft rejection
are not completely understood (Krams 1993) Initiation of al-
lograft rejection is thought to involve the recognition of donor
class II major histocompatibility complex alloantigens by recipient
CD4+ T cells (Vierling 1992) Activated CD4+ T cells produce
cytokines that induce lymphocyte proliferation and the matura-
tion of CD8+ cytotoxic T cells which are specific for donor class I
major histocompatibility complex antigens (Calmus 1990) Both
the bile duct epithelium and central vein endothelium are rich in
class I and class II major histocompatibility complex antigens dur-
ing rejection whereas hepatocytes display a relative paucity of class
I antigens and virtually no class II antigen (Vierling 1992) There-
2Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
fore the bile duct epithelium and central vein endothelium are
the primary targets attacked by cytotoxic T cells during rejection
Impairment of the bile flow in the grafted liver may also cause re-
jection (Ericzon 1990) Mild cholestasis is a common finding after
liver transplantation and its association with clinically significant
pathology is unlikely Nevertheless severe cholestasis should be
treated as a potential cause of allograft rejection (Corbani 2008)
In the study by Fusai 2006 the development of cholestasis was sig-
nificantly related to prolonged warm ischaemia of the liver trans-
plant Cholestasis can induce hyper-expression of major histocom-
patibility complex class I molecules by hepatocytes and thereby
lymphocyte CD8+-dependent cytotoxicity (Calmus 1992)
Bile acids include chenodeoxycholic acid deoxycholic acid litho-
cholic acid and ursodeoxycholic acid (UDCA) (Fuchs 1999)
In the course of cholestasis intrahepatic accumulation of chen-
odeoxycholic acid and deoxycholic acid is thought to induce liver
damage (Palmer 1972) In fact the direct damage of membrane
phospholipids and cholesterol components caused by the deter-
gent-like properties of hydrophobic bile acids results in hepato-
cyte necrosis (Sholmerich 1984 Perez 2009) It is also suggested
that oxidative stress induced by hydrophobic bile acids plays an
important role in liver damage during cholestasis These effects
can be prevented by the addition of UDCA which modifies the
bile acid pool resulting in an increase of the hydrophilic frac-
tion and stabilisation of the cell membranes (Armstrong 1982
Perez 2009) Several studies on animal models showed evidence
of potential immunomodulatory beneficial effects of UDCA and
tauro-ursodeoxycholic acid (TUDCA) by suppressing cytokine
and immunoglobulin production and T-cell mediated cytotoxic-
ity (Yoshikawa 1998) In the study by Calmus 1990 it has been
observed that UDCA down-regulates the expression of abnormal
major histocompatibility complex class I molecules in periportal
hepatocytes in patients with primary biliary cirrhosis Treatment
with UDCA has been reported to have potential beneficial ef-
fects in various cholestatic liver conditions including primary bil-
iary cirrhosis (Gong 2008) primary sclerosing cholangitis (Chen
2003a) and cystic fibrosis (Cheng 2002)
It has previously been suggested that UDCA and perhaps tauro-
UDCA (TUDCA) may reduce the incidence of acute rejection
and steroid-resistant rejection in liver-transplanted patients when
administered with combination of immunosuppressive treatment
There are several potential mechanisms by which UDCA may in-
hibit allograft rejection in liver transplant recipients (Okolicsanyi
1986 Merion 1989 Calmus 1990 Terasaki 1991 Heuman 1993
Al-Quaiz 1994 Friman 1994 Soderdahl 1998 Yoshikawa 1998
Assy 2007 Perez 2009) However most of these studies included
a relatively small number of patients were not randomised and
often did not include histological information (Persson 1990
Friman 1992 Koneru 1993 Sharara 1995)
The previous version of this review by Chen 2003b stated that
there was no convincing beneficial effects from the use of bile acids
in liver-transplanted patients the risk of bias in the seven included
trials was high The review also found that there was a low occur-
rence of adverse events and hence the use of bile acids could be
considered safe It should be noted however that this observation
is based on reports from four trials with few patients We have
been unable to identify any other meta-analyses or systematic re-
views either This review represents an update of the Chen 2003b
Cochrane hepato-Biliary Group review
O B J E C T I V E S
To evaluate the beneficial and harmful effects of bile acids for liver-
transplanted patients by comparing bile acids versus placebo no
intervention or another intervention in randomised clinical trials
M E T H O D S
Criteria for considering studies for this review
Types of studies
We included randomised clinical trials irrespective of blinding
publication status year of publication or language We assessed
both included and excluded studies for the report of adverse events
We listed all studies reporting on adverse events in an additional
table (Table 1) However only data from the included trials were
used in the statistical analysis
Table 1 Adverse events
Study Pts in experimental
group
Patients in control
group
AE in experimental
group
AE in control group Authorrsquos conclusion
Barnes 1997 28 24 Diarrhoea (1 pt) Diarrhoea (1 pt) Adverse
reactions attributable
to study medication
were rare
3Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Table 1 Adverse events (Continued)
Keiding 1997 54 48 Diarrhoea and diffi-
culties in swallowing
capsules (5 pts)
Diarrhoea and diffi-
culties in swallowing
capsules (5 pts)
No other presumed
drug-induced side ef-
fects were observed
Angelico 1999 16 17 No AE No AE TUDCA administra-
tion was well tol-
erated in all pa-
tients and no drug-
related side effects
were recorded
Assy 2007 14 12 Mild diarrhoea (1 pt) No AE No dose reduction
was required
pt(s) = patient(s)
AE = adverse events
Types of participants
Patients who underwent liver transplantation
Types of interventions
Any dose of a bile acid or duration of treatment versus placebo
no intervention or another intervention
We allowed co-interventions if received equally by the intervention
groups within a trial
Types of outcome measures
The primary outcome measures were
1 All-cause mortality
2 Death due to allograft rejection (acute cellular rejection or
chronic rejection or liver retransplantation because of rejection)
Acute cellular rejection was diagnosed by the combination of ab-
normal liver biochemical variables (bilirubin aspartate transam-
inase alanine transaminase alkaline phosphatases andor gam-
maglutamyl transpeptidase) clinical signs such as fever and liver
histological changes including mononuclear portal inflammation
bile duct damage and subendothelial inflammation of portal or
terminal hepatic veins (IWP 1995) Chronic rejection was charac-
terised by liver histological changes including the progressive loss
of interlobular bile ducts and arteriopathy characterised by foam
cell infiltration of the arterial intima
The secondary outcome measures were
3 Number of patients who experienced rejection - irrespective of
the type acute cellular rejection chronic rejection or both types
of rejections
4 Number of patients with acute cellular rejection
5 Number of patients with chronic rejection
6 Number of patients with steroid-resistant rejection
7 Biochemical responses serum activities of alkaline phos-
phatases gammaglutamyl transpeptidase alanine aminotrans-
ferase and aspartate aminotransferase and serum bilirubin con-
centration andor number of patients with abnormal liver bio-
chemical variables mentioned above
8 Adverse events Adverse events were defined as any untoward
medical occurrence not necessarily having a causal relationship
with the treatment but resulting in a dose reduction or discontin-
uation of treatment (ICH-GCP 1997)
9 Quality of life
10 Cost-effectiveness
Search methods for identification of studies
We performed searches of The Cochrane Hepato-Biliary GroupControlled Trials Register (September 2009)(Gluud 2010) and TheCochrane Central Register of Controlled Trials (CENTRAL) in TheCochrane Library (Issue 3 2009) by combining the terms rsquoliverrsquo
and rsquotransplantationrsquo with the individual bile acid name (litho-
cholic acid chenodeoxycholic acid ursodeoxycholic acid deoxy-
cholic acid dehydrocholic acid and tauro-ursodeoxycholic acid)
We searched MEDLINE (January 1966 to September 2009) EM-BASE (January 1980 to September 2009) and Science Citation In-dex Expanded (1945 to September 2009) by using the terms rsquoliverrsquo
4Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
and rsquotransplantationrsquo in combination with the bile acids mentioned
above (Royle 2003) The search strategies with the time span of
the searches are given in Appendix 1 We contacted the Chinese
Cochrane Centre regarding the search of The Chinese BiomedicalDatabase and received a reply that they are unable to help us with
this search Therefore the latter database could not be included
in the search strategy of this update
Further trials were identified by reading the reference lists of the
identified studies We wrote to the principal authors of the reports
of the identified randomised clinical trials in September 2009 and
enquired about additional trials which they might know of The
first team of authors had also written to pharmaceutical companies
involved in the production of bile acids to obtain information on
published or unpublished randomised clinical trials in 2002 but
no information had been received at that time
Data collection and analysis
The update of this review was conducted according to the proto-
col previously published in The Cochrane Library (Chen 2003b)
and following the recommendations given by the Cochrane Hand-book for Systematic Reviews of Interventions (Higgins 2008) and the
Cochrane Hepato-Biliary Group Module (Gluud 2010)
Trial identification
Identified trials were listed and the two review authors evaluated
whether the trials fulfilled the inclusion criteria Excluded trials
were listed with the reasons for exclusion
Data extraction
GP and VG extracted the data independently and disagreements
were resolved by discussion or by CG We extracted the following
characteristics from each trial primary author number of patients
randomised patient inclusion and exclusion criteria methodolog-
ical quality follow-up (number and reasons for withdrawal) sam-
ple size calculation intention-to-treat analysis intervention reg-
imens mean age proportion of males and females aetiology of
liver disease origin of allograft matching criteria between donor
and recipient time to follow-up number of outcomes and num-
ber and type of adverse events in both the intervention and the
control groups Additional information was sought by correspon-
dence with the principal investigator or co-investigators of the trial
in cases where the relevant data were not published
Assessment of risk of bias
Risk of bias was defined as the confidence that the study design and
reporting restricted bias in the intervention comparison (Schulz
1995 Moher 1998 Kjaergard 2001 Wood 2008) Due to the risk
of overestimation of intervention effects in randomised trials with
unclear or inadequate components we assessed the risk of bias by
separate domains
Allocation sequence generation
bull Adequate if the allocation sequence was generated by a
computer or random number table Drawing of lots tossing of a
coin shuffling of cards or throwing dice was considered as
adequate if a person who was not otherwise involved in the
recruitment of participants performed the procedure
bull Unclear if the trial was described as randomised but the
method used for the allocation sequence generation was not
described
bull Inadequate if a system involving dates names or
admittance numbers were used for the allocation of patients
Such quasi-randomised studies were excluded
Allocation concealment
bull Adequate if the allocation of patients involved a central
independent unit on-site locked computer identically appearing
numbered drug bottles or containers prepared by an
independent pharmacist or investigator or serially numbered
sealed and opaque envelopes
bull Unclear if the trial was described as randomised but the
method used to conceal the allocation was not described
bull Inadequate if the allocation sequence was known to the
investigators who assigned participants or if the study was quasi-
randomised The latter studies were excluded
Blinding
bull Adequate the trial was described as blinded the parties that
were blinded and the method of blinding was described so that
knowledge of allocation was adequately prevented during the
trial
bull Unclear the trial was described as double blind but the
method of blinding was not described so that knowledge of
allocation was possible during the trial
bull Not performed the trial was not blinded so that the
allocation was known during the trial
Incomplete outcome data
bull Adequate if the numbers and reasons for dropouts and
withdrawals in all intervention groups were described or if it was
specified that there were no dropouts or withdrawals
bull Unclear if the report gave the impression that there had
been no dropouts or withdrawals but this was not specifically
stated
bull Inadequate if the number or reasons for dropouts and
withdrawals were not described
Selective outcome reporting
bull Adequate if study protocol is available and all pre-specified
outcomes are reported in the manuscript or if the study protocol
is not available but it is clear that the report includes all expected
outcomes
bull Unclear if there are no sufficient information to permit
judgement
bull Inadequate if not all of the pre-specified outcomes were
reported andor were reported incompletely or one or more
reported outcomes were not pre-specified
Baseline imbalance
5Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
bull Adequate if there is no baseline imbalance in the main
characteristics
bull Unclear if there is no sufficient information to assess
baseline characteristics
bull Inadequate if there was a baseline imbalance due to chance
or due to imbalanced exclusion after randomisation
Early stopping
bull Adequate if sample size calculation was reported and the
trial was not stopped or the trial was stopped early by formal
stopping rules at a point where the likelihood of observing an
extreme intervention effect due to chance was low
bull Unclear if sample size calculation was not reported and it is
not clear whether the trial was stopped early or not
bull Inadequate if the trial was stopped early due to informal
stopping rules or the trial was stopped early by a formal stopping
rule at a point where the likelihood of observing an extreme
intervention effect due to chance was high
Furthermore we registered whether the randomised clinical trials
had used an intention-to-treat analysis (Gluud 2001) and had
calculated a sample size estimate
Statistical methods
We performed the analyses in RevMan 5 (RevMan 2008) Anal-
yses included all patients irrespective of compliance or follow-up
according to the intention-to-treat principle and using the last
reported observed response (rsquocarry forwardrsquo) Regarding death
both a worst-best-case scenario analysis considering all dropped-
out patients in the bile acid group as dead and the dropped-out
patients in the control group as alive and a best-worst-case sce-
nario analysis considering all dropped-out patients in the bile acid
group as alive and the dropped-out patients in the control group as
dead were performed Both a random-effects model (DerSimonian
1986) and a fixed-effect model (DeMets 1987) were used The re-
sults of the fixed-effect model were reported if there were no differ-
ences between the results produced by the two models otherwise
we reported the results produced by both models We presented
binary outcome measures as relative risks (RR) with 95 confi-
dence intervals (CI) and continuous outcome measures as mean
differences (MD) with 95 CI
The risk of type I errors increases in single trials with interim anal-
yses To avoid type I errors group sequential monitoring bound-
aries (Lan 1983) can be performed when deciding to terminate the
trial earlier than planned This requires analyses at different time
intervals to record when the P-value has become sufficiently small
that is when the cumulative Z-curve will cross the monitoring
boundaries Sequential monitoring boundaries the so called rsquotrial
sequential monitoring boundariesrsquo can also be applied to meta-
analyses In a trial sequential analysis (TSA) every trial that is
added in a cumulative meta-analysis is regarded as an interim meta-
analysis and the information it adds on helps on deciding if more
trials need to be included
The interpretation of the TSA is as follows if the cumulative Z-
curve has crossed the boundary a sufficient level of evidence is
reached and no further trials may be needed If the Z-curve has
not crossed the boundary then the evidence is insufficient in order
to reach a conclusion To construct the trial sequential monitor-
ing boundaries information size is needed It is calculated as the
minimum number of participants needed in a well-powered single
trial (Pogue 1997 Pogue 1998 Brok 2008 Wetterslev 2008) We
applied TSA since it prevents an increase of the risk of type I error
due to sparse and multiple updating in a cumulative meta-analysis
and provides us with important information in order to estimate
the level of evidence of the experimental intervention Addition-
ally TSA provides us with important information regarding the
need for additional trials and the required information size We
applied trial sequential monitoring boundaries according to an in-
formation size suggested by the trials with low risk of bias and a
50 relative risk reduction (RRR)
Subgroup analyses
We planned to perform the following subgroup analyses on the
main outcome measures (all-cause mortality and number of pa-
tients with acute rejection)
1 Risk of bias of the trials comparing the intervention effect for
trials with low risk of bias components to the intervention effect
in trials with unclear or high risk of bias components
2 Dose and duration of treatment with bile acids comparing the
intervention effect in trials administrating bile acid at or above the
median dose multiplied by duration to the intervention effect of
trials administrating bile acid at less than the median dose multi-
plied by duration
3 Time between transplantation and the start of bile acids com-
paring the intervention effect of trials having less than three days
between transplantation and starting bile acid intake to the inter-
vention effect of trials with a duration of three days or more be-
tween transplantation and the start of bile acid intake (Neuberger
1999)
4 Co-interventions comparing the intervention effect of trials
with co-interventions to the intervention effect of trials without
co-interventions
Funnel plot analysis
We planned to explore bias by funnel plot analysis (Egger 1997)
R E S U L T S
Description of studies
See Characteristics of included studies Characteristics of excluded
studies
The performed electronic searches resulted in a total of 378 ref-
erences We excluded 362 duplicates or irrelevant references by
reading abstracts We excluded eight of the 16 further assessed ref-
erences because they were observational studies case series or ran-
6Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
domised clinical trials with a different reason for exclusion They
are listed under rsquoCharacteristic of excluded studiesrsquo with reasons
for exclusion Seven references already included in the previous
version of this review and one new reference referring to an al-
ready included trial (Barnes 1997) were included in this review
We were not able to identify more trials by reading the reference
lists of the identified studies contacting the principle authors of
the identified trials or approaching pharmaceutical companies for
unpublished trials
Seven publications included in the review (five full publications
and two abstracts) were randomised clinical trials that reported
the random allocation of liver-transplanted patients into groups
receiving bile acid placebo or no treatment We listed these trials
in the table of Characteristics of included studies All seven trials
were published in English Three randomised clinical trials were
from the United States (Koneru 1993 Barnes 1997 Fleckenstein
1998) two from Italy (Sama 1991 Angelico 1999) one from
France (Pageaux 1995) and one from Denmark (Keiding 1997)
Patients
In the included trials all patients received blood group-compatible
grafts The median size of the seven trials was 40 patients (range
29 to 102 patients) In total 335 patients were randomised
Five trials were published as full publications (Pageaux 1995
Barnes 1997 Keiding 1997 Fleckenstein 1998 Angelico 1999)
which allowed us to extract detailed information on 263 of the
patients The mean age of the patients ranged from 44 to 51 years
One trial (Keiding 1997) also enrolled children ranging in age
from 0 to 13 years (median 15 years) The male to female ratio in
these five trials was 159104 The diseases that led to liver trans-
plantation were alcoholic cirrhosis in 51 patients (194) cirrho-
sis caused by chronic hepatitis C in 40 patients (152) primary
biliary cirrhosis in 36 patients (137) cryptogenic cirrhosis in
22 patients (84) metabolic diseases in 19 patients (72) pri-
mary sclerosing cholangitis in 17 patients (65) non-specified
post-hepatitis cirrhosis in 17 patients (65) cirrhosis caused by
chronic hepatitis B in 13 patients (49) 9 with autoimmune
hepatitis and cirrhosis (34) six with liver cancer (23) five
with biliary atresia (19) and 28 with other diseases (106)
Only one trial reported the severity of liver function according to
the Child-Pugh class (Barnes 1997)
Bile acids and collateral interventions
Six trials (Sama 1991 Koneru 1993 Pageaux 1995 Barnes
1997 Keiding 1997 Fleckenstein 1998) compared UDCA versus
placebo or no intervention One trial (Angelico 1999) compared
TUDCA versus no intervention Bile acid treatment began one
day after transplantation in the Keiding 1997 trial three days after
transplantation in the Koneru 1993 trial three or five days in the
Fleckenstein 1998 and Pageaux 1995 trials five days after trans-
plantation in the Barnes 1997 and Angelico 1999 trials and five
or seven days after transplantation in the Sama 1991 trial
Patients received UCDA (10 to 15 mgkg body weightday) for
two months in the Pageaux 1995 trial for three months in the
Koneru 1993 Barnes 1997 Keiding 1997 and Fleckenstein 1998
trials and for six months in the Sama 1991 trial In the Barnes
1997 trial patients were followed up for 18 months Patients in the
Fleckenstein 1998 trial and the Keiding 1997 trial were followed
up for nine months There was no post-treatment follow-up in
three trials (Sama 1991 Koneru 1993 Pageaux 1995) Patients
received TUDCA (500 mgday) for one year and no follow-up
was conducted in the Angelico 1999 trial
In addition to the bile acids or control intervention all patients
in the seven trials received standard triple-drug regimens (steroids
azathioprine and cyclosporine or tacrolimus) The patients who
had steroid-resistant rejection received treatment with immuno-
suppressive antibodies (OKT3)
Outcome measures
The outcome measures reported by most trials were all-cause mor-
tality and acute cellular rejection Three trials reported on death
related to rejection (Barnes 1997 Keiding 1997 Angelico 1999)
two trials reported the number of patients who received retrans-
plantation due to rejection (Keiding 1997 Fleckenstein 1998)
three trials reported the number of patients with chronic rejection
(Barnes 1997 Keiding 1997 Fleckenstein 1998) and four trials
reported the number of patients with steroid-resistant rejection
(Pageaux 1995 Barnes 1997 Keiding 1997 Fleckenstein 1998)
Four trials had adverse events as outcome measures (Barnes 1997
Keiding 1997 Fleckenstein 1998 Angelico 1999) Serum biliru-
bin level was only reported by the Fleckenstein 1998 trial No tri-
als provided data on other liver biochemical parameters quality
of life or cost-effectiveness
Risk of bias in included studies
Two trials reported adequate allocation sequence generation by
using computer-generated random tables (Barnes 1997 Angelico
1999) One trial (Keiding 1997) reported adequate allocation con-
cealment by using sealed serially numbered envelopes Three tri-
als (Barnes 1997 Keiding 1997 Fleckenstein 1998) reported ad-
equate blinding by using placebo with an identical appearance
and taste Five trials (Pageaux 1995 Barnes 1997 Keiding 1997
Fleckenstein 1998 Angelico 1999) reported adequate description
of incomplete outcome data by the number of withdrawals the
reasons for withdrawal or no patients dropped out The trial by
Keiding 1997 is the only one free of selective reporting since all
the pre-specified outcomes were fairly reported Two trials (Barnes
1997 Keiding 1997) performed sample-size calculations Only
the trial by Keiding 1997 seemed to be free of baseline imbalance
and it is the only trial achieving the calculated sample size and
therefore probably the only that was not terminated early Other
trials did not perform sample size calculation or the authors did
not report whether the calculated sample size was achieved The
lack of this information made it unclear for us to judge whether
7Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
a trial was terminated early that is before an adequate number
of patients was included in the trial Three trials (Barnes 1997
Keiding 1997 Fleckenstein 1998) stated that intention-to-treat
analyses were used (Figure 1 Figure 2)
Figure 1 Methodological quality graph review authorsrsquo judgements about each methodological quality
item presented as percentages across all included studies
8Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Figure 2 Methodological quality summary review authorsrsquo judgements about each methodological quality
item for each included study
9Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Following the assessment of risk of bias domains none of the seven
trials were considered to have low risk of bias that is having all
the nine domains for risk of bias assessed as adequate
Effects of interventions
We were able to include seven randomised clinical trials in this
review Six trials with 306 liver-transplanted patients compared
ursodeoxycholic acid (UDCA) with placebo or no intervention
and one trial with 29 liver-transplanted patients compared tauro-
UDCA (TUDCA) with no intervention
All-cause mortality
Five trials including 257 liver-transplanted patients reported on
all-cause mortality at the end of treatment or at maximum follow-
up Bile acids did not significantly reduce all-cause mortality (RR
085 95 CI 053 to 136) there were 26 deaths among 132
patients treated with bile acids (197) versus 29 deaths among
125 patients in the control groups (232) (Analysis 11) There
was no statistically significant heterogeneity (I2 = 141)
Four trials (Sama 1991 Barnes 1997 Keiding 1997 Fleckenstein
1998) showed that UDCA did not significantly reduce all-cause
mortality (RR 080 95 CI 049 to 130) 23 deaths among 116
patients treated with UCDA (198) versus 27 deaths among
108 patients in the control groups (250) The Angelico 1999
trial demonstrated that TUDCA was not able to reduce all-cause
mortality (RR 159 95 CI 030 to 833) there were 3 deaths
among 16 patients (188) versus 2 deaths among 17 patients
(118)
The Fleckenstein 1998 trial and the Sama 1991 trial did not report
the causes of deaths In the three other trials the deaths were
considered to be caused by infections (n = 11) hepatic failure (n =
7) abdominal bleeding (n = 3) renal failure (n = 2) multiple organ
failure (n = 2) hepatitis B virus fibrosis (n = 2) acute rejection
(n = 1) hepatic artery thrombosis (n = 1) encephalitis (n = 1)
lymphoproliferative disorder (n = 1) cerebral haemorrhage (n =
1) or other reasons (n = 6)
Worst-best case and best-worst case scenario analyses
In the worst-best case scenario analysis bile acids did not signif-
icantly reduce all-cause mortality when compared with placebo
or no intervention (RR 130 95 CI 086 to 196) 40 deaths
among 132 patients on bile acids (303) versus 29 deaths among
125 patients in the control groups (232) However all-cause
mortality was significantly reduced by bile acids in the best-worst
case scenario analysis (RR 058 95 CI 038 to 090) 26 deaths
among 132 patients (197) versus 42 deaths among 125 patients
in the control groups (336) (Analysis 12)
Subgroup analyses
We performed subgroup analyses regarding the time that bile acid
intake was started The Keiding 1997 trial started bile acid intake
less than three days after liver transplantation and demonstrated
no significant effect of UDCA on all-cause mortality (RR 124
95 CI 061 to 254) 14 deaths out of 54 patients (259)
versus 10 out of 48 control patients (208) The same effect
was noticed in the four other trials (Sama 1991 Barnes 1997
Fleckenstein 1998 Angelico 1999) which started bile acids three
days or more after liver transplantation (RR 063 95 CI 033
to 120) 12 deaths among 78 patients (154) versus 9 deaths
among 77 control patients (247) (Analysis 13) There were no
statistically significant differences between the two estimates
We also performed subgroup analyses regarding the duration of
bile acid treatment Bile acids were administrated for less than six
months in three trials (Barnes 1997 Keiding 1997 Fleckenstein
1998) and were not able to significantly decrease all-cause mor-
tality (RR 078 95 CI 045 to 138) 18 deaths in a group of
96 treated patients (188) versus 21 deaths among 88 control
patients (239) In the other two trials (Sama 1991 Angelico
1999) patients were treated with bile acids for six months or more
The treatment did not show statistically significant decrease in all-
cause mortality (RR 102 95 CI 043 to 24) 8 deaths in a
group of 36 treated patients (222) versus 8 deaths in a group
of 37 control patients (216) (Analysis 14) There were no sta-
tistically significant differences between the two estimates
Mortality related to allograft rejection
We did not find statistically significant reduction in mortality re-
lated to allograft rejection at maximum follow-up in the three tri-
als reporting cause of death (Barnes 1997 Keiding 1997 Angelico
1999) (RR 030 95 CI 001 to 712) 098 (0) versus 189
(11)) (Analysis 15) The only death due to acute rejection was
found in the placebo group of the Keiding 1997 trial
Number of liver retransplantations
Two trials (Fleckenstein 1998 Keiding 1997) including 132 liver-
transplanted patients reported the number of liver retransplan-
tations UDCA did not significantly reduce the risk of liver re-
transplantation at maximum follow-up (RR 076 95 CI 020
to 286) 368 (44) versus 464 (63)) (Analysis 16) In the
Keiding 1997 trial one patient in the UDCA group was retrans-
planted due to chronic rejection and four patients in the placebo
group were retransplanted either due to chronic rejection (three
cases) or acute rejection (one case) In the Fleckenstein 1998 trial
two patients in the UDCA group were retransplanted due to acute
rejection (one case) and chronic rejection (one case) respectively
Number of patients with acute cellular rejection
Seven trials reported the number of patients who had acute cellu-
lar rejection after liver transplantation Bile acids did not signifi-
cantly reduce the number of patients who experienced acute cel-
lular rejection (RR 089 95 CI 074 to 106) 93174(535)
versus 99165 (600)) There was no significant heterogeneity
(I2 = 0)
Six trials (Sama 1991 Koneru 1993 Pageaux 1995 Barnes 1997
10Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Keiding 1997 Fleckenstein 1998) compared UDCA with placebo
or no intervention and demonstrated that UDCA did not signifi-
cantly reduce the number of patients with acute cellular rejection
after liver transplantation (RR 089 95 CI 074 to 108 85
158 (538) versus 89148 (601)) Neither did the Angelico
1999 trial demonstrate significant reduction of the number of pa-
tients with acute cellular rejection with TUDCA (RR 085 95
CI 045 to 160) 816 (500) versus 1017 (588) (Analysis
17)
Subgroup analyses
Two trials (Koneru 1993 Keiding 1997) in which the patients
started bile acids intake less than three days after liver transplan-
tation did not demonstrate any significant reduction of the risk
of acute cellular rejection by bile acids (RR 084 95 CI 063 to
111) 3870 (543) versus 4164 (641) The other five tri-
als (Sama 1991 Pageaux 1995 Barnes 1997 Fleckenstein 1998
Angelico 1999) in which the patients were started on bile acid
intake three days or more after liver transplantation did not find
a significant reduction of the risk of acute cellular rejection by bile
acids (RR 092 95 CI 072 to 117) 55104 (529) versus 58
101 (574) (Analysis 18) There was no significant difference
between the two estimates
Bile acids did not significantly reduce the risk of acute cellular
rejection in the five trials (Koneru 1993 Pageaux 1995 Barnes
1997 Keiding 1997 Fleckenstein 1998) in which the patients
received treatment with bile acids less than six months (RR 087
95 CI 071 to 107) 72138 (522) versus 76128 (594)
Neither did bile acids in the two other trials (Sama 1991 Angelico
1999) in which the patients received bile acids for more than six
months (RR 094 95 CI 065 to 136) 2136 (583) versus
2337 (622) (Analysis 19) There were no significant difference
between the two estimates
Number of patients with chronic rejection
Three trials comparing UDCA versus placebo (Barnes 1997
Keiding 1997 Fleckenstein 1998) reported the number of patients
with chronic rejection after liver transplantation UDCA signifi-
cantly reduced the number of patients with chronic rejection in
the fixed-effect model analysis (RR 028 95 CI 008 to 095)
396 (31) versus 1088 (114) (Analysis 110) but not in the
random-effects model analysis (RR 030 95 CI 008 to 113) 3
96 (31) versus 1088 (114) There was no statistically signifi-
cant heterogeneity (I2 0) We performed trial sequential analysis
for the available data from three trials (Figure 3) with heterogene-
ity corrected required information size based on proportion of this
outcome of 12 in the control group a relative risk reduction of
50 in the intervention group at a type I error of 5 and a type
II error of 10 We obtained a required information size of 957
patients UDCA was not able to reach or break the trial sequential
monitoring boundary and only 183 out of 957 (19) patients
were randomised regarding this outcome
11Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Figure 3 Trial sequential analysis for the number of patients with chronic rejection at maximum follow-up
We calculated the heterogeneity-corrected required information size (HCRIS) based on a proportion of 12 of
the patients in the placebo group with chronic rejection at maximum follow-up a 50 risk ratio reduction in
the bile acid group an alpha of 5 a beta of 10 and a heterogeneity of 0 Only 184 patients have been
randomised reporting this outcome which is only 19 of the HCRIS of 957 patients The cumulative Z-score
crosses the conventional boundaries for P 005 but not the monitoring boundaries
Number of patients with steroid-resistant rejection
Four trials (Pageaux 1995 Barnes 1997 Keiding 1997
Fleckenstein 1998) reported the number of patients with steroid-
resistant rejection These trials demonstrated that UDCA did not
significantly reduce the number of patients with steroid-resistant
rejection when compared with placebo (22122 (18) versus 26
112 (232) (RR 077 95 CI 047 to 127) (Analysis 111)
There was no significant heterogeneity (I2 0)
Liver biochemistry
The Fleckenstein 1998 trial reported serum bilirubin levels after
a three-month-treatment period in 30 liver-transplanted patients
There was no statistically significant difference in serum bilirubin
levels between the UDCA group and the placebo group (MD 260
mgdl 95 CI -096 to 616 mgdl) (Analysis 112)
No data were available for other liver biochemical variables
Cost-effectiveness
One trial (Barnes 1997) with 52 liver-transplanted patients re-
ported the days of hospitalisation after liver transplantation
UDCA significantly decreased the number of days of hospitali-
sation when compared with placebo (MD -850 days 95 CI -
1667 to -033 days) (Analysis 113) We were not able to extract
other medical cost from the trials
Adverse events
Among all the included and excluded trials only four reported on
adverse events however adverse events only occurred in two of
the included trials (Barnes 1997 Keiding 1997) There were no
significant differences regarding adverse events (RR 088 95 CI
030 to 260) 6112 (54) versus 6105 (57) (Analysis 114)
In the Barnes 1997 trial diarrhoea was reported by two patients
(one in the UDCA group and one in the placebo group) In the
Keiding 1997 trial five UDCA patients and five placebo patients
stopped intake of the trial medicine because of diarrhoea or dif-
ficulties in swallowing the capsules The remaining included trial
by Angelico 1999 stated that no adverse events occurred during
the study period The excluded trial by Assy 2007 was the only
one reporting on a case of mild diarrhoea in one patient in the
12Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
intervention group No other excluded studies reported on adverse
events (see Table 1)
Quality of life
None of the included studies assessed quality of life as an outcome
Other subgroup analyses
We planned to perform subgroup analyses regarding the risk of
bias of trials the dosage of bile acid and any co-intervention
However none of the trials were considered to be of low risk of
bias they all used a similar dosage of bile acid and patients in all
trials received similar immunosuppressive treatment as co-inter-
ventions (steroids azathioprine and cyclosporine or tacrolimus)
after liver transplantation Therefore we were not able to perform
the planned subgroup analyses
Funnel plot asymmetry
We did not draw a funnel plot analysis due to the limited number
of trials included in the present review
D I S C U S S I O N
In the update of this review we included no new trials assessing
the use of bile acids for liver-transplanted patients The analyses
of the seven previously included trials showed that bile acids did
not significantly affect mortality acute cellular rejection steroid-
resistant rejection retransplantation or serum bilirubin Bile acids
might significantly decrease the length of hospital stay and the
number of patients with chronic rejection included in these tri-
als but more supportive evidence is needed The number of pa-
tients with chronic rejection was not significantly influenced by
bile acids when a random-effects model was used and length of
stay was assessed in one single trial Furthermore none of the trials
were considered to be of low risk of bias and few patients were en-
rolled Therefore our positive findings may be due to bias (Schulz
1995 Moher 1998 Kjaergard 2001 Wood 2008) or random er-
rors (Wetterslev 2008 Brok 2009 Thorlund 2009) On the other
hand we are not able to exclude type II errors (that is finding
no significant differences when in fact they exist) due to the low
number of participants Therefore this topic could be of potential
interest in future large randomised trials with adequate control of
bias
All-cause mortality at one year after liver transplantation is re-
ported to be about 20 (Thuluvath 2003) which we also ob-
served for the patients included in the present review According to
our subgroup analyses neither UDCA nor TUDCA significantly
decreased all-cause mortality We also performed a subgroup anal-
ysis regarding treatment duration but we were not able to find any
difference between short (less than six months) and long treatment
duration (six months or more) Thus bile acids do not seem to
have statistically significant effects in reducing all-cause mortal-
ity after liver transplantation We performed both worst-best-case
scenario and best-worst-case scenario analyses In the worst-best-
case scenario bile acids did not differ significantly from placebo or
no intervention regarding all-cause mortality However bile acids
significantly decreased all-cause mortality in the best-worst-case
scenario analysis However such an analysis is very extreme and
may not be realistic We have also found that UDCA may be able
to decrease the risk of chronic rejection in liver-transplanted pa-
tients but trial sequential analysis could not confirm this result
Due to a limited number of patients (Ioannidis 2001) we are not
able to exclude the possibility that it may be relevant to perform
placebo-controlled trials with low risk of bias on the use of bile
acids for liver-transplanted patients
We looked into the causes of deaths that were reported by the trials
and only one trial reported one death related to rejection At the
same time the number of retransplantations was 3 among 68 liver-
transplanted patients who received treatment with UDCA and 4
among 64 liver-transplanted patients who received treatment with
placebo We noticed that all patients in the included trials received
co-interventions of standard triple-drug regimens (steroids aza-
thioprine and cyclosporine or tacrolimus) which were able to
control the possible acute or chronic rejection and prevent deaths
due to allograft rejection (FK506 1994)
The assumption that UDCA might reduce the incidence of acute
graft rejection came from the findings that UDCA could regulate
major histocompatibility complex antigen expression in bile ducts
and liver endothelia and inhibit lymphocyte activity (Calmus
1990 Terasaki 1991 Perez 2009) However in the present review
bile acids did not significantly reduce the risk of acute cellular re-
jection in liver-transplanted patients Considering that acute cellu-
lar rejection is commonly found within a few days after liver trans-
plantation (Vierling 1992) some might argue that the adminis-
tration of bile acids was started too late to prevent acute cellular
rejection We performed subgroup analyses regarding the time bile
acids were started and no statistically significant difference was
found Furthermore bile acids were not able to decrease the risk
of steroid-resistant rejection Therefore the lack of effects of bile
acids does not seem to be due to a delayed start to bile acid ad-
ministration after liver transplantation However it is a possibility
that one should start bile acids intake before liver transplantation
A retrospective study found that rejection rates differed signifi-
cantly between patients with primary biliary cirrhosis treated with
or without UDCA before liver transplantation (Heathcote 1999)
One could argue whether UDCA-induced delay in transplantation
has an adverse effect on post-transplantation outcome Since we
did not find any prospective randomised clinical trials addressing
this issue further research might be needed Furthermore some
studies may provide an explanation why UDCA was not able to
prevent acute cellular rejection These studies found that UDCA
did not appear to change the expression of major histocompatibil-
ity complex class II antigens but rather major histocompatibility
complex class I antigens (Calmus 1990) The initial mechanism
of acute rejection is thought to be recognition of MHC class II
13Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
antigens by CD4+ T cells (Vierling 1992) Moreover the inhibi-
tion of the production of interleukin-2 by peripheral blood lym-
phocytes with UDCA (Heuman 1993) might be negated by the
immunosuppressive treatment after liver transplantation (van den
Berg 1998) so that UDCA is unable to demonstrate effects on
graft rejection In a recent study by Assy 2007 a significant re-
duction in the mean dose of immunosuppressive medications was
achieved in stable liver graft recipients treated with UDCA indi-
cating a possible influence of UDCA on rejection mechanisms
In accordance with previous systematic reviews (Chen 2003a
Chen 2007 Gong 2008) bile acids were not associated with the
occurrence of serious adverse events or any major occurrence of
adverse events
In summary our results do not support or refute the use of bile
acids (UDCA and TUDCA) additional to standard immunosup-
pressive treatment in liver-transplanted patients
A U T H O R S rsquo C O N C L U S I O N SImplications for practice
There seems to be no evidence to support or refute the use of bile
acids for liver-transplanted patients receiving standard immuno-
suppressive treatment
Implications for research
We need more randomised placebo-controlled clinical trials with
enough statistical power and low risk of bias to explore the poten-
tial effects of bile acids on chronic rejection and mortality in liver-
transplanted patients Such trials should also consider evaluation
of quality of life and length of hospitalisation Such trials may
consider starting bile acid and placebo interventions before liver
transplantation we were not able to identify any randomised trials
addressing this regimen Such trials ought to be reported accord-
ing to the CONSORT statement (wwwconsort-statementorg)
However before embarking on such trials the effects of bile acids
in other patient groups should be scrutinised as they may have
small or negative effects
A C K N O W L E D G E M E N T S
We thank all the patients and investigators who were involved in
the clinical trials mentioned in this review We thank Wendong
Chen for his work and contribution on the previous version of this
review We thank the staff of The Cochrane Hepato-Biliary Group
Editorial Team especially Dimitrinka Nikolova and Sarah Louise
Klingenberg for excellent collaboration and assistance during the
update of this review
Peer Reviewers Carlo Merkel Italy M Tomikawa Japan
Contact Editor Bodil Als-Nielsen Denmark
R E F E R E N C E S
References to studies included in this review
Angelico 1999 published data only
Angelico M Tisone G Baiocchi L Palmieri G Pisani F Negrini S
et alOne-year pilot study on tauroursodeoxycholic acid as an
adjuvant treatment after liver transplantation Italian Journal of
Gastroenterology and Hepatology 199931(6)462ndash8 [MEDLINE
10575563]
Barnes 1997 published data onlylowast Barnes D Talenti D Cammell G Goormastic M Farquhar L
Henderson M et alA randomized clinical trial of ursodeoxycholic
acid as adjuvant treatment to prevent liver transplant rejection
Hepatology 199726(4)853ndash7 [MEDLINE 9328304]
Barnes D Talenti D Goormastic M Farquhar L Cammell G
Henderson M et alUrsodeoxycholic acid (UDCA) reduces hepatic
allograft rejection after orthotopic liver transplantation (OLT) - a
prospective randomized placebo-controlled double-blind trial
Hepatology 199522149A
Fleckenstein 1998 published data only
Fleckenstein JF Paredes M Thuluvath PJ A prospective
randomized double-blind trial evaluating the efficacy of
ursodeoxycholic acid in prevention of liver transplant rejection
Liver Transplantation and Surgery 19984(4)276ndash9 [MEDLINE
9649640]
Keiding 1997 published data only
Keiding S Hockerstedt K Bjoro K Bondesen S Hjortrup A
Isoniemi H et alThe Nordic multicenter double-blind randomized
controlled trial of prophylactic ursodeoxycholic acid in liver
transplant patients Transplantation 199763(11)1591ndash4
[MEDLINE 9197351]
Koneru 1993 published data only
Koneru B Tint GS Wilson DJ Leevy CB Salen F Randomised
prospective trial of ursodeoxycholic acid in liver transplant
recipients Hepatology 199318336A
Pageaux 1995 published data only
Pageaux GP Blanc P Perrigault PF Navarro F Fabre JM Souche B
et alFailure of ursodeoxycholic acid to prevent acute cellular
rejection after liver transplantation Journal of Hepatology 199523
(2)119ndash22 [MEDLINE 7499781]
Sama 1991 published data only
Sama C Mazziotti A Grigioni W Morselli AM Chianura A
Stefanini GF et alUrsodeoxycholic acid administration does not
14Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
prevent rejection after OLT Journal of Hepatology 199113(Suppl
2)68
References to studies excluded from this review
Assy 2007 published data only
Assy N Adams PC Myers P Simon V Minuk GY Wall W et
alRandomized controlled trial of total immunosuppression
withdrawal in liver transplant recipients role of ursodeoxycholic
acid Transplantation 200783(12)1571ndash6 [MEDLINE
17589339]
Clavien 1996 published data only
Clavien PA Sharara AI Camargo CA Jr Harland RC Fitz JG
Evidence that ursodeoxycholic acid prevents steroid-resistant
rejection in adult liver transplantation Clinical Transplantation
199610(6 Pt 2)658ndash62 [MEDLINE 8996761]
Friman 1992 published data only
Friman S Persson H Schersten T Svanvik J Karlberg I Adjuvant
treatment with ursodeoxycholic acid reduces acute rejection after
liver transplantation Transplantation Proceedings 199224(1)
389ndash90 [MEDLINE 1539328]
Heathcote 1999 published data onlylowast Heathcote EJ Stone J Cauch-Dudek K Poupon R Chazouilleres
O Lindor KD et alEffect of pretransplantation ursodeoxycholic
acid therapy on the outcome of liver transplantation in patients
with primary biliary cirrhosis Liver Transplantation and Surgery
19995(4)269ndash74 [MEDLINE 10388499]
Henriksson 1991 published data only
Henriksson BA Persson H Friman S Wangberg B Svanvik J
Karlberg I Adjuvant ursodeoxycholic acid prevents acute rejection
in liver transplant recipients Transplantation Proceedings 199123
(3)1971 [MEDLINE 2063453]
Persson 1990 published data only
Persson H Friman S Schersten T Svanvik J Karlberg I
Ursodeoxycholic acid for prevention of acute rejection in liver
transplant recipients Lancet 1990336(8706)52ndash3 [MEDLINE
1973232]
Rafael 1995 published data only
Rafael E Duraj F Rudstrom H Wilczek H Ericzon B Effect of
ursodeoxycholic acid treatment for cholestasis in liver transplant
recipients Transplantation Proceedings 199527(6)3501ndash2
[MEDLINE 8540069]
Sama 1998 published data only
Sama C Morselli-Labate AM Grazi GL Mastroianni A Danesi G
Pianta P et alUrsodeoxycholic acid in liver transplantation effect
on cholestasis and rejection Gastroenterology 1998114(4 Suppl)
A1332
Additional references
Adams 1990
Adams DH Neuberger JM Patterns of graft rejection following
liver transplantation Journal of Hepatology 199010(1)113ndash9
[MEDLINE 2407770]
Al-Quaiz 1994
Al-Quaiz M OrsquoGrady J Tredger J Williams R Variable effect of
ursodeoxycholic acid on cyclosporin absorption after orthotopic
liver transplantation Transplant International 19947(3)190ndash4
[MEDLINE 8060468]
Armstrong 1982
Armstrong MJ Carey MC The hydrophobic-hydrophilic balance
of bile salt Inverse correlation between reverse phase high
performance liquid chromatographic mobilities and micellar
cholesterol-solubilizing capacities Journal of Lipid Research 1982
23(1)70ndash80 [MEDLINE 7057113]
Ascher 1988
Ascher NL Stock PG Baumgardner GL Payne WD Najarian JS
Infection and rejection of primary hepatic transplant in 93
consecutive patients treated with triple immunosuppressive therapy
Surgery Gynecology amp Obstetrics 1988167(6)474ndash84
[MEDLINE 3055368]
Brok 2008
Brok J Thorlund K Gluud C Wetterslev J Trial sequential
analysis reveals insufficient information size and potentially false
positive results in many meta-analyses Journal of Clinical
Epidemiology 200861(8)763ndash9 [MEDLINE 18411040]
Brok 2009
Brok J Thorlund K Wetterslev J Gluud C Apparently conclusive
meta-analysis may be inconclusive - Trial sequential analysis
adjustment of random error risk due to repetitive testing of
accumulating data in apparently conclusive neonatal meta-analysis
International Journal of Epidemiology 200938(1)298ndash303
[MEDLINE 18824466]
Calmus 1990
Calmus Y Gane P Rouger P Poupon R Hepatic expression of class
I and class II major histocompatibility complex molecules in
primary biliary cirrhosis effect of ursodeoxycholic acid Hepatology
199011(1)12ndash5 [MEDLINE 2403961]
Calmus 1992
Calmus Y Arvieux C Gane P Boucher E Nordlinger B Rouger P
et alCholestasis induces major histocompatibility complex class I
expression in hepatocytes Gastroenterology 1992102(4 Pt 1)
1371ndash7 [MEDLINE 1551542]
Chen 2003a
Chen W Gluud C Bile acids for primary sclerosing cholangitis
Cochrane Database of Systematic Reviews 2003 Issue 2 [DOI
10100214651858CD003626]
Chen 2007
Chen W Liu J Gluud C Bile acids for viral hepatitis Cochrane
Database of Systematic Reviews 2007 Issue 4 [DOI 101002
14651858CD003181pub2]
Cheng 2002
Cheng K Ashby D Smyth R Ursodeoxycholic acid for cystic
fibrosis-related liver disease Cochrane Database of Systematic
Reviews 2002 Issue 2 [DOI 10100214651858CD000222]
Corbani 2008
Corbani A Burroughs AK Intrahepatic cholestasis after liver
transplantation Clinics in Liver Disease 200812(1)111ndash29
[MEDLINE 18242500]
DeMets 1987
DeMets DL Methods for combining randomised clinical trials
strengths and limitations Statistics in Medicine 19876(3)341ndash50
[MEDLINE 3616287]
15Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
DerSimonian 1986
DerSimonian R Laird N Meta-analysis in clinical trials Controlled
Clinical Trials 19867(3)177ndash88 [MEDLINE 3802833]
Egger 1997
Egger M Davey Smith G Schneider M Minder C Bias in meta-
analysis detected by a simple graphical test BMJ (Clinical Research
Ed) 1997315(7109)629ndash34 [MEDLINE 9310563]
Ericzon 1990
Ericzon BG Eusufzai S Kubota K Einarsson K Angelin B
Characteristics of biliary lipid metabolism after liver
transplantation Hepatology 199012(5)1222ndash8 [MEDLINE
2227822]
FK506 1994
The US Multicenter FK506 Liver Study Group A comparison of
tacrolimus (FK506) and cyclosporine for immunosuppression in
liver transplantation New England Journal of Medicine 1994331
(17)1110ndash5 [MEDLINE 7523946]
Friman 1994
Friman S Svanvik J A possible role of ursodeoxycholic acid in liver
transplantation Scandinavian Journal of Gastroenterology 1994204
62ndash4 [MEDLINE 7824880]
Fuchs 1999
Fuchs M Stange EF Metabolism of bile acids In Johannes
Bircher Jean-Pierre Benhamou Neil McIntyre Mario Rizzetto
Juan Rodes editor(s) Oxford Textbook of Clinical Hepatology 2
Vol 1 Oxford Oxford University Press 1999223ndash56
Fusai 2006
Fusai G Dhaliwal P Rolando N Sabin CA Patch D Davidson BR
et alIncidence and risk factors for the development of prolonged
and severe intrahepatic cholestasis after liver transplantation Liver
Transplantation 200612(11)1626ndash33 [DOI 101002lt20870]
Gluud 2001
Gluud C Alcoholic hepatitis no glucocorticosteroids In
Leuschner U James OFW Dancygier H editor(s) Steatohepatitis
(NASH and ASH) Falk Symposium 121 Lancaster Kluwer
Academic Publisher 2001322ndash42
Gluud 2010
Gluud C Nikolova D Klingenberg SL Alexakis N Als-Nielsen B
Colli A et alCochrane Hepato-Biliary Group About The
Cochrane Collaboration (Cochrane Review Groups (CRGs))
2010 Issue 1 Art No LIVER
Gong 2008
Gong Y Huang ZB Christiansen E Gluud C Ursodeoxycholic
acid for primary biliary cirrhosis Cochrane Database of Systematic
Reviews 2008 Issue 3 [DOI 101002
14651858CD000551pub2]
Haddad 2006
Haddad EM McAlister VC Renouf E Malthaner R Kjaer MS
Gluud LL Cyclosporin versus tacrolimus for liver transplanted
patients Cochrane Database of Systematic Reviews 2006 Issue 4
[DOI 10100214651858CD005161pub2]
Heuman 1993
Heuman DM Hepatoprotective properties of ursodeoxycholic acid
Gastroenterology 1993104(6)1865ndash9 [MEDLINE 8500748]
Higgins 2008
Higgins PTJ Green S editors Cochrane Handbook for Systematic
Reviews of Interventions West Sussex England Wiley-Blackwell
2008
Hirschfield 2009
Hirschfield GM Gibbs P Griffiths WJH Adult liver
transplantation what non-specialists need to know BMJ (Clinical
Research Ed) 2009338(b1670)1321ndash7 [DOI 101136
bmjb1670]
Hussain 2002
Hussain HK Nghiem HV Imaging of hepatic transplantation
Clinics in Liver Disease 20026(1)247ndash70 [MEDLINE
11933592]
ICH-GCP 1997
International Conference on Harmonisation Expert Working
Group Code of Federal Regulations amp International Conference on
Harmonization Guidelines Media Parexel Barnett 1997
Ioannidis 2001
Ioannidis JPA Lau J Evolution of treatment effects over time
Empirical insight from recursive cumulative meta analyses
Proceedings of the National Academy of Sciences 200198(3)831ndash6
IWP 1995
International Working Party Terminology for hepatic allograft
rejection Hepatology 199522(2)648ndash54 [MEDLINE 7635435]
Kjaergard 2001
Kjaergard LL Villumsen J Gluud C Reported methodological
quality and discrepancies between large and small randomised trials
in meta-analyses Annals of Internal Medicine 2001135(11)982ndash9
[MEDLINE 11730399]
Klintmalm 1989
Klintmalm GB Nery JR Husberg BS Gonwa TA Tillery GW
Rejection in liver transplantation Hepatology 198910(6)978ndash85
[MEDLINE 2583691]
Knechtle 2009
Knechtle SJ Kwun J Unique aspects of rejection and tolerance in
liver transplantation Seminars in Liver Disease 200929(1)91ndash101
[MEDLINE 19235662]
Krams 1993
Krams SM Ascher NL Martinez OM New immunologic insights
into mechanisms of allograft rejection Gastroenterology Clinics of
North America 199318(2)374ndash7 [MEDLINE 8509176]
Lan 1983
Lan KKG DeMets DL Discrete sequential boundaries for clinical
trials Biometrika 198370659ndash63
Merion 1989
Merion RM Gorski DH Burtch GD Turcotte JG Colletti LM
Campbell DA Jr Bile refeeding after liver transplantation and
avoidance of intravenous cyclosporine Surgery 1989106(4)
604ndash9 [MEDLINE 2799635]
Moher 1998
Moher D Pham B Jones A Cook DJ Jadad AR Moher M et
alDoes quality of reports of randomised trials affect estimates of
intervention efficacy reported in meta-analyses Lancet 1998352
(9128)609ndash13 [MEDLINE 9746022]
16Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Neuberger 1999
Neuberger J Incidence timing and risk factors for acute and
chronic rejection Liver Transplantation and Surgery 19995(4 Suppl
1)S30ndashS36 [MEDLINE 10431015]
Okolicsanyi 1986
Okolicsanyi L Lirussi F Strazzabosco M Jemmolo RM Orlando R
Nassuato G et alThe effect of drugs on bile flow and composition
An overview Drugs 198631(5)430ndash48 [MEDLINE 2872047]
Palmer 1972
Palmer RH Bile acids liver injury and liver disease Archives of
Internal Medicine 1972130(4)606ndash17 [MEDLINE 4627840]
Perez 2009
Perez MJ Briz O Bile-acid-induced cell injury and protection
World Journal of Gastroenterology 200915(14)1677ndash89
[MEDLINE 19360911]
Pogue 1997
Pogue JM Yusuf S Cumulating evidence from randomized trials
Utilizing sequential monitoring boundaries for cumulative meta-
analysis Controlled Clinical Trials 199718(6)580ndash93
[MEDLINE 9408720]
Pogue 1998
Pogue J Yusuf S Overcoming the limitations of current meta-
analysis of randomised controlled trials Lancet 1998351(9095)
45ndash52 [MEDLINE 9433436]
RevMan 2008
The Nordic Cochrane Centre The Cochrane Collaboration
Review Manager (RevMan) 50 Copenhagen The Nordic
Cochrane Centre The Cochrane Collaboration 2008
Royle 2003
Royle P Milne R Literature searching for randomized controlled
trials used in Cochrane reviews rapid versus exhaustive searches
International Journal of Technology Assessment in Health Care 2003
19(4)591ndash603
Schulz 1995
Schulz KF Chalmers I Hayer R Altman D Empirical evidence of
bias JAMA 1995273(5)408ndash12 [MEDLINE 7823387]
Sharara 1995
Sharara AI Camargo CA Clavien PA Ursodeoxycholic acid
prevents steroid resistant rejection in liver transplant recipients
Gastroenterology 1995108A1168
Sholmerich 1984
Sholmerich J Becher MS Schmidt KH Schubert R Kremer B
Felhaus S et alInfluence of hydroxylation and conjugation of bile
salts on their membrane damaging properties Hepatology 19844
(4)661ndash7 [MEDLINE 6745854]
Soderdahl 1998
Soderdahl G Nowak G Duraj F Wang FH Einarsson C Ericzon
BG Ursodeoxycholic acid increased bile flow and affects bile
composition in the early postoperative phase following liver
transplantation Transplantation International 199811(Suppl 1)
S231ndashS238 [MEDLINE 9664985]
Terasaki 1991
Terasaki S Nakanuma Y Ogino H Unoura M Kobayashi K
Hepatocellular and biliary expression of HLA antigens in primary
biliary cirrhosis before and after ursodeoxycholic acid therapy
American Journal of Gastroenterology 199186(9)1194ndash9
[MEDLINE 1882800]
Thalheimer 2002
Thalheimer U Capra F Liver transplantation making the best out
of what we have Digestive Diseases and Sciences 200247(5)
945ndash53 [MEDLINE 12018919]
Thorlund 2009
Thorlund K Devereaux PJ Wetterslev J Guyatt G Ioannidis JP
Thabane L et alCan trial sequential monitoring boundaries reduce
spurious inferences from meta-analyses International Journal of
Epidemiology 200938(1)276ndash86 [MEDLINE 18824467]
Thuluvath 2003
Thuluvath PJ Yoo HY Thompson RE A model to predict survival
at one month one year and five years after liver transplantation
based on pretransplant clinical characteristics Liver Transplantation
20039(5)527ndash32 [MEDLINE 12740799]
van den Berg 1998
van den Berg AP Twilhaar WN Mesander G van Son WJ van der
Bij W Klompmaker IJ et alQuantitation of immunosuppression
by flow cytometric measurement of the capacity of T cells for
interleukin-2 production Transplantation 199865(8)1066ndash71
[MEDLINE 9583867]
Vierling 1992
Vierling J Immunologic mechanisms of hepatic allograft rejection
Seminars in Liver Disease 199212(1)16ndash27 [MEDLINE
1570548]
Wetterslev 2008
Wetterslev J Thorlund K Brok J Gluud C Trial sequential
analysis may establish when firm evidence is reached in cumulative
meta-analysis Journal of Clinical Epidemiology 200861(1)64ndash75
[MEDLINE 18083463]
Wiesner 1992
Wiesner RH Acute cellular rejection following liver
transplantation incidence risk factors and outcome in the
NIDDK Liver Transplant Database (LTD) study Gastroenterology
1992102A910
Wood 2008
Wood L Egger M Gluud LL Schulz KF Juni P Altman DG et
alEmpirical evidence of bias in treatment effect estimates in
controlled trials with different interventions and outcomes meta-
epidemiological study BMJ (Clinical Research Ed) 2008336
(7644)601ndash5 [MEDLINE 18316340]
Yoshikawa 1998
Yoshikawa M Matsui Y Kawamoto H Toyohara M Matsumura
K Yamao J et alIntragastric administration of ursodeoxycholic
acid suppresses immunoglobulin secretion by lymphocytes from
liver but not from peripheral blood spleen or Peyerrsquos patches in
mice International Journal of Immunopharmacology 199820(1-3)
29ndash38 [MEDLINE 9717080]
References to other published versions of this review
17Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Chen 2003b
Chen W Gluud C Bile acids for liver transplanted patients
Cochrane Database of Systematic Reviews 2005 Issue 3 [DOI
10100214651858CD005442]lowast Indicates the major publication for the study
18Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
C H A R A C T E R I S T I C S O F S T U D I E S
Characteristics of included studies [ordered by study ID]
Angelico 1999
Methods Study design open-label randomised one-year pilot study
Participants Country Italy
Publication language English
Inclusion criteria
- patients who underwent liver transplantation from April 1994 to December 1994
Exclusion criteria
- not mentioned
Participants
Two patients in TUDCA group and two patients in control group were excluded from
the basic information of participants by the study due to withdrawal
- TUDCA group (n = 14)
Mean age (years +- SD)
467 +- 84
Ratio of sex (malefemale) 122
Origins of liver diseases
hepatitis C cirrhosis (9) hepatitis B cirrhosis (2) hepatitis B and C cirrhosis (1) cryp-
togenic cirrhosis (2) alcoholic cirrhosis (0) Wilson cirrhosis (0)
- Control group (n = 15)
Mean age (years +- SD)
474 +- 74
Ratio of sex (malefemale) 123
Origins of liver diseases
hepatitis C cirrhosis (7) hepatitis B cirrhosis (2) hepatitis B and C cirrhosis (2) cryp-
togenic cirrhosis (2) alcoholic cirrhosis (1) Wilson cirrhosis (1)
Interventions TUDCA group
- Dose 500 mgday in two divided doses
- Route orally
- Duration the treatment was started on day 5 after transplantation and continued for
one year
Control group
- no treatment
Co-interventions all patients received standard triple-drug regimens (steroids azathio-
prine and cyclosporine or tacrolimus)
Outcomes All cause mortality
Number of patients with rejection after liver transplantation
Notes Letter was sent to the authors in September 2009 A reply with additional information
was received shortly after
Risk of bias
19Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Angelico 1999 (Continued)
Item Authorsrsquo judgement Description
Adequate sequence generation Yes Computer generated table
Allocation concealment Unclear No information provided
Blinding No Not performed
Incomplete outcome data addressed
All outcomes
Yes Withdrawal two patients from the
TUDCA group and two patients from the
placebo group Three of them died due to
transplant non-function in the first postop-
erative week and one patient was regrafted
due to thrombosis of hepatic artery
Free of selective reporting Unclear Post-transplant cholestasis and liver bio-
chemistry specified as outcomes Differ-
ence reported as not significant but no ac-
tual data given
Sample size calculation No Not reported
Intention-to-treat analysis No Not stated and not used
Baseline imbalance Unclear Not enough information provided
Early stopping of trial Unclear Not enough information provided
Barnes 1997
Methods Study design randomised placebo-controlled double-blind trial
Participants Country United States
Publication language English
Inclusion criteria
- patients aged 18 years or older who underwent liver transplantation at the Cleveland
Clinic Foundation from April 1992 through June of 1994
Exclusion criteria
- patients who were found to have cancer at surgically resected margins of the biliary
tree
- patents who underwent retransplantation
Participants
- UDCA group (n = 28)
Mean age (years +- SD)
505 +- 116
Ratio of sex (malefemale) 1810
Child class A 7
20Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Barnes 1997 (Continued)
B 13
and C 8
Origins of liver diseases Laennecrsquos cirrhosis 4
PBC 3
cryptogenic cirrhosis 6
hepatitis Ccirrhosis 4
hepatitis Bcirrhosis 3
autoimmune hepatitis with cirrhosis 3
PSC 2
other 3
- Placebo group (n = 24)
Mean age (years +- SD)
507 +- 93
Ratio of sex (malefemale) 159
Child class A 6
B 14
and C 4
Origins of liver diseases Laennecrsquos cirrhosis 9
PBC 5
cryptogenic cirrhosis 1
hepatitis Ccirrhosis 1
hepatitis Bcirrhosis 1
autoimmune hepatitis with cirrhosis 1
PSC 2
other 4
Interventions UDCA group
- Dose 10-15 mgkg body weightday in divided doses
- Route orally
- Duration immediately after intestinal transit recovery usually between postoperative
days three and five and continue for three months
Placebo group
- identical-appearing capsules administered in the same quantity and manner
Co-interventions all patients received standard triple-drug regimens (steroids azathio-
prine and cyclosporine or tacrolimus)
Outcomes All cause mortality
Number of patients with acute cellular rejection
Number of patients with chronic rejection
Number of patients with steroid-resistant rejection
Number of days of hospitalisation
Adverse events
Notes Letter was sent to the authors in September 2009 A reply with additional information
was received shortly after
Risk of bias
Item Authorsrsquo judgement Description
21Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Barnes 1997 (Continued)
Adequate sequence generation Yes Computer generated table
Allocation concealment Unclear No information provided
Blinding Yes Quote ldquorandomised to receive either
UDCA or an identical placebo capsulerdquo
Incomplete outcome data addressed
All outcomes
Yes Mean follow-up time 18 months Ten pa-
tients withdrawn from study 6 in UDCA
group and 4 in placebo group Reasons
for withdrawal were reported Four patients
died in the placebo group
Free of selective reporting Yes All expected outcomes reported
Sample size calculation Unclear The trial reported the method of sample
size calculation but the actual number of
patients needed was not reported
Intention-to-treat analysis Yes Stated and used
Baseline imbalance Unclear Not enough information provided
Early stopping of trial Unclear The number of patients needed to gain the
actual power was not reported Whether
the trial was terminated early is not clear
Fleckenstein 1998
Methods Study design prospective randomised double-blind trial
Participants Country United States
Publication language English
Inclusion criteria
- patients who underwent liver transplantation at the Johns Hopkins Hospital
Exclusion criteria
- patients who were under 18 years old undergoing repeat transplantation had primary
graft nonfunction or refused consent
Participants
- UDCA group (n = 14)
Mean age (years +- SD)
443 +- 127
Ratio of sex (malefemale) 68
Origins of liver diseases hepatitis C 6
alcohol 2
autoimmune 1
PBC 2
22Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Fleckenstein 1998 (Continued)
PSC 1
autoimmune cholangiopathy 1
hepatitis B 1
- Placebo group (n = 16)
Mean age (years +- SD)
496 +- 109
Ratio of sex (malefemale) 124
Origins of liver diseases hepatitis C 3
alcohol 3
autoimmune 3
PBC 1
PSC 2
cryptogenic 2
hepatitis B 1
alpha1-antitrypsin deficiency 1
Interventions UDCA group
- Dose 15 mgkg body weightday in divided doses
- Route orally
- Duration immediately after intestinal transit recovery usually between postoperative
days three and five and continue for three months
Placebo group
- Identical-appearing capsules administered in the same quantity and manner
Co-interventions all patients received standard triple-drug regimens (steroids azathio-
prine and cyclosporine or tacrolimus)
Outcomes All cause mortality
Number with retransplantation
Number of patients with acute cellular rejection
Number of patients with chronic rejection
Serum bilirubin levels at the end of treatment
Notes Follow-up time nine months
Letter was sent to the authors in September 2009 No reply was received
Risk of bias
Item Authorsrsquo judgement Description
Adequate sequence generation Unclear No information provided
Allocation concealment Unclear No information provided
Blinding Yes Method of blinding not described but
probably adequate
Incomplete outcome data addressed
All outcomes
Yes Withdrawal one patient from the UDCA
group and two patients from the placebo
group because of capsule size
23Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Fleckenstein 1998 (Continued)
Free of selective reporting Unclear Outcomes were not completely described
Sample size calculation No Not reported
Intention-to-treat analysis Yes Quote ldquoThree patients withdrew after in-
clusionThey were included in the statis-
tical analysisrdquo
Baseline imbalance Unclear Not enough information provided
Early stopping of trial Unclear Not enough information provided
Keiding 1997
Methods Study design prospective randomised placebo-controlled multicenter study
Participants Country Denmark Finland Norway and Sweden
Publication language English
Inclusion criteria
- patients who underwent liver transplantation in Denmark Finland Norway and Swe-
den from September 1 1992 to May 31 1994
Exclusion criteria
- patients with malignant diseases
Participants
The age of the children ranged from 0 to 13 years (median 15) and the age of adults
ranged from 14 to 59 years old (median 44) MaleFemale ratio was 96 for children and
4344 for adults
- UDCA group (n = 54)
Origins of liver diseases
paracetamol intoxication 1 hepatitis B 1 autoimmune hepatitis 0 biliary atresia 2
metabolic diseases 7 neonatal hepatitis 2 PBC 13 post hepatitis cirrhosis 8 PSC 3
cryptogenic cirrhosis 7 alcoholic cirrhosis 2 other reasons 8
- Placebo group (n = 48)
Origins of liver diseases paracetamol intoxication 1 hepatitis B 0 autoimmune hepatitis
1 biliary atresia 3 metabolic diseases 11 neonatal hepatitis 0 PBC 7 post hepatitis
cirrhosis 5 PSC 7 cryptogenic cirrhosis 2 alcoholic cirrhosis 6 other reasons 5
Interventions UDCA group
- Dose 15 mgkg body weightday in two or three divided doses
- Route orally
- Duration immediately after intestinal transit recovery usually between postoperative
days three and five and continue for three months
Placebo group
- Identical-appearing capsules administered in the same quantity and manner
Co-interventions all patients received standard triple-drug regimens (steroids azathio-
prine and cyclosporine or tacrolimus)
24Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Keiding 1997 (Continued)
Outcomes All cause mortality
Number of deaths related to rejection
Number of patients with acute cellular rejection
Number of patients with chronic rejection
Number of patients with steroid-resistant rejection
Adverse events
Notes Letter was sent to the authors in September 2009 No reply was received
Risk of bias
Item Authorsrsquo judgement Description
Adequate sequence generation Unclear Patients were randomised at a ratio of 11
Allocation concealment Yes Quote ldquo The allocation was performed in
blocks of 10 patients using the sealed serial
envelope methodrdquo
Blinding Yes Quote ldquoThe UDCA and the placebo cap-
sules had identical appearance and tasterdquo
Incomplete outcome data addressed
All outcomes
Yes Follow-up time 12 months Five UDCA
patients and five placebo patients withdrew
from study Reasons were reported
Free of selective reporting Unclear Insufficient information
Sample size calculation Yes Performed and allowed for a difference in
the incidence of at least one episode of
acute rejection of 50 between the treat-
ment and placebo groups with 90 statisti-
cal power and a significance level of P value
less than 005 The calculated sample size
was 80 patients
Intention-to-treat analysis Yes Stated and used
Baseline imbalance Yes The study seems to be free of baseline im-
balance
Early stopping of trial Yes Study attained the pre-specified sample
size
25Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Koneru 1993
Methods Study design randomised controlled trial
Participants Country United States
Publication language English
Inclusion criteria
- patients who underwent liver transplantation
Exclusion criteria
- not mentioned
Participants
- UDCA group (n = 16)
Mean age (years +- SD)
no information
Ratio of sex (malefemale) no information
Origins of liver diseases
no information
- Control group (n = 16)
Mean age (years +- SD)
no information
Ratio of sex (malefemale) no information
Origins of liver diseases
no information
Interventions UDCA group
- Dose 900 mgday
- Route orally
- Duration immediately after intestinal transit recovery usually between postoperative
days three and five and continue for three months
Control group
- no treatment
Co-interventions all patients received standard triple-drug regimens (steroids azathio-
prine and cyclosporine)
Outcomes Number of patients with retransplantation due to rejection
Number of patients with rejection episodes
Notes Abstract
Letter was sent to the authors in September 2009 No reply was received
Risk of bias
Item Authorsrsquo judgement Description
Adequate sequence generation Unclear No information provided
Allocation concealment Unclear No information provided
Blinding No Not performed
26Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Koneru 1993 (Continued)
Incomplete outcome data addressed
All outcomes
Unclear The study gives the impression that there
were no withdrawals but this was not ex-
plicitly stated
Free of selective reporting Unclear Insufficient information provided
Sample size calculation No Not performed
Intention-to-treat analysis Unclear No information provided
Baseline imbalance Unclear Not enough information provided
Early stopping of trial Unclear Not enough information provided
Pageaux 1995
Methods Study design double-blind randomised study
Participants Country France
Publication language English
Inclusion criteria
- patients who underwent liver transplantation
Exclusion criteria
- not mentioned
Participants
- UDCA group (n=26)
Mean age (years +- SD)
47 +- 10
Ratio of sex (malefemale) 179
Origins of liver diseases alcoholic cirrhosis 14
post-hepatic B cirrhosis 2
post-hepatitis C cirrhosis 4
PBC 2
liver cancer 2
fulminant hepatitis 1
miscellaneous 1
- Placebo group (n = 24)
Mean age (years +- SD)
51+- 9
Ratio of sex (malefemale) 159
Origins of liver diseases alcoholic cirrhosis 10
post-hepatic B cirrhosis 0
post-hepatic C cirrhosis 6
PBC 3
liver cancer 4
fulminant hepatitis 0
miscellaneous 1
27Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Pageaux 1995 (Continued)
Interventions UDCA group
- Dose 600 mgday in three divided doses
- Route orally
- Duration immediately after intestinal transit recovery usually between postoperative
days three and five and continue for two months
Placebo group
- identical-appearing capsules administered in the same quantity and manner
Co-interventions all patients received standard triple-drug regimens (steroids azathio-
prine and cyclosporine or tacrolimus)
Outcomes Number of patients with acute cellular rejection
Number of patients with steroid-resistant rejection
Notes Letter was sent to the authors in September 2009 No reply was received
Risk of bias
Item Authorsrsquo judgement Description
Adequate sequence generation Unclear No information provided
Allocation concealment Unclear No information provided
Blinding Unclear Method of blinding not described
Incomplete outcome data addressed
All outcomes
Yes Five patients died from non-immunologi-
cal causes before the end of the first month
and were excluded from the study Reasons
were reported
Free of selective reporting Unclear Not enough information provided
Sample size calculation No Not performed
Intention-to-treat analysis No Not stated and not used
Baseline imbalance Unclear Not enough information provided
Early stopping of trial Unclear Not enough information provided
Sama 1991
Methods Study design randomised controlled trial
Participants Country Italy
Publication language English
Inclusion criteria
28Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Sama 1991 (Continued)
- patients who underwent liver transplantation
Exclusion criteria
- not mentioned
Participants
- UDCA group (n = 20)
Mean age (years +- SD)
no information
Ratio of sex (malefemale) no information
Origins of liver diseases
no information
- Control group (n = 20)
Mean age (years +- SD)
no information
Ratio of sex (malefemale) no information
Origins of liver diseases
no information
Interventions UDCA group
- Dose 600 mgday in two divided doses
- Route orally
- Duration immediately after intestinal transit recovery usually between postoperative
day five and day seven and continue for six months
Control group
- no treatment
Co-interventions all patients received standard immunosuppressive treatment (steroids
and cyclosporine)
Outcomes All cause mortality
Number of patients with acute cellular rejection
Notes Abstract
Letter was sent to the authors in September 2009 No reply was received
Risk of bias
Item Authorsrsquo judgement Description
Adequate sequence generation Unclear A randomisation list was performed before
patients were admitted to the trial (infor-
mation from principal author)
Allocation concealment Unclear No information provided
Blinding Unclear The principle author provided information
that the study was made according to a
single-blind randomised protocol The pri-
mary outcome was the occurrence of biopsy
proven rejection episodes The pathologists
were blind but the patients were not
29Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Sama 1991 (Continued)
Incomplete outcome data addressed
All outcomes
Unclear Five patients from the UDCA group and
six patients from the placebo group were
excluded Reasons for exclusion were not
fully stated
Free of selective reporting No Data about survival of patients were not
adequately reported
Sample size calculation No Not performed
Intention-to-treat analysis No Not stated and not used
Baseline imbalance Unclear Basic characteristics of patients not re-
ported
Early stopping of trial Unclear Not enough information provided
UDCA = ursodeoxycholic acid
TUDCA = tauroursodeoxycholic acid
PBC = primary biliary cirrhosis
PSC = primary sclerosing cholangitis
OKT3 = anti-CD3 monoclonal antibody
Characteristics of excluded studies [ordered by study ID]
Assy 2007 A randomised controlled trial that included only recipients of liver transplantation with stable graft function and
no episodes of rejection for at least 2 years that were then offered total immunosuppression withdrawal Fourteen
patients received UDCA (15 mgkg body weightday) and 12 received placebo Rejection occurred in 43 and
75 of patients respectively (no significant difference) None developed chronic rejection After follow-up two
patients were free of immunosuppression 80 were steroid free and 50 were able to reduce their dose of
cyclosporine
Clavien 1996 Case series Fifty consecutive liver-transplanted patients were treated with a standard cyclosporine immunosup-
pressive regimen Twenty three of the 43 survivors developed an episode of rejection and UDCA (10 mgkg
weightday) was initiated Only one patient had a second episode of rejection
Friman 1992 Observational study Thirty-three liver-transplanted patients received 10 mg UDCAkg body weightday for
median of 10 months (range four to 21 months) Eight historical liver-transplanted patients served as control
group The rejection incidence was significantly lower in the patients who received the treatment with UDCA
Biochemistry one month after transplantation demonstrated significantly lower average values of aminotrans-
ferases and alkaline phosphatases in patients treated with UDCA than in the control group
30Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
Heathcote 1999 Observational study From 1987 to 1996 37 UDCA treated and 53 placebo treated patients with primary biliary
cirrhosis were referred for transplantation Posttransplantation survival rates at one month were 939 in the
UDCA group and 884 in the placebo group and one year survival rates were 903 and 784 respectively
(no significant differences) However rejection (type not defined - a secondary outcome measure) occurred
significantly less often in the UDCA group (429) than in placebo group (688)
Henriksson 1991 Observational study All patients in this study were given sequential quadruple immunosuppression with anti-
lymphocyte globulin azathioprine steroids and cyclosporine All patients with primary graft function (n = 11)
were treated with 10 mg UDCAkg body weightday starting during the first postoperative week Patients who
received liver transplantation in the first 6 months of 1989 (n = 8) served as controls In the control group one
patient died after 9 months with chronic graft dysfunction and six patients had rejection episodes during the
first postoperative month All patients in the UDCA group were alive without rejection episodes
Persson 1990 Observational study All 11 adult patients transplanted between August 1989 and January 1990 with primary
graft function were treated with 10 mg UDCA kg body weightday Eight patients transplanted during the first
half of 1989 served as control UDCA was started during the first postoperative week and the treatment was
continued for six months All patients in the UDCA treated group survived with satisfactory graft function In
the control group six patients had at least one rejection episode needing treatment during the first postoperative
month
Rafael 1995 Observational study Seventeen patients who underwent liver transplantation between February 1990 and April
1993 and developed biliary complications after transplantation were retrospectively analysed regarding treatment
with UDCA UDCA was given in a dose of 500 to 1000 mgday Ten patients were treated for at least one year while
seven patients were treated for 14 to 250 days UDCA significantly improved gammaglutamyl transpeptidase in
liver graft recipients with biliary complications There was also a trend towards improvement in serum bilirubin
and alanine transaminase values
Sama 1998 Observational study Thirty-four patients who underwent liver transplantation between January 1995 and June
1996 were included in the study Seventeen were treated with UDCA 10 mgkg body weightday during 6
months while 17 served as controls on the basis of having undergone liver transplantation closest to UDCA
patients A significant decrease in serum bilirubin levels was observed in UDCA patients There was a significantly
higher incidence of recurrent hepatitis in the control group
UDCA ursodeoxycholic acid
31Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
D A T A A N D A N A L Y S E S
Comparison 1 Bile acids for liver-transplanted patients
Outcome or subgroup titleNo of
studies
No of
participants Statistical method Effect size
1 All-cause mortality at maximum
follow-up
5 257 Risk Ratio (M-H Fixed 95 CI) 085 [053 136]
11 UDCA versus placebo or
no treatment
4 224 Risk Ratio (M-H Fixed 95 CI) 080 [049 130]
12 TUDCA versus no
treatment
1 33 Risk Ratio (M-H Fixed 95 CI) 159 [030 833]
2 All-cause mortality worst-best
case and best-worst case
scenarios
5 Risk Ratio (M-H Fixed 95 CI) Subtotals only
21 Worst-best case scenario 5 257 Risk Ratio (M-H Fixed 95 CI) 130 [086 196]
22 Best-worst case scenario 5 257 Risk Ratio (M-H Fixed 95 CI) 058 [038 090]
3 Subgroup analyses all-cause
mortality at maximum
follow-up according to time of
start of bile acids
5 257 Risk Ratio (M-H Fixed 95 CI) 085 [053 136]
31 Less than three days after
transplantation
1 102 Risk Ratio (M-H Fixed 95 CI) 124 [061 254]
32 Three days or more after
transplantation
4 155 Risk Ratio (M-H Fixed 95 CI) 063 [033 120]
4 Subgroup analyses all cause
mortality at maximum
follow-up according to
treatment duration
5 257 Risk Ratio (M-H Fixed 95 CI) 085 [053 136]
41 Less than six months 3 184 Risk Ratio (M-H Fixed 95 CI) 078 [045 138]
42 Six months or more 2 73 Risk Ratio (M-H Fixed 95 CI) 102 [043 240]
5 Number of deaths related
to rejection at maximum
follow-up
1 102 Risk Ratio (M-H Fixed 95 CI) 030 [001 712]
51 UDCA versus placebo 1 102 Risk Ratio (M-H Fixed 95 CI) 030 [001 712]
6 Number of retransplantations at
maximum follow-up
2 132 Risk Ratio (M-H Fixed 95 CI) 076 [020 286]
7 Number of patients with acute
cellular rejection at maximum
follow-up
7 339 Risk Ratio (M-H Fixed 95 CI) 089 [074 106]
71 UDCA versus placebo or
no treatment
6 306 Risk Ratio (M-H Fixed 95 CI) 089 [074 108]
72 TUDCA versus no
treatment
1 33 Risk Ratio (M-H Fixed 95 CI) 085 [045 160]
8 Subgroup analysis number of
patients with acute cellular
rejection according to time of
start of bile acid
7 339 Risk Ratio (M-H Fixed 95 CI) 089 [074 106]
32Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
81 Less than three days after
transplantation
2 134 Risk Ratio (M-H Fixed 95 CI) 084 [063 111]
82 Three days or more after
liver transplantation
5 205 Risk Ratio (M-H Fixed 95 CI) 092 [072 117]
9 Subgroup analysis number
of patients with acute
cellular rejection according to
treatment duration
7 339 Risk Ratio (M-H Fixed 95 CI) 089 [074 106]
91 Less than six months 5 266 Risk Ratio (M-H Fixed 95 CI) 087 [071 107]
92 Six months or more 2 73 Risk Ratio (M-H Fixed 95 CI) 094 [065 136]
10 Number of patients with
chronic rejection at maximum
follow-up
3 184 Risk Ratio (M-H Fixed 95 CI) 028 [008 095]
11 Number of patients with
steroid-resistant rejection at
maximum follow-up
4 234 Risk Ratio (M-H Fixed 95 CI) 077 [047 127]
12 Serum bilirubin (mgdl) at the
end of treatment
1 30 Mean Difference (IV Fixed 95 CI) 26 [-096 616]
13 Number of days of
hospitalisation after liver
transplantation
1 52 Mean Difference (IV Fixed 95 CI) -85 [-1667 -033]
14 Adverse events 3 187 Risk Ratio (M-H Fixed 95 CI) 088 [030 260]
Analysis 11 Comparison 1 Bile acids for liver-transplanted patients Outcome 1 All-cause mortality at
maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 1 All-cause mortality at maximum follow-up
Study or subgroup Favours bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 UDCA versus placebo or no treatment
Barnes 1997 228 724 253 024 [ 006 107 ]
Fleckenstein 1998 214 416 125 057 [ 012 266 ]
Keiding 1997 1454 1048 355 124 [ 061 254 ]
Sama 1991 520 620 201 083 [ 030 229 ]
Subtotal (95 CI) 116 108 935 080 [ 049 130 ]
Total events 23 (Favours bile acids) 27 (Control)
Heterogeneity Chi2 = 416 df = 3 (P = 025) I2 =28
Test for overall effect Z = 091 (P = 036)
01 02 05 1 2 5 10
Favours bile acids Favours control
(Continued )
33Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Favours bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
2 TUDCA versus no treatment
Angelico 1999 316 217 65 159 [ 030 833 ]
Subtotal (95 CI) 16 17 65 159 [ 030 833 ]
Total events 3 (Favours bile acids) 2 (Control)
Heterogeneity not applicable
Test for overall effect Z = 055 (P = 058)
Total (95 CI) 132 125 1000 085 [ 053 136 ]
Total events 26 (Favours bile acids) 29 (Control)
Heterogeneity Chi2 = 466 df = 4 (P = 032) I2 =14
Test for overall effect Z = 069 (P = 049)
01 02 05 1 2 5 10
Favours bile acids Favours control
Analysis 12 Comparison 1 Bile acids for liver-transplanted patients Outcome 2 All-cause mortality worst-
best case and best-worst case scenarios
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 2 All-cause mortality worst-best case and best-worst case scenarios
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 Worst-best case scenario
Angelico 1999 516 217 65 266 [ 060 1180 ]
Barnes 1997 828 724 253 098 [ 042 230 ]
Fleckenstein 1998 314 416 125 086 [ 023 319 ]
Keiding 1997 1954 1048 355 169 [ 087 327 ]
Sama 1991 520 620 201 083 [ 030 229 ]
Subtotal (95 CI) 132 125 1000 130 [ 086 196 ]
Total events 40 (Bile acids) 29 (Control)
Heterogeneity Chi2 = 303 df = 4 (P = 055) I2 =00
Test for overall effect Z = 123 (P = 022)
2 Best-worst case scenario
005 02 1 5 20
Favours bile acids Favours control
(Continued )
34Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Angelico 1999 316 417 90 080 [ 021 302 ]
Barnes 1997 228 1124 274 016 [ 004 063 ]
Fleckenstein 1998 214 616 130 038 [ 009 159 ]
Keiding 1997 1454 1548 368 083 [ 045 154 ]
Sama 1991 520 620 139 083 [ 030 229 ]
Subtotal (95 CI) 132 125 1000 058 [ 038 090 ]
Total events 26 (Bile acids) 42 (Control)
Heterogeneity Chi2 = 567 df = 4 (P = 023) I2 =29
Test for overall effect Z = 247 (P = 0014)
005 02 1 5 20
Favours bile acids Favours control
Analysis 13 Comparison 1 Bile acids for liver-transplanted patients Outcome 3 Subgroup analyses all-
cause mortality at maximum follow-up according to time of start of bile acids
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 3 Subgroup analyses all-cause mortality at maximum follow-up according to time of start of bile acids
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 Less than three days after transplantation
Keiding 1997 1454 1048 355 124 [ 061 254 ]
Subtotal (95 CI) 54 48 355 124 [ 061 254 ]
Total events 14 (Bile acids) 10 (Control)
Heterogeneity not applicable
Test for overall effect Z = 060 (P = 055)
2 Three days or more after transplantation
Angelico 1999 316 217 65 159 [ 030 833 ]
Barnes 1997 228 724 253 024 [ 006 107 ]
Fleckenstein 1998 214 416 125 057 [ 012 266 ]
Sama 1991 520 620 201 083 [ 030 229 ]
005 02 1 5 20
Favours bile acids Favours control
(Continued )
35Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Subtotal (95 CI) 78 77 645 063 [ 033 120 ]
Total events 12 (Bile acids) 19 (Control)
Heterogeneity Chi2 = 310 df = 3 (P = 038) I2 =3
Test for overall effect Z = 141 (P = 016)
Total (95 CI) 132 125 1000 085 [ 053 136 ]
Total events 26 (Bile acids) 29 (Control)
Heterogeneity Chi2 = 466 df = 4 (P = 032) I2 =14
Test for overall effect Z = 069 (P = 049)
005 02 1 5 20
Favours bile acids Favours control
Analysis 14 Comparison 1 Bile acids for liver-transplanted patients Outcome 4 Subgroup analyses all
cause mortality at maximum follow-up according to treatment duration
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 4 Subgroup analyses all cause mortality at maximum follow-up according to treatment duration
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 Less than six months
Barnes 1997 228 724 253 024 [ 006 107 ]
Fleckenstein 1998 214 416 125 057 [ 012 266 ]
Keiding 1997 1454 1048 355 124 [ 061 254 ]
Subtotal (95 CI) 96 88 734 078 [ 045 138 ]
Total events 18 (Bile acids) 21 (Control)
Heterogeneity Chi2 = 417 df = 2 (P = 012) I2 =52
Test for overall effect Z = 084 (P = 040)
2 Six months or more
Angelico 1999 316 217 65 159 [ 030 833 ]
Sama 1991 520 620 201 083 [ 030 229 ]
Subtotal (95 CI) 36 37 266 102 [ 043 240 ]
Total events 8 (Bile acids) 8 (Control)
Heterogeneity Chi2 = 043 df = 1 (P = 051) I2 =00
005 02 1 5 20
Favours bile acids Favours control
(Continued )
36Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Test for overall effect Z = 004 (P = 097)
Total (95 CI) 132 125 1000 085 [ 053 136 ]
Total events 26 (Bile acids) 29 (Control)
Heterogeneity Chi2 = 466 df = 4 (P = 032) I2 =14
Test for overall effect Z = 069 (P = 049)
005 02 1 5 20
Favours bile acids Favours control
Analysis 15 Comparison 1 Bile acids for liver-transplanted patients Outcome 5 Number of deaths related
to rejection at maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 5 Number of deaths related to rejection at maximum follow-up
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 UDCA versus placebo
Keiding 1997 054 148 1000 030 [ 001 712 ]
Total (95 CI) 54 48 1000 030 [ 001 712 ]
Total events 0 (Bile acids) 1 (Control)
Heterogeneity not applicable
Test for overall effect Z = 075 (P = 045)
0001 001 01 1 10 100 1000
Favours bile acids Favours control
37Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 16 Comparison 1 Bile acids for liver-transplanted patients Outcome 6 Number of
retransplantations at maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 6 Number of retransplantations at maximum follow-up
Study or subgroup Bile acids Placebo Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Fleckenstein 1998 214 016 100 567 [ 029 10891 ]
Keiding 1997 154 448 900 022 [ 003 192 ]
Total (95 CI) 68 64 1000 076 [ 020 286 ]
Total events 3 (Bile acids) 4 (Placebo)
Heterogeneity Chi2 = 303 df = 1 (P = 008) I2 =67
Test for overall effect Z = 040 (P = 069)
0001 001 01 1 10 100 1000
Favours bile acids Favours placebo
Analysis 17 Comparison 1 Bile acids for liver-transplanted patients Outcome 7 Number of patients with
acute cellular rejection at maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 7 Number of patients with acute cellular rejection at maximum follow-up
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 UDCA versus placebo or no treatment
Barnes 1997 1728 1724 180 086 [ 058 127 ]
Fleckenstein 1998 814 916 83 102 [ 054 190 ]
Keiding 1997 3554 3248 333 097 [ 073 129 ]
Koneru 1993 316 916 89 033 [ 011 101 ]
Pageaux 1995 926 924 92 092 [ 044 193 ]
Sama 1991 1320 1320 128 100 [ 063 158 ]
Subtotal (95 CI) 158 148 905 089 [ 074 108 ]
01 02 05 1 2 5 10
Favours bile acids Favours control
(Continued )
38Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Total events 85 (Bile acids) 89 (Control)
Heterogeneity Chi2 = 387 df = 5 (P = 057) I2 =00
Test for overall effect Z = 120 (P = 023)
2 TUDCA versus no treatment
Angelico 1999 816 1017 95 085 [ 045 160 ]
Subtotal (95 CI) 16 17 95 085 [ 045 160 ]
Total events 8 (Bile acids) 10 (Control)
Heterogeneity not applicable
Test for overall effect Z = 050 (P = 061)
Total (95 CI) 174 165 1000 089 [ 074 106 ]
Total events 93 (Bile acids) 99 (Control)
Heterogeneity Chi2 = 392 df = 6 (P = 069) I2 =00
Test for overall effect Z = 130 (P = 019)
01 02 05 1 2 5 10
Favours bile acids Favours control
Analysis 18 Comparison 1 Bile acids for liver-transplanted patients Outcome 8 Subgroup analysis
number of patients with acute cellular rejection according to time of start of bile acid
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 8 Subgroup analysis number of patients with acute cellular rejection according to time of start of bile acid
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 Less than three days after transplantation
Keiding 1997 3554 3248 333 097 [ 073 129 ]
Koneru 1993 316 916 89 033 [ 011 101 ]
Subtotal (95 CI) 70 64 422 084 [ 063 111 ]
Total events 38 (Bile acids) 41 (Control)
Heterogeneity Chi2 = 374 df = 1 (P = 005) I2 =73
Test for overall effect Z = 124 (P = 022)
2 Three days or more after liver transplantation
Angelico 1999 816 1017 95 085 [ 045 160 ]
01 02 05 1 2 5 10
Favours bile acids Favours control
(Continued )
39Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Barnes 1997 1728 1724 180 086 [ 058 127 ]
Fleckenstein 1998 814 916 83 102 [ 054 190 ]
Pageaux 1995 926 924 92 092 [ 044 193 ]
Sama 1991 1320 1320 128 100 [ 063 158 ]
Subtotal (95 CI) 104 101 578 092 [ 072 117 ]
Total events 55 (Bile acids) 58 (Control)
Heterogeneity Chi2 = 041 df = 4 (P = 098) I2 =00
Test for overall effect Z = 067 (P = 050)
Total (95 CI) 174 165 1000 089 [ 074 106 ]
Total events 93 (Bile acids) 99 (Control)
Heterogeneity Chi2 = 392 df = 6 (P = 069) I2 =00
Test for overall effect Z = 130 (P = 019)
01 02 05 1 2 5 10
Favours bile acids Favours control
40Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 19 Comparison 1 Bile acids for liver-transplanted patients Outcome 9 Subgroup analysis
number of patients with acute cellular rejection according to treatment duration
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 9 Subgroup analysis number of patients with acute cellular rejection according to treatment duration
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 Less than six months
Barnes 1997 1728 1724 180 086 [ 058 127 ]
Fleckenstein 1998 814 916 83 102 [ 054 190 ]
Keiding 1997 3554 3248 333 097 [ 073 129 ]
Koneru 1993 316 916 89 033 [ 011 101 ]
Pageaux 1995 926 924 92 092 [ 044 193 ]
Subtotal (95 CI) 138 128 777 087 [ 071 107 ]
Total events 72 (Bile acids) 76 (Control)
Heterogeneity Chi2 = 374 df = 4 (P = 044) I2 =00
Test for overall effect Z = 129 (P = 020)
2 Six months or more
Angelico 1999 816 1017 95 085 [ 045 160 ]
Sama 1991 1320 1320 128 100 [ 063 158 ]
Subtotal (95 CI) 36 37 223 094 [ 065 136 ]
Total events 21 (Bile acids) 23 (Control)
Heterogeneity Chi2 = 017 df = 1 (P = 068) I2 =00
Test for overall effect Z = 035 (P = 073)
Total (95 CI) 174 165 1000 089 [ 074 106 ]
Total events 93 (Bile acids) 99 (Control)
Heterogeneity Chi2 = 392 df = 6 (P = 069) I2 =00
Test for overall effect Z = 130 (P = 019)
01 02 05 1 2 5 10
Favours bile acids Favours control
41Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 110 Comparison 1 Bile acids for liver-transplanted patients Outcome 10 Number of patients
with chronic rejection at maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 10 Number of patients with chronic rejection at maximum follow-up
Study or subgroup Bile acids Placebo Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Barnes 1997 128 624 611 014 [ 002 110 ]
Fleckenstein 1998 114 116 88 114 [ 008 1663 ]
Keiding 1997 154 348 300 030 [ 003 275 ]
Total (95 CI) 96 88 1000 028 [ 008 095 ]
Total events 3 (Bile acids) 10 (Placebo)
Heterogeneity Chi2 = 148 df = 2 (P = 048) I2 =00
Test for overall effect Z = 204 (P = 0041)
0001 001 01 1 10 100 1000
Favours bile acids Favours placebo
Analysis 111 Comparison 1 Bile acids for liver-transplanted patients Outcome 11 Number of patients
with steroid-resistant rejection at maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 11 Number of patients with steroid-resistant rejection at maximum follow-up
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Barnes 1997 328 724 277 037 [ 011 127 ]
Fleckenstein 1998 314 316 103 114 [ 027 478 ]
Keiding 1997 1454 1548 583 083 [ 045 154 ]
Pageaux 1995 226 124 38 185 [ 018 1908 ]
Total (95 CI) 122 112 1000 077 [ 047 127 ]
Total events 22 (Bile acids) 26 (Control)
Heterogeneity Chi2 = 226 df = 3 (P = 052) I2 =00
Test for overall effect Z = 102 (P = 031)
001 01 1 10 100
Favours bile acids Favours placebo
42Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 112 Comparison 1 Bile acids for liver-transplanted patients Outcome 12 Serum bilirubin (mgdl)
at the end of treatment
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 12 Serum bilirubin (mgdl) at the end of treatment
Study or subgroup Bile acids Placebo Mean Difference Weight Mean Difference
N Mean(SD) N Mean(SD) IVFixed95 CI IVFixed95 CI
Fleckenstein 1998 14 319 (68) 16 059 (022) 1000 260 [ -096 616 ]
Total (95 CI) 14 16 1000 260 [ -096 616 ]
Heterogeneity not applicable
Test for overall effect Z = 143 (P = 015)
-10 -5 0 5 10
Favours bile acids Favours placebo
Analysis 113 Comparison 1 Bile acids for liver-transplanted patients Outcome 13 Number of days of
hospitalisation after liver transplantation
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 13 Number of days of hospitalisation after liver transplantation
Study or subgroup Bile acids Placebo Mean Difference Weight Mean Difference
N Mean(SD) N Mean(SD) IVFixed95 CI IVFixed95 CI
Barnes 1997 28 25 (17) 24 335 (13) 1000 -850 [ -1667 -033 ]
Total (95 CI) 28 24 1000 -850 [ -1667 -033 ]
Heterogeneity not applicable
Test for overall effect Z = 204 (P = 0041)
-100 -50 0 50 100
Favours bile acids Favours placebo
43Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 114 Comparison 1 Bile acids for liver-transplanted patients Outcome 14 Adverse events
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 14 Adverse events
Study or subgroup Bile acids Placebo Risk Ratio Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Angelico 1999 016 017 00 [ 00 00 ]
Barnes 1997 128 124 086 [ 006 1298 ]
Keiding 1997 554 548 089 [ 027 288 ]
Total (95 CI) 98 89 088 [ 030 260 ]
Total events 6 (Bile acids) 6 (Placebo)
Heterogeneity Chi2 = 000 df = 1 (P = 098) I2 =00
Test for overall effect Z = 022 (P = 082)
001 01 1 10 100
Favours bile acids Favours placebo
A P P E N D I C E S
Appendix 1 Search strategies
Data Base Date of Search Search Strategy
The Cochrane Hepato-Biliary Group Con-
trolled Trials Register
September 2009 1 rsquoliver transplantationrsquo and rsquochenodeoxy-
cholicrsquo
2 rsquoliver transplantationrsquo and rsquocholicrsquo
3 rsquoliver transplantationrsquo and rsquodeoxycholicrsquo
4 rsquoliver transplantationrsquo and rsquoglycochen-
odeoxycholicrsquo
5 rsquoliver transplantationrsquo and rsquoglycocholicrsquo
6 rsquoliver transplantationrsquo and rsquoglycodeoxy-
cholicrsquo
7 rsquoliver transplantationrsquo and rsquoglycolitho-
cholicrsquo
8 rsquoliver transplantationrsquo and rsquohyodeoxy-
cholicrsquo
9 rsquoliver transplantationrsquo and rsquolithocholicrsquo
10 rsquoliver transplantationrsquo and rsquotaurochen-
odeoxycholicrsquo
44Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
11 rsquoliver transplantationrsquo and rsquotauro-
cholicrsquo
12 rsquoliver transplantationrsquo and rsquotaurodehy-
drocholicrsquo
13 rsquoliver transplantationrsquo and rsquotau-
rodeoxycholicrsquo
14 rsquoliver transplantationrsquo and rsquotauroglyco-
cholicrsquo
15 rsquoliver transplantationrsquo and rsquotaurolitho-
cholicrsquo
16 rsquoliver transplantationrsquo and rsquotaurosel-
cholicrsquo
17 rsquoliver transplantationrsquo and rsquotaurourso-
cholicrsquo
18 rsquoliver transplantationrsquo and rsquotaurour-
sodeoxycholicrsquo
19 rsquoliver transplantationrsquo and rsquoursocholicrsquo
20 rsquoliver transplantationrsquo and rsquoursodeoxy-
cholicrsquo
The Cochrane Central Register of Con-
trolled Trials in The Cochrane Library
Issue 3 2009 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
6 3 or 4
7 5 and 6
MEDLINE September 2009 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
45Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
6 3 or 4
7 5 and 6
8 RANDOMIZED-CONTROLLED-
TRIAL ME
9 RANDOM
10 8 or 9
11 7 and 10
EMBASE September 2009 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
6 3 or 4
7 5 and 6
8 RANDOMIZED-CONTROLLED-
TRIAL ME
9 RANDOM
10 8 or 9
11 7 and 10
46Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
Science Citation Index Expanded September 2009 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
6 3 or 4
7 5 and 6
8 RANDOMIZED-CONTROLLED-
TRIAL ME
9 RANDOM
10 8 or 9
11 7 and 10
The Chinese Biomedical Database Searched from January 1980 to April 2002 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
47Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
6 3 or 4
7 5 and 6
8 RANDOMIZED-CONTROLLED-
TRIAL ME
9 RANDOM
10 8 or 9
11 7 and 10
W H A T rsquo S N E W
Last assessed as up-to-date 8 February 2010
18 September 2009 New citation required but conclusions have not
changed
This review is an updated version of a review that was
published for the first time in Issue 3 2005 of TheCochrane Library by Chen 2003b
18 September 2009 New search has been performed No new studies fulfilled the inclusion criteria
H I S T O R Y
Protocol first published Issue 3 2003
Review first published Issue 3 2005
C O N T R I B U T I O N S O F A U T H O R S
GP and VG independently performed searches of relevant databases GP validated the search selected trials for inclusion contacted
the authors of the trials performed data extraction and data analysis and drafted the systematic review VG revised the review update
CG and DS revised the review update solved discrepancies of data extraction validated data analyses and provided consultation
D E C L A R A T I O N S O F I N T E R E S T
None known
48Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
S O U R C E S O F S U P P O R T
Internal sources
bull Copenhagen Trial Unit Denmark
External sources
bull Danish Medical Research Councilrsquos Grant on Getting Research into Practice (GRIP) Denmark
D I F F E R E N C E S B E T W E E N P R O T O C O L A N D R E V I E W
We assessed the risk of bias in the included studies for another four domains that were added to the review protocol (incomplete
outcome data selective outcome reporting baseline imbalance and early stopping of trial) In general the text of the risk of bias
domains were updated following Higgins 2008 Trials were considered at low risk of bias when judged as adequate in all domains
Quasi-randomised studies observational and case-control studies were included for the report of adverse events
We performed trial sequential analysis for outcomes demonstrating a statistically significant result
I N D E X T E R M S
Medical Subject Headings (MeSH)
lowastLiver Transplantation Cholagogues and Choleretics [lowasttherapeutic use] Graft Rejection [lowastprevention amp control] Randomized Con-
trolled Trials as Topic Taurochenodeoxycholic Acid [lowasttherapeutic use] Ursodeoxycholic Acid [lowasttherapeutic use]
MeSH check words
Humans
49Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
did not significantly change all-cause mortality (RR 085 95 CI 053 to 136) mortality related to allograft rejection (RR 030
95 CI 001 to 712) retransplantation (RR 076 95 CI 020 to 286) acute cellular rejection or number of patients with steroid-
resistant rejection Bile acids significantly reduced the number of patients who had chronic rejection in a fixed-effect model but not in
a random-effects model meta-analysis Bile acids were safe and well tolerated by liver-transplanted patients However this observation
is based on data analysis from three trials with only 187 patients
Authorsrsquo conclusions
We did not find evidence to support or refute bile acids for liver-transplanted patients Further randomised trials are necessary before
bile acids can be recommended to liver-transplanted patients
P L A I N L A N G U A G E S U M M A R Y
Bile acids for liver-transplanted patients
Liver transplantation is a major surgical procedure that has been practiced for more than forty years and has nowadays become a
generally accepted treatment option in patients with end-stage liver disease The most common cause for liver transplantation in adults
is cirrhosis caused by various types of liver injuries such as infections (hepatitis B and C) alcohol autoimmune liver diseases early-
stage liver cancer metabolic and hereditary disorders but also diseases of unknown aetiology All transplant recipients need lifetime
immunosuppressive therapy to prevent transplant rejection
Bile acids are being used for a variety of chronic liver diseases mainly primary biliary cirrhosis and primary sclerosing cholangitis
However their mechanisms of action and beneficial and harmful effects are poorly understood This has led to the idea of the potential
use of bile acids to prevent rejection in liver-transplanted patients
Results of the seven randomised clinical trials included in the review in which patients received standard immunosuppressive treatment
(steroids azathioprine and cyclosporine or tacrolimus) with or without bile acids after liver transplantation did not show any significant
effects of bile acids on all-cause mortality mortality related to rejection acute cellular rejection steroid resistant rejection or need for
retransplantation One analysis suggested that bile acids might beneficially influence number of patients with chronic rejection but was
contradicted by the analyses The evidence that the use of ursodeoxycholic acid might have beneficial effects on chronic rejection and
length of hospitalisation is weak as it is produced from trials with high risk of bias and insufficient number of included patients That
bile acids seemed well tolerated with no reports of serious adverse events is good knowledge but much more research is needed before
their use is acquitted None of the randomised clinical trials assessed the effects of bile acids on quality of life or cost-effectiveness
B A C K G R O U N D
Liver transplantation has become a widely accepted treatment
for numerous end-stage liver diseases (Hussain 2002 Thalheimer
2002) Previous studies report an incidence of acute cellular rejec-
tion to range from 50 to 80 in adult recipients (Ascher 1988
Klintmalm 1989 Adams 1990 Wiesner 1992 FK506 1994)
However recent data suggest that the proportion of patients with
rejection is currently down to 30 (Hirschfield 2009 Knechtle
2009) Despite advances in immunosuppressive treatment and
care-quality of liver-transplanted patients allograft rejection is still
a major problem in the post-transplantation period
Acute cellular rejection usually occurs within the first 15 to 30 days
after transplantation even if immunosuppression is achieved with
tacrolimus or cyclosporine (FK506 1994 Haddad 2006 Corbani
2008) The cellular mechanisms of acute liver allograft rejection
are not completely understood (Krams 1993) Initiation of al-
lograft rejection is thought to involve the recognition of donor
class II major histocompatibility complex alloantigens by recipient
CD4+ T cells (Vierling 1992) Activated CD4+ T cells produce
cytokines that induce lymphocyte proliferation and the matura-
tion of CD8+ cytotoxic T cells which are specific for donor class I
major histocompatibility complex antigens (Calmus 1990) Both
the bile duct epithelium and central vein endothelium are rich in
class I and class II major histocompatibility complex antigens dur-
ing rejection whereas hepatocytes display a relative paucity of class
I antigens and virtually no class II antigen (Vierling 1992) There-
2Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
fore the bile duct epithelium and central vein endothelium are
the primary targets attacked by cytotoxic T cells during rejection
Impairment of the bile flow in the grafted liver may also cause re-
jection (Ericzon 1990) Mild cholestasis is a common finding after
liver transplantation and its association with clinically significant
pathology is unlikely Nevertheless severe cholestasis should be
treated as a potential cause of allograft rejection (Corbani 2008)
In the study by Fusai 2006 the development of cholestasis was sig-
nificantly related to prolonged warm ischaemia of the liver trans-
plant Cholestasis can induce hyper-expression of major histocom-
patibility complex class I molecules by hepatocytes and thereby
lymphocyte CD8+-dependent cytotoxicity (Calmus 1992)
Bile acids include chenodeoxycholic acid deoxycholic acid litho-
cholic acid and ursodeoxycholic acid (UDCA) (Fuchs 1999)
In the course of cholestasis intrahepatic accumulation of chen-
odeoxycholic acid and deoxycholic acid is thought to induce liver
damage (Palmer 1972) In fact the direct damage of membrane
phospholipids and cholesterol components caused by the deter-
gent-like properties of hydrophobic bile acids results in hepato-
cyte necrosis (Sholmerich 1984 Perez 2009) It is also suggested
that oxidative stress induced by hydrophobic bile acids plays an
important role in liver damage during cholestasis These effects
can be prevented by the addition of UDCA which modifies the
bile acid pool resulting in an increase of the hydrophilic frac-
tion and stabilisation of the cell membranes (Armstrong 1982
Perez 2009) Several studies on animal models showed evidence
of potential immunomodulatory beneficial effects of UDCA and
tauro-ursodeoxycholic acid (TUDCA) by suppressing cytokine
and immunoglobulin production and T-cell mediated cytotoxic-
ity (Yoshikawa 1998) In the study by Calmus 1990 it has been
observed that UDCA down-regulates the expression of abnormal
major histocompatibility complex class I molecules in periportal
hepatocytes in patients with primary biliary cirrhosis Treatment
with UDCA has been reported to have potential beneficial ef-
fects in various cholestatic liver conditions including primary bil-
iary cirrhosis (Gong 2008) primary sclerosing cholangitis (Chen
2003a) and cystic fibrosis (Cheng 2002)
It has previously been suggested that UDCA and perhaps tauro-
UDCA (TUDCA) may reduce the incidence of acute rejection
and steroid-resistant rejection in liver-transplanted patients when
administered with combination of immunosuppressive treatment
There are several potential mechanisms by which UDCA may in-
hibit allograft rejection in liver transplant recipients (Okolicsanyi
1986 Merion 1989 Calmus 1990 Terasaki 1991 Heuman 1993
Al-Quaiz 1994 Friman 1994 Soderdahl 1998 Yoshikawa 1998
Assy 2007 Perez 2009) However most of these studies included
a relatively small number of patients were not randomised and
often did not include histological information (Persson 1990
Friman 1992 Koneru 1993 Sharara 1995)
The previous version of this review by Chen 2003b stated that
there was no convincing beneficial effects from the use of bile acids
in liver-transplanted patients the risk of bias in the seven included
trials was high The review also found that there was a low occur-
rence of adverse events and hence the use of bile acids could be
considered safe It should be noted however that this observation
is based on reports from four trials with few patients We have
been unable to identify any other meta-analyses or systematic re-
views either This review represents an update of the Chen 2003b
Cochrane hepato-Biliary Group review
O B J E C T I V E S
To evaluate the beneficial and harmful effects of bile acids for liver-
transplanted patients by comparing bile acids versus placebo no
intervention or another intervention in randomised clinical trials
M E T H O D S
Criteria for considering studies for this review
Types of studies
We included randomised clinical trials irrespective of blinding
publication status year of publication or language We assessed
both included and excluded studies for the report of adverse events
We listed all studies reporting on adverse events in an additional
table (Table 1) However only data from the included trials were
used in the statistical analysis
Table 1 Adverse events
Study Pts in experimental
group
Patients in control
group
AE in experimental
group
AE in control group Authorrsquos conclusion
Barnes 1997 28 24 Diarrhoea (1 pt) Diarrhoea (1 pt) Adverse
reactions attributable
to study medication
were rare
3Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Table 1 Adverse events (Continued)
Keiding 1997 54 48 Diarrhoea and diffi-
culties in swallowing
capsules (5 pts)
Diarrhoea and diffi-
culties in swallowing
capsules (5 pts)
No other presumed
drug-induced side ef-
fects were observed
Angelico 1999 16 17 No AE No AE TUDCA administra-
tion was well tol-
erated in all pa-
tients and no drug-
related side effects
were recorded
Assy 2007 14 12 Mild diarrhoea (1 pt) No AE No dose reduction
was required
pt(s) = patient(s)
AE = adverse events
Types of participants
Patients who underwent liver transplantation
Types of interventions
Any dose of a bile acid or duration of treatment versus placebo
no intervention or another intervention
We allowed co-interventions if received equally by the intervention
groups within a trial
Types of outcome measures
The primary outcome measures were
1 All-cause mortality
2 Death due to allograft rejection (acute cellular rejection or
chronic rejection or liver retransplantation because of rejection)
Acute cellular rejection was diagnosed by the combination of ab-
normal liver biochemical variables (bilirubin aspartate transam-
inase alanine transaminase alkaline phosphatases andor gam-
maglutamyl transpeptidase) clinical signs such as fever and liver
histological changes including mononuclear portal inflammation
bile duct damage and subendothelial inflammation of portal or
terminal hepatic veins (IWP 1995) Chronic rejection was charac-
terised by liver histological changes including the progressive loss
of interlobular bile ducts and arteriopathy characterised by foam
cell infiltration of the arterial intima
The secondary outcome measures were
3 Number of patients who experienced rejection - irrespective of
the type acute cellular rejection chronic rejection or both types
of rejections
4 Number of patients with acute cellular rejection
5 Number of patients with chronic rejection
6 Number of patients with steroid-resistant rejection
7 Biochemical responses serum activities of alkaline phos-
phatases gammaglutamyl transpeptidase alanine aminotrans-
ferase and aspartate aminotransferase and serum bilirubin con-
centration andor number of patients with abnormal liver bio-
chemical variables mentioned above
8 Adverse events Adverse events were defined as any untoward
medical occurrence not necessarily having a causal relationship
with the treatment but resulting in a dose reduction or discontin-
uation of treatment (ICH-GCP 1997)
9 Quality of life
10 Cost-effectiveness
Search methods for identification of studies
We performed searches of The Cochrane Hepato-Biliary GroupControlled Trials Register (September 2009)(Gluud 2010) and TheCochrane Central Register of Controlled Trials (CENTRAL) in TheCochrane Library (Issue 3 2009) by combining the terms rsquoliverrsquo
and rsquotransplantationrsquo with the individual bile acid name (litho-
cholic acid chenodeoxycholic acid ursodeoxycholic acid deoxy-
cholic acid dehydrocholic acid and tauro-ursodeoxycholic acid)
We searched MEDLINE (January 1966 to September 2009) EM-BASE (January 1980 to September 2009) and Science Citation In-dex Expanded (1945 to September 2009) by using the terms rsquoliverrsquo
4Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
and rsquotransplantationrsquo in combination with the bile acids mentioned
above (Royle 2003) The search strategies with the time span of
the searches are given in Appendix 1 We contacted the Chinese
Cochrane Centre regarding the search of The Chinese BiomedicalDatabase and received a reply that they are unable to help us with
this search Therefore the latter database could not be included
in the search strategy of this update
Further trials were identified by reading the reference lists of the
identified studies We wrote to the principal authors of the reports
of the identified randomised clinical trials in September 2009 and
enquired about additional trials which they might know of The
first team of authors had also written to pharmaceutical companies
involved in the production of bile acids to obtain information on
published or unpublished randomised clinical trials in 2002 but
no information had been received at that time
Data collection and analysis
The update of this review was conducted according to the proto-
col previously published in The Cochrane Library (Chen 2003b)
and following the recommendations given by the Cochrane Hand-book for Systematic Reviews of Interventions (Higgins 2008) and the
Cochrane Hepato-Biliary Group Module (Gluud 2010)
Trial identification
Identified trials were listed and the two review authors evaluated
whether the trials fulfilled the inclusion criteria Excluded trials
were listed with the reasons for exclusion
Data extraction
GP and VG extracted the data independently and disagreements
were resolved by discussion or by CG We extracted the following
characteristics from each trial primary author number of patients
randomised patient inclusion and exclusion criteria methodolog-
ical quality follow-up (number and reasons for withdrawal) sam-
ple size calculation intention-to-treat analysis intervention reg-
imens mean age proportion of males and females aetiology of
liver disease origin of allograft matching criteria between donor
and recipient time to follow-up number of outcomes and num-
ber and type of adverse events in both the intervention and the
control groups Additional information was sought by correspon-
dence with the principal investigator or co-investigators of the trial
in cases where the relevant data were not published
Assessment of risk of bias
Risk of bias was defined as the confidence that the study design and
reporting restricted bias in the intervention comparison (Schulz
1995 Moher 1998 Kjaergard 2001 Wood 2008) Due to the risk
of overestimation of intervention effects in randomised trials with
unclear or inadequate components we assessed the risk of bias by
separate domains
Allocation sequence generation
bull Adequate if the allocation sequence was generated by a
computer or random number table Drawing of lots tossing of a
coin shuffling of cards or throwing dice was considered as
adequate if a person who was not otherwise involved in the
recruitment of participants performed the procedure
bull Unclear if the trial was described as randomised but the
method used for the allocation sequence generation was not
described
bull Inadequate if a system involving dates names or
admittance numbers were used for the allocation of patients
Such quasi-randomised studies were excluded
Allocation concealment
bull Adequate if the allocation of patients involved a central
independent unit on-site locked computer identically appearing
numbered drug bottles or containers prepared by an
independent pharmacist or investigator or serially numbered
sealed and opaque envelopes
bull Unclear if the trial was described as randomised but the
method used to conceal the allocation was not described
bull Inadequate if the allocation sequence was known to the
investigators who assigned participants or if the study was quasi-
randomised The latter studies were excluded
Blinding
bull Adequate the trial was described as blinded the parties that
were blinded and the method of blinding was described so that
knowledge of allocation was adequately prevented during the
trial
bull Unclear the trial was described as double blind but the
method of blinding was not described so that knowledge of
allocation was possible during the trial
bull Not performed the trial was not blinded so that the
allocation was known during the trial
Incomplete outcome data
bull Adequate if the numbers and reasons for dropouts and
withdrawals in all intervention groups were described or if it was
specified that there were no dropouts or withdrawals
bull Unclear if the report gave the impression that there had
been no dropouts or withdrawals but this was not specifically
stated
bull Inadequate if the number or reasons for dropouts and
withdrawals were not described
Selective outcome reporting
bull Adequate if study protocol is available and all pre-specified
outcomes are reported in the manuscript or if the study protocol
is not available but it is clear that the report includes all expected
outcomes
bull Unclear if there are no sufficient information to permit
judgement
bull Inadequate if not all of the pre-specified outcomes were
reported andor were reported incompletely or one or more
reported outcomes were not pre-specified
Baseline imbalance
5Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
bull Adequate if there is no baseline imbalance in the main
characteristics
bull Unclear if there is no sufficient information to assess
baseline characteristics
bull Inadequate if there was a baseline imbalance due to chance
or due to imbalanced exclusion after randomisation
Early stopping
bull Adequate if sample size calculation was reported and the
trial was not stopped or the trial was stopped early by formal
stopping rules at a point where the likelihood of observing an
extreme intervention effect due to chance was low
bull Unclear if sample size calculation was not reported and it is
not clear whether the trial was stopped early or not
bull Inadequate if the trial was stopped early due to informal
stopping rules or the trial was stopped early by a formal stopping
rule at a point where the likelihood of observing an extreme
intervention effect due to chance was high
Furthermore we registered whether the randomised clinical trials
had used an intention-to-treat analysis (Gluud 2001) and had
calculated a sample size estimate
Statistical methods
We performed the analyses in RevMan 5 (RevMan 2008) Anal-
yses included all patients irrespective of compliance or follow-up
according to the intention-to-treat principle and using the last
reported observed response (rsquocarry forwardrsquo) Regarding death
both a worst-best-case scenario analysis considering all dropped-
out patients in the bile acid group as dead and the dropped-out
patients in the control group as alive and a best-worst-case sce-
nario analysis considering all dropped-out patients in the bile acid
group as alive and the dropped-out patients in the control group as
dead were performed Both a random-effects model (DerSimonian
1986) and a fixed-effect model (DeMets 1987) were used The re-
sults of the fixed-effect model were reported if there were no differ-
ences between the results produced by the two models otherwise
we reported the results produced by both models We presented
binary outcome measures as relative risks (RR) with 95 confi-
dence intervals (CI) and continuous outcome measures as mean
differences (MD) with 95 CI
The risk of type I errors increases in single trials with interim anal-
yses To avoid type I errors group sequential monitoring bound-
aries (Lan 1983) can be performed when deciding to terminate the
trial earlier than planned This requires analyses at different time
intervals to record when the P-value has become sufficiently small
that is when the cumulative Z-curve will cross the monitoring
boundaries Sequential monitoring boundaries the so called rsquotrial
sequential monitoring boundariesrsquo can also be applied to meta-
analyses In a trial sequential analysis (TSA) every trial that is
added in a cumulative meta-analysis is regarded as an interim meta-
analysis and the information it adds on helps on deciding if more
trials need to be included
The interpretation of the TSA is as follows if the cumulative Z-
curve has crossed the boundary a sufficient level of evidence is
reached and no further trials may be needed If the Z-curve has
not crossed the boundary then the evidence is insufficient in order
to reach a conclusion To construct the trial sequential monitor-
ing boundaries information size is needed It is calculated as the
minimum number of participants needed in a well-powered single
trial (Pogue 1997 Pogue 1998 Brok 2008 Wetterslev 2008) We
applied TSA since it prevents an increase of the risk of type I error
due to sparse and multiple updating in a cumulative meta-analysis
and provides us with important information in order to estimate
the level of evidence of the experimental intervention Addition-
ally TSA provides us with important information regarding the
need for additional trials and the required information size We
applied trial sequential monitoring boundaries according to an in-
formation size suggested by the trials with low risk of bias and a
50 relative risk reduction (RRR)
Subgroup analyses
We planned to perform the following subgroup analyses on the
main outcome measures (all-cause mortality and number of pa-
tients with acute rejection)
1 Risk of bias of the trials comparing the intervention effect for
trials with low risk of bias components to the intervention effect
in trials with unclear or high risk of bias components
2 Dose and duration of treatment with bile acids comparing the
intervention effect in trials administrating bile acid at or above the
median dose multiplied by duration to the intervention effect of
trials administrating bile acid at less than the median dose multi-
plied by duration
3 Time between transplantation and the start of bile acids com-
paring the intervention effect of trials having less than three days
between transplantation and starting bile acid intake to the inter-
vention effect of trials with a duration of three days or more be-
tween transplantation and the start of bile acid intake (Neuberger
1999)
4 Co-interventions comparing the intervention effect of trials
with co-interventions to the intervention effect of trials without
co-interventions
Funnel plot analysis
We planned to explore bias by funnel plot analysis (Egger 1997)
R E S U L T S
Description of studies
See Characteristics of included studies Characteristics of excluded
studies
The performed electronic searches resulted in a total of 378 ref-
erences We excluded 362 duplicates or irrelevant references by
reading abstracts We excluded eight of the 16 further assessed ref-
erences because they were observational studies case series or ran-
6Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
domised clinical trials with a different reason for exclusion They
are listed under rsquoCharacteristic of excluded studiesrsquo with reasons
for exclusion Seven references already included in the previous
version of this review and one new reference referring to an al-
ready included trial (Barnes 1997) were included in this review
We were not able to identify more trials by reading the reference
lists of the identified studies contacting the principle authors of
the identified trials or approaching pharmaceutical companies for
unpublished trials
Seven publications included in the review (five full publications
and two abstracts) were randomised clinical trials that reported
the random allocation of liver-transplanted patients into groups
receiving bile acid placebo or no treatment We listed these trials
in the table of Characteristics of included studies All seven trials
were published in English Three randomised clinical trials were
from the United States (Koneru 1993 Barnes 1997 Fleckenstein
1998) two from Italy (Sama 1991 Angelico 1999) one from
France (Pageaux 1995) and one from Denmark (Keiding 1997)
Patients
In the included trials all patients received blood group-compatible
grafts The median size of the seven trials was 40 patients (range
29 to 102 patients) In total 335 patients were randomised
Five trials were published as full publications (Pageaux 1995
Barnes 1997 Keiding 1997 Fleckenstein 1998 Angelico 1999)
which allowed us to extract detailed information on 263 of the
patients The mean age of the patients ranged from 44 to 51 years
One trial (Keiding 1997) also enrolled children ranging in age
from 0 to 13 years (median 15 years) The male to female ratio in
these five trials was 159104 The diseases that led to liver trans-
plantation were alcoholic cirrhosis in 51 patients (194) cirrho-
sis caused by chronic hepatitis C in 40 patients (152) primary
biliary cirrhosis in 36 patients (137) cryptogenic cirrhosis in
22 patients (84) metabolic diseases in 19 patients (72) pri-
mary sclerosing cholangitis in 17 patients (65) non-specified
post-hepatitis cirrhosis in 17 patients (65) cirrhosis caused by
chronic hepatitis B in 13 patients (49) 9 with autoimmune
hepatitis and cirrhosis (34) six with liver cancer (23) five
with biliary atresia (19) and 28 with other diseases (106)
Only one trial reported the severity of liver function according to
the Child-Pugh class (Barnes 1997)
Bile acids and collateral interventions
Six trials (Sama 1991 Koneru 1993 Pageaux 1995 Barnes
1997 Keiding 1997 Fleckenstein 1998) compared UDCA versus
placebo or no intervention One trial (Angelico 1999) compared
TUDCA versus no intervention Bile acid treatment began one
day after transplantation in the Keiding 1997 trial three days after
transplantation in the Koneru 1993 trial three or five days in the
Fleckenstein 1998 and Pageaux 1995 trials five days after trans-
plantation in the Barnes 1997 and Angelico 1999 trials and five
or seven days after transplantation in the Sama 1991 trial
Patients received UCDA (10 to 15 mgkg body weightday) for
two months in the Pageaux 1995 trial for three months in the
Koneru 1993 Barnes 1997 Keiding 1997 and Fleckenstein 1998
trials and for six months in the Sama 1991 trial In the Barnes
1997 trial patients were followed up for 18 months Patients in the
Fleckenstein 1998 trial and the Keiding 1997 trial were followed
up for nine months There was no post-treatment follow-up in
three trials (Sama 1991 Koneru 1993 Pageaux 1995) Patients
received TUDCA (500 mgday) for one year and no follow-up
was conducted in the Angelico 1999 trial
In addition to the bile acids or control intervention all patients
in the seven trials received standard triple-drug regimens (steroids
azathioprine and cyclosporine or tacrolimus) The patients who
had steroid-resistant rejection received treatment with immuno-
suppressive antibodies (OKT3)
Outcome measures
The outcome measures reported by most trials were all-cause mor-
tality and acute cellular rejection Three trials reported on death
related to rejection (Barnes 1997 Keiding 1997 Angelico 1999)
two trials reported the number of patients who received retrans-
plantation due to rejection (Keiding 1997 Fleckenstein 1998)
three trials reported the number of patients with chronic rejection
(Barnes 1997 Keiding 1997 Fleckenstein 1998) and four trials
reported the number of patients with steroid-resistant rejection
(Pageaux 1995 Barnes 1997 Keiding 1997 Fleckenstein 1998)
Four trials had adverse events as outcome measures (Barnes 1997
Keiding 1997 Fleckenstein 1998 Angelico 1999) Serum biliru-
bin level was only reported by the Fleckenstein 1998 trial No tri-
als provided data on other liver biochemical parameters quality
of life or cost-effectiveness
Risk of bias in included studies
Two trials reported adequate allocation sequence generation by
using computer-generated random tables (Barnes 1997 Angelico
1999) One trial (Keiding 1997) reported adequate allocation con-
cealment by using sealed serially numbered envelopes Three tri-
als (Barnes 1997 Keiding 1997 Fleckenstein 1998) reported ad-
equate blinding by using placebo with an identical appearance
and taste Five trials (Pageaux 1995 Barnes 1997 Keiding 1997
Fleckenstein 1998 Angelico 1999) reported adequate description
of incomplete outcome data by the number of withdrawals the
reasons for withdrawal or no patients dropped out The trial by
Keiding 1997 is the only one free of selective reporting since all
the pre-specified outcomes were fairly reported Two trials (Barnes
1997 Keiding 1997) performed sample-size calculations Only
the trial by Keiding 1997 seemed to be free of baseline imbalance
and it is the only trial achieving the calculated sample size and
therefore probably the only that was not terminated early Other
trials did not perform sample size calculation or the authors did
not report whether the calculated sample size was achieved The
lack of this information made it unclear for us to judge whether
7Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
a trial was terminated early that is before an adequate number
of patients was included in the trial Three trials (Barnes 1997
Keiding 1997 Fleckenstein 1998) stated that intention-to-treat
analyses were used (Figure 1 Figure 2)
Figure 1 Methodological quality graph review authorsrsquo judgements about each methodological quality
item presented as percentages across all included studies
8Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Figure 2 Methodological quality summary review authorsrsquo judgements about each methodological quality
item for each included study
9Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Following the assessment of risk of bias domains none of the seven
trials were considered to have low risk of bias that is having all
the nine domains for risk of bias assessed as adequate
Effects of interventions
We were able to include seven randomised clinical trials in this
review Six trials with 306 liver-transplanted patients compared
ursodeoxycholic acid (UDCA) with placebo or no intervention
and one trial with 29 liver-transplanted patients compared tauro-
UDCA (TUDCA) with no intervention
All-cause mortality
Five trials including 257 liver-transplanted patients reported on
all-cause mortality at the end of treatment or at maximum follow-
up Bile acids did not significantly reduce all-cause mortality (RR
085 95 CI 053 to 136) there were 26 deaths among 132
patients treated with bile acids (197) versus 29 deaths among
125 patients in the control groups (232) (Analysis 11) There
was no statistically significant heterogeneity (I2 = 141)
Four trials (Sama 1991 Barnes 1997 Keiding 1997 Fleckenstein
1998) showed that UDCA did not significantly reduce all-cause
mortality (RR 080 95 CI 049 to 130) 23 deaths among 116
patients treated with UCDA (198) versus 27 deaths among
108 patients in the control groups (250) The Angelico 1999
trial demonstrated that TUDCA was not able to reduce all-cause
mortality (RR 159 95 CI 030 to 833) there were 3 deaths
among 16 patients (188) versus 2 deaths among 17 patients
(118)
The Fleckenstein 1998 trial and the Sama 1991 trial did not report
the causes of deaths In the three other trials the deaths were
considered to be caused by infections (n = 11) hepatic failure (n =
7) abdominal bleeding (n = 3) renal failure (n = 2) multiple organ
failure (n = 2) hepatitis B virus fibrosis (n = 2) acute rejection
(n = 1) hepatic artery thrombosis (n = 1) encephalitis (n = 1)
lymphoproliferative disorder (n = 1) cerebral haemorrhage (n =
1) or other reasons (n = 6)
Worst-best case and best-worst case scenario analyses
In the worst-best case scenario analysis bile acids did not signif-
icantly reduce all-cause mortality when compared with placebo
or no intervention (RR 130 95 CI 086 to 196) 40 deaths
among 132 patients on bile acids (303) versus 29 deaths among
125 patients in the control groups (232) However all-cause
mortality was significantly reduced by bile acids in the best-worst
case scenario analysis (RR 058 95 CI 038 to 090) 26 deaths
among 132 patients (197) versus 42 deaths among 125 patients
in the control groups (336) (Analysis 12)
Subgroup analyses
We performed subgroup analyses regarding the time that bile acid
intake was started The Keiding 1997 trial started bile acid intake
less than three days after liver transplantation and demonstrated
no significant effect of UDCA on all-cause mortality (RR 124
95 CI 061 to 254) 14 deaths out of 54 patients (259)
versus 10 out of 48 control patients (208) The same effect
was noticed in the four other trials (Sama 1991 Barnes 1997
Fleckenstein 1998 Angelico 1999) which started bile acids three
days or more after liver transplantation (RR 063 95 CI 033
to 120) 12 deaths among 78 patients (154) versus 9 deaths
among 77 control patients (247) (Analysis 13) There were no
statistically significant differences between the two estimates
We also performed subgroup analyses regarding the duration of
bile acid treatment Bile acids were administrated for less than six
months in three trials (Barnes 1997 Keiding 1997 Fleckenstein
1998) and were not able to significantly decrease all-cause mor-
tality (RR 078 95 CI 045 to 138) 18 deaths in a group of
96 treated patients (188) versus 21 deaths among 88 control
patients (239) In the other two trials (Sama 1991 Angelico
1999) patients were treated with bile acids for six months or more
The treatment did not show statistically significant decrease in all-
cause mortality (RR 102 95 CI 043 to 24) 8 deaths in a
group of 36 treated patients (222) versus 8 deaths in a group
of 37 control patients (216) (Analysis 14) There were no sta-
tistically significant differences between the two estimates
Mortality related to allograft rejection
We did not find statistically significant reduction in mortality re-
lated to allograft rejection at maximum follow-up in the three tri-
als reporting cause of death (Barnes 1997 Keiding 1997 Angelico
1999) (RR 030 95 CI 001 to 712) 098 (0) versus 189
(11)) (Analysis 15) The only death due to acute rejection was
found in the placebo group of the Keiding 1997 trial
Number of liver retransplantations
Two trials (Fleckenstein 1998 Keiding 1997) including 132 liver-
transplanted patients reported the number of liver retransplan-
tations UDCA did not significantly reduce the risk of liver re-
transplantation at maximum follow-up (RR 076 95 CI 020
to 286) 368 (44) versus 464 (63)) (Analysis 16) In the
Keiding 1997 trial one patient in the UDCA group was retrans-
planted due to chronic rejection and four patients in the placebo
group were retransplanted either due to chronic rejection (three
cases) or acute rejection (one case) In the Fleckenstein 1998 trial
two patients in the UDCA group were retransplanted due to acute
rejection (one case) and chronic rejection (one case) respectively
Number of patients with acute cellular rejection
Seven trials reported the number of patients who had acute cellu-
lar rejection after liver transplantation Bile acids did not signifi-
cantly reduce the number of patients who experienced acute cel-
lular rejection (RR 089 95 CI 074 to 106) 93174(535)
versus 99165 (600)) There was no significant heterogeneity
(I2 = 0)
Six trials (Sama 1991 Koneru 1993 Pageaux 1995 Barnes 1997
10Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Keiding 1997 Fleckenstein 1998) compared UDCA with placebo
or no intervention and demonstrated that UDCA did not signifi-
cantly reduce the number of patients with acute cellular rejection
after liver transplantation (RR 089 95 CI 074 to 108 85
158 (538) versus 89148 (601)) Neither did the Angelico
1999 trial demonstrate significant reduction of the number of pa-
tients with acute cellular rejection with TUDCA (RR 085 95
CI 045 to 160) 816 (500) versus 1017 (588) (Analysis
17)
Subgroup analyses
Two trials (Koneru 1993 Keiding 1997) in which the patients
started bile acids intake less than three days after liver transplan-
tation did not demonstrate any significant reduction of the risk
of acute cellular rejection by bile acids (RR 084 95 CI 063 to
111) 3870 (543) versus 4164 (641) The other five tri-
als (Sama 1991 Pageaux 1995 Barnes 1997 Fleckenstein 1998
Angelico 1999) in which the patients were started on bile acid
intake three days or more after liver transplantation did not find
a significant reduction of the risk of acute cellular rejection by bile
acids (RR 092 95 CI 072 to 117) 55104 (529) versus 58
101 (574) (Analysis 18) There was no significant difference
between the two estimates
Bile acids did not significantly reduce the risk of acute cellular
rejection in the five trials (Koneru 1993 Pageaux 1995 Barnes
1997 Keiding 1997 Fleckenstein 1998) in which the patients
received treatment with bile acids less than six months (RR 087
95 CI 071 to 107) 72138 (522) versus 76128 (594)
Neither did bile acids in the two other trials (Sama 1991 Angelico
1999) in which the patients received bile acids for more than six
months (RR 094 95 CI 065 to 136) 2136 (583) versus
2337 (622) (Analysis 19) There were no significant difference
between the two estimates
Number of patients with chronic rejection
Three trials comparing UDCA versus placebo (Barnes 1997
Keiding 1997 Fleckenstein 1998) reported the number of patients
with chronic rejection after liver transplantation UDCA signifi-
cantly reduced the number of patients with chronic rejection in
the fixed-effect model analysis (RR 028 95 CI 008 to 095)
396 (31) versus 1088 (114) (Analysis 110) but not in the
random-effects model analysis (RR 030 95 CI 008 to 113) 3
96 (31) versus 1088 (114) There was no statistically signifi-
cant heterogeneity (I2 0) We performed trial sequential analysis
for the available data from three trials (Figure 3) with heterogene-
ity corrected required information size based on proportion of this
outcome of 12 in the control group a relative risk reduction of
50 in the intervention group at a type I error of 5 and a type
II error of 10 We obtained a required information size of 957
patients UDCA was not able to reach or break the trial sequential
monitoring boundary and only 183 out of 957 (19) patients
were randomised regarding this outcome
11Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Figure 3 Trial sequential analysis for the number of patients with chronic rejection at maximum follow-up
We calculated the heterogeneity-corrected required information size (HCRIS) based on a proportion of 12 of
the patients in the placebo group with chronic rejection at maximum follow-up a 50 risk ratio reduction in
the bile acid group an alpha of 5 a beta of 10 and a heterogeneity of 0 Only 184 patients have been
randomised reporting this outcome which is only 19 of the HCRIS of 957 patients The cumulative Z-score
crosses the conventional boundaries for P 005 but not the monitoring boundaries
Number of patients with steroid-resistant rejection
Four trials (Pageaux 1995 Barnes 1997 Keiding 1997
Fleckenstein 1998) reported the number of patients with steroid-
resistant rejection These trials demonstrated that UDCA did not
significantly reduce the number of patients with steroid-resistant
rejection when compared with placebo (22122 (18) versus 26
112 (232) (RR 077 95 CI 047 to 127) (Analysis 111)
There was no significant heterogeneity (I2 0)
Liver biochemistry
The Fleckenstein 1998 trial reported serum bilirubin levels after
a three-month-treatment period in 30 liver-transplanted patients
There was no statistically significant difference in serum bilirubin
levels between the UDCA group and the placebo group (MD 260
mgdl 95 CI -096 to 616 mgdl) (Analysis 112)
No data were available for other liver biochemical variables
Cost-effectiveness
One trial (Barnes 1997) with 52 liver-transplanted patients re-
ported the days of hospitalisation after liver transplantation
UDCA significantly decreased the number of days of hospitali-
sation when compared with placebo (MD -850 days 95 CI -
1667 to -033 days) (Analysis 113) We were not able to extract
other medical cost from the trials
Adverse events
Among all the included and excluded trials only four reported on
adverse events however adverse events only occurred in two of
the included trials (Barnes 1997 Keiding 1997) There were no
significant differences regarding adverse events (RR 088 95 CI
030 to 260) 6112 (54) versus 6105 (57) (Analysis 114)
In the Barnes 1997 trial diarrhoea was reported by two patients
(one in the UDCA group and one in the placebo group) In the
Keiding 1997 trial five UDCA patients and five placebo patients
stopped intake of the trial medicine because of diarrhoea or dif-
ficulties in swallowing the capsules The remaining included trial
by Angelico 1999 stated that no adverse events occurred during
the study period The excluded trial by Assy 2007 was the only
one reporting on a case of mild diarrhoea in one patient in the
12Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
intervention group No other excluded studies reported on adverse
events (see Table 1)
Quality of life
None of the included studies assessed quality of life as an outcome
Other subgroup analyses
We planned to perform subgroup analyses regarding the risk of
bias of trials the dosage of bile acid and any co-intervention
However none of the trials were considered to be of low risk of
bias they all used a similar dosage of bile acid and patients in all
trials received similar immunosuppressive treatment as co-inter-
ventions (steroids azathioprine and cyclosporine or tacrolimus)
after liver transplantation Therefore we were not able to perform
the planned subgroup analyses
Funnel plot asymmetry
We did not draw a funnel plot analysis due to the limited number
of trials included in the present review
D I S C U S S I O N
In the update of this review we included no new trials assessing
the use of bile acids for liver-transplanted patients The analyses
of the seven previously included trials showed that bile acids did
not significantly affect mortality acute cellular rejection steroid-
resistant rejection retransplantation or serum bilirubin Bile acids
might significantly decrease the length of hospital stay and the
number of patients with chronic rejection included in these tri-
als but more supportive evidence is needed The number of pa-
tients with chronic rejection was not significantly influenced by
bile acids when a random-effects model was used and length of
stay was assessed in one single trial Furthermore none of the trials
were considered to be of low risk of bias and few patients were en-
rolled Therefore our positive findings may be due to bias (Schulz
1995 Moher 1998 Kjaergard 2001 Wood 2008) or random er-
rors (Wetterslev 2008 Brok 2009 Thorlund 2009) On the other
hand we are not able to exclude type II errors (that is finding
no significant differences when in fact they exist) due to the low
number of participants Therefore this topic could be of potential
interest in future large randomised trials with adequate control of
bias
All-cause mortality at one year after liver transplantation is re-
ported to be about 20 (Thuluvath 2003) which we also ob-
served for the patients included in the present review According to
our subgroup analyses neither UDCA nor TUDCA significantly
decreased all-cause mortality We also performed a subgroup anal-
ysis regarding treatment duration but we were not able to find any
difference between short (less than six months) and long treatment
duration (six months or more) Thus bile acids do not seem to
have statistically significant effects in reducing all-cause mortal-
ity after liver transplantation We performed both worst-best-case
scenario and best-worst-case scenario analyses In the worst-best-
case scenario bile acids did not differ significantly from placebo or
no intervention regarding all-cause mortality However bile acids
significantly decreased all-cause mortality in the best-worst-case
scenario analysis However such an analysis is very extreme and
may not be realistic We have also found that UDCA may be able
to decrease the risk of chronic rejection in liver-transplanted pa-
tients but trial sequential analysis could not confirm this result
Due to a limited number of patients (Ioannidis 2001) we are not
able to exclude the possibility that it may be relevant to perform
placebo-controlled trials with low risk of bias on the use of bile
acids for liver-transplanted patients
We looked into the causes of deaths that were reported by the trials
and only one trial reported one death related to rejection At the
same time the number of retransplantations was 3 among 68 liver-
transplanted patients who received treatment with UDCA and 4
among 64 liver-transplanted patients who received treatment with
placebo We noticed that all patients in the included trials received
co-interventions of standard triple-drug regimens (steroids aza-
thioprine and cyclosporine or tacrolimus) which were able to
control the possible acute or chronic rejection and prevent deaths
due to allograft rejection (FK506 1994)
The assumption that UDCA might reduce the incidence of acute
graft rejection came from the findings that UDCA could regulate
major histocompatibility complex antigen expression in bile ducts
and liver endothelia and inhibit lymphocyte activity (Calmus
1990 Terasaki 1991 Perez 2009) However in the present review
bile acids did not significantly reduce the risk of acute cellular re-
jection in liver-transplanted patients Considering that acute cellu-
lar rejection is commonly found within a few days after liver trans-
plantation (Vierling 1992) some might argue that the adminis-
tration of bile acids was started too late to prevent acute cellular
rejection We performed subgroup analyses regarding the time bile
acids were started and no statistically significant difference was
found Furthermore bile acids were not able to decrease the risk
of steroid-resistant rejection Therefore the lack of effects of bile
acids does not seem to be due to a delayed start to bile acid ad-
ministration after liver transplantation However it is a possibility
that one should start bile acids intake before liver transplantation
A retrospective study found that rejection rates differed signifi-
cantly between patients with primary biliary cirrhosis treated with
or without UDCA before liver transplantation (Heathcote 1999)
One could argue whether UDCA-induced delay in transplantation
has an adverse effect on post-transplantation outcome Since we
did not find any prospective randomised clinical trials addressing
this issue further research might be needed Furthermore some
studies may provide an explanation why UDCA was not able to
prevent acute cellular rejection These studies found that UDCA
did not appear to change the expression of major histocompatibil-
ity complex class II antigens but rather major histocompatibility
complex class I antigens (Calmus 1990) The initial mechanism
of acute rejection is thought to be recognition of MHC class II
13Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
antigens by CD4+ T cells (Vierling 1992) Moreover the inhibi-
tion of the production of interleukin-2 by peripheral blood lym-
phocytes with UDCA (Heuman 1993) might be negated by the
immunosuppressive treatment after liver transplantation (van den
Berg 1998) so that UDCA is unable to demonstrate effects on
graft rejection In a recent study by Assy 2007 a significant re-
duction in the mean dose of immunosuppressive medications was
achieved in stable liver graft recipients treated with UDCA indi-
cating a possible influence of UDCA on rejection mechanisms
In accordance with previous systematic reviews (Chen 2003a
Chen 2007 Gong 2008) bile acids were not associated with the
occurrence of serious adverse events or any major occurrence of
adverse events
In summary our results do not support or refute the use of bile
acids (UDCA and TUDCA) additional to standard immunosup-
pressive treatment in liver-transplanted patients
A U T H O R S rsquo C O N C L U S I O N SImplications for practice
There seems to be no evidence to support or refute the use of bile
acids for liver-transplanted patients receiving standard immuno-
suppressive treatment
Implications for research
We need more randomised placebo-controlled clinical trials with
enough statistical power and low risk of bias to explore the poten-
tial effects of bile acids on chronic rejection and mortality in liver-
transplanted patients Such trials should also consider evaluation
of quality of life and length of hospitalisation Such trials may
consider starting bile acid and placebo interventions before liver
transplantation we were not able to identify any randomised trials
addressing this regimen Such trials ought to be reported accord-
ing to the CONSORT statement (wwwconsort-statementorg)
However before embarking on such trials the effects of bile acids
in other patient groups should be scrutinised as they may have
small or negative effects
A C K N O W L E D G E M E N T S
We thank all the patients and investigators who were involved in
the clinical trials mentioned in this review We thank Wendong
Chen for his work and contribution on the previous version of this
review We thank the staff of The Cochrane Hepato-Biliary Group
Editorial Team especially Dimitrinka Nikolova and Sarah Louise
Klingenberg for excellent collaboration and assistance during the
update of this review
Peer Reviewers Carlo Merkel Italy M Tomikawa Japan
Contact Editor Bodil Als-Nielsen Denmark
R E F E R E N C E S
References to studies included in this review
Angelico 1999 published data only
Angelico M Tisone G Baiocchi L Palmieri G Pisani F Negrini S
et alOne-year pilot study on tauroursodeoxycholic acid as an
adjuvant treatment after liver transplantation Italian Journal of
Gastroenterology and Hepatology 199931(6)462ndash8 [MEDLINE
10575563]
Barnes 1997 published data onlylowast Barnes D Talenti D Cammell G Goormastic M Farquhar L
Henderson M et alA randomized clinical trial of ursodeoxycholic
acid as adjuvant treatment to prevent liver transplant rejection
Hepatology 199726(4)853ndash7 [MEDLINE 9328304]
Barnes D Talenti D Goormastic M Farquhar L Cammell G
Henderson M et alUrsodeoxycholic acid (UDCA) reduces hepatic
allograft rejection after orthotopic liver transplantation (OLT) - a
prospective randomized placebo-controlled double-blind trial
Hepatology 199522149A
Fleckenstein 1998 published data only
Fleckenstein JF Paredes M Thuluvath PJ A prospective
randomized double-blind trial evaluating the efficacy of
ursodeoxycholic acid in prevention of liver transplant rejection
Liver Transplantation and Surgery 19984(4)276ndash9 [MEDLINE
9649640]
Keiding 1997 published data only
Keiding S Hockerstedt K Bjoro K Bondesen S Hjortrup A
Isoniemi H et alThe Nordic multicenter double-blind randomized
controlled trial of prophylactic ursodeoxycholic acid in liver
transplant patients Transplantation 199763(11)1591ndash4
[MEDLINE 9197351]
Koneru 1993 published data only
Koneru B Tint GS Wilson DJ Leevy CB Salen F Randomised
prospective trial of ursodeoxycholic acid in liver transplant
recipients Hepatology 199318336A
Pageaux 1995 published data only
Pageaux GP Blanc P Perrigault PF Navarro F Fabre JM Souche B
et alFailure of ursodeoxycholic acid to prevent acute cellular
rejection after liver transplantation Journal of Hepatology 199523
(2)119ndash22 [MEDLINE 7499781]
Sama 1991 published data only
Sama C Mazziotti A Grigioni W Morselli AM Chianura A
Stefanini GF et alUrsodeoxycholic acid administration does not
14Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
prevent rejection after OLT Journal of Hepatology 199113(Suppl
2)68
References to studies excluded from this review
Assy 2007 published data only
Assy N Adams PC Myers P Simon V Minuk GY Wall W et
alRandomized controlled trial of total immunosuppression
withdrawal in liver transplant recipients role of ursodeoxycholic
acid Transplantation 200783(12)1571ndash6 [MEDLINE
17589339]
Clavien 1996 published data only
Clavien PA Sharara AI Camargo CA Jr Harland RC Fitz JG
Evidence that ursodeoxycholic acid prevents steroid-resistant
rejection in adult liver transplantation Clinical Transplantation
199610(6 Pt 2)658ndash62 [MEDLINE 8996761]
Friman 1992 published data only
Friman S Persson H Schersten T Svanvik J Karlberg I Adjuvant
treatment with ursodeoxycholic acid reduces acute rejection after
liver transplantation Transplantation Proceedings 199224(1)
389ndash90 [MEDLINE 1539328]
Heathcote 1999 published data onlylowast Heathcote EJ Stone J Cauch-Dudek K Poupon R Chazouilleres
O Lindor KD et alEffect of pretransplantation ursodeoxycholic
acid therapy on the outcome of liver transplantation in patients
with primary biliary cirrhosis Liver Transplantation and Surgery
19995(4)269ndash74 [MEDLINE 10388499]
Henriksson 1991 published data only
Henriksson BA Persson H Friman S Wangberg B Svanvik J
Karlberg I Adjuvant ursodeoxycholic acid prevents acute rejection
in liver transplant recipients Transplantation Proceedings 199123
(3)1971 [MEDLINE 2063453]
Persson 1990 published data only
Persson H Friman S Schersten T Svanvik J Karlberg I
Ursodeoxycholic acid for prevention of acute rejection in liver
transplant recipients Lancet 1990336(8706)52ndash3 [MEDLINE
1973232]
Rafael 1995 published data only
Rafael E Duraj F Rudstrom H Wilczek H Ericzon B Effect of
ursodeoxycholic acid treatment for cholestasis in liver transplant
recipients Transplantation Proceedings 199527(6)3501ndash2
[MEDLINE 8540069]
Sama 1998 published data only
Sama C Morselli-Labate AM Grazi GL Mastroianni A Danesi G
Pianta P et alUrsodeoxycholic acid in liver transplantation effect
on cholestasis and rejection Gastroenterology 1998114(4 Suppl)
A1332
Additional references
Adams 1990
Adams DH Neuberger JM Patterns of graft rejection following
liver transplantation Journal of Hepatology 199010(1)113ndash9
[MEDLINE 2407770]
Al-Quaiz 1994
Al-Quaiz M OrsquoGrady J Tredger J Williams R Variable effect of
ursodeoxycholic acid on cyclosporin absorption after orthotopic
liver transplantation Transplant International 19947(3)190ndash4
[MEDLINE 8060468]
Armstrong 1982
Armstrong MJ Carey MC The hydrophobic-hydrophilic balance
of bile salt Inverse correlation between reverse phase high
performance liquid chromatographic mobilities and micellar
cholesterol-solubilizing capacities Journal of Lipid Research 1982
23(1)70ndash80 [MEDLINE 7057113]
Ascher 1988
Ascher NL Stock PG Baumgardner GL Payne WD Najarian JS
Infection and rejection of primary hepatic transplant in 93
consecutive patients treated with triple immunosuppressive therapy
Surgery Gynecology amp Obstetrics 1988167(6)474ndash84
[MEDLINE 3055368]
Brok 2008
Brok J Thorlund K Gluud C Wetterslev J Trial sequential
analysis reveals insufficient information size and potentially false
positive results in many meta-analyses Journal of Clinical
Epidemiology 200861(8)763ndash9 [MEDLINE 18411040]
Brok 2009
Brok J Thorlund K Wetterslev J Gluud C Apparently conclusive
meta-analysis may be inconclusive - Trial sequential analysis
adjustment of random error risk due to repetitive testing of
accumulating data in apparently conclusive neonatal meta-analysis
International Journal of Epidemiology 200938(1)298ndash303
[MEDLINE 18824466]
Calmus 1990
Calmus Y Gane P Rouger P Poupon R Hepatic expression of class
I and class II major histocompatibility complex molecules in
primary biliary cirrhosis effect of ursodeoxycholic acid Hepatology
199011(1)12ndash5 [MEDLINE 2403961]
Calmus 1992
Calmus Y Arvieux C Gane P Boucher E Nordlinger B Rouger P
et alCholestasis induces major histocompatibility complex class I
expression in hepatocytes Gastroenterology 1992102(4 Pt 1)
1371ndash7 [MEDLINE 1551542]
Chen 2003a
Chen W Gluud C Bile acids for primary sclerosing cholangitis
Cochrane Database of Systematic Reviews 2003 Issue 2 [DOI
10100214651858CD003626]
Chen 2007
Chen W Liu J Gluud C Bile acids for viral hepatitis Cochrane
Database of Systematic Reviews 2007 Issue 4 [DOI 101002
14651858CD003181pub2]
Cheng 2002
Cheng K Ashby D Smyth R Ursodeoxycholic acid for cystic
fibrosis-related liver disease Cochrane Database of Systematic
Reviews 2002 Issue 2 [DOI 10100214651858CD000222]
Corbani 2008
Corbani A Burroughs AK Intrahepatic cholestasis after liver
transplantation Clinics in Liver Disease 200812(1)111ndash29
[MEDLINE 18242500]
DeMets 1987
DeMets DL Methods for combining randomised clinical trials
strengths and limitations Statistics in Medicine 19876(3)341ndash50
[MEDLINE 3616287]
15Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
DerSimonian 1986
DerSimonian R Laird N Meta-analysis in clinical trials Controlled
Clinical Trials 19867(3)177ndash88 [MEDLINE 3802833]
Egger 1997
Egger M Davey Smith G Schneider M Minder C Bias in meta-
analysis detected by a simple graphical test BMJ (Clinical Research
Ed) 1997315(7109)629ndash34 [MEDLINE 9310563]
Ericzon 1990
Ericzon BG Eusufzai S Kubota K Einarsson K Angelin B
Characteristics of biliary lipid metabolism after liver
transplantation Hepatology 199012(5)1222ndash8 [MEDLINE
2227822]
FK506 1994
The US Multicenter FK506 Liver Study Group A comparison of
tacrolimus (FK506) and cyclosporine for immunosuppression in
liver transplantation New England Journal of Medicine 1994331
(17)1110ndash5 [MEDLINE 7523946]
Friman 1994
Friman S Svanvik J A possible role of ursodeoxycholic acid in liver
transplantation Scandinavian Journal of Gastroenterology 1994204
62ndash4 [MEDLINE 7824880]
Fuchs 1999
Fuchs M Stange EF Metabolism of bile acids In Johannes
Bircher Jean-Pierre Benhamou Neil McIntyre Mario Rizzetto
Juan Rodes editor(s) Oxford Textbook of Clinical Hepatology 2
Vol 1 Oxford Oxford University Press 1999223ndash56
Fusai 2006
Fusai G Dhaliwal P Rolando N Sabin CA Patch D Davidson BR
et alIncidence and risk factors for the development of prolonged
and severe intrahepatic cholestasis after liver transplantation Liver
Transplantation 200612(11)1626ndash33 [DOI 101002lt20870]
Gluud 2001
Gluud C Alcoholic hepatitis no glucocorticosteroids In
Leuschner U James OFW Dancygier H editor(s) Steatohepatitis
(NASH and ASH) Falk Symposium 121 Lancaster Kluwer
Academic Publisher 2001322ndash42
Gluud 2010
Gluud C Nikolova D Klingenberg SL Alexakis N Als-Nielsen B
Colli A et alCochrane Hepato-Biliary Group About The
Cochrane Collaboration (Cochrane Review Groups (CRGs))
2010 Issue 1 Art No LIVER
Gong 2008
Gong Y Huang ZB Christiansen E Gluud C Ursodeoxycholic
acid for primary biliary cirrhosis Cochrane Database of Systematic
Reviews 2008 Issue 3 [DOI 101002
14651858CD000551pub2]
Haddad 2006
Haddad EM McAlister VC Renouf E Malthaner R Kjaer MS
Gluud LL Cyclosporin versus tacrolimus for liver transplanted
patients Cochrane Database of Systematic Reviews 2006 Issue 4
[DOI 10100214651858CD005161pub2]
Heuman 1993
Heuman DM Hepatoprotective properties of ursodeoxycholic acid
Gastroenterology 1993104(6)1865ndash9 [MEDLINE 8500748]
Higgins 2008
Higgins PTJ Green S editors Cochrane Handbook for Systematic
Reviews of Interventions West Sussex England Wiley-Blackwell
2008
Hirschfield 2009
Hirschfield GM Gibbs P Griffiths WJH Adult liver
transplantation what non-specialists need to know BMJ (Clinical
Research Ed) 2009338(b1670)1321ndash7 [DOI 101136
bmjb1670]
Hussain 2002
Hussain HK Nghiem HV Imaging of hepatic transplantation
Clinics in Liver Disease 20026(1)247ndash70 [MEDLINE
11933592]
ICH-GCP 1997
International Conference on Harmonisation Expert Working
Group Code of Federal Regulations amp International Conference on
Harmonization Guidelines Media Parexel Barnett 1997
Ioannidis 2001
Ioannidis JPA Lau J Evolution of treatment effects over time
Empirical insight from recursive cumulative meta analyses
Proceedings of the National Academy of Sciences 200198(3)831ndash6
IWP 1995
International Working Party Terminology for hepatic allograft
rejection Hepatology 199522(2)648ndash54 [MEDLINE 7635435]
Kjaergard 2001
Kjaergard LL Villumsen J Gluud C Reported methodological
quality and discrepancies between large and small randomised trials
in meta-analyses Annals of Internal Medicine 2001135(11)982ndash9
[MEDLINE 11730399]
Klintmalm 1989
Klintmalm GB Nery JR Husberg BS Gonwa TA Tillery GW
Rejection in liver transplantation Hepatology 198910(6)978ndash85
[MEDLINE 2583691]
Knechtle 2009
Knechtle SJ Kwun J Unique aspects of rejection and tolerance in
liver transplantation Seminars in Liver Disease 200929(1)91ndash101
[MEDLINE 19235662]
Krams 1993
Krams SM Ascher NL Martinez OM New immunologic insights
into mechanisms of allograft rejection Gastroenterology Clinics of
North America 199318(2)374ndash7 [MEDLINE 8509176]
Lan 1983
Lan KKG DeMets DL Discrete sequential boundaries for clinical
trials Biometrika 198370659ndash63
Merion 1989
Merion RM Gorski DH Burtch GD Turcotte JG Colletti LM
Campbell DA Jr Bile refeeding after liver transplantation and
avoidance of intravenous cyclosporine Surgery 1989106(4)
604ndash9 [MEDLINE 2799635]
Moher 1998
Moher D Pham B Jones A Cook DJ Jadad AR Moher M et
alDoes quality of reports of randomised trials affect estimates of
intervention efficacy reported in meta-analyses Lancet 1998352
(9128)609ndash13 [MEDLINE 9746022]
16Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Neuberger 1999
Neuberger J Incidence timing and risk factors for acute and
chronic rejection Liver Transplantation and Surgery 19995(4 Suppl
1)S30ndashS36 [MEDLINE 10431015]
Okolicsanyi 1986
Okolicsanyi L Lirussi F Strazzabosco M Jemmolo RM Orlando R
Nassuato G et alThe effect of drugs on bile flow and composition
An overview Drugs 198631(5)430ndash48 [MEDLINE 2872047]
Palmer 1972
Palmer RH Bile acids liver injury and liver disease Archives of
Internal Medicine 1972130(4)606ndash17 [MEDLINE 4627840]
Perez 2009
Perez MJ Briz O Bile-acid-induced cell injury and protection
World Journal of Gastroenterology 200915(14)1677ndash89
[MEDLINE 19360911]
Pogue 1997
Pogue JM Yusuf S Cumulating evidence from randomized trials
Utilizing sequential monitoring boundaries for cumulative meta-
analysis Controlled Clinical Trials 199718(6)580ndash93
[MEDLINE 9408720]
Pogue 1998
Pogue J Yusuf S Overcoming the limitations of current meta-
analysis of randomised controlled trials Lancet 1998351(9095)
45ndash52 [MEDLINE 9433436]
RevMan 2008
The Nordic Cochrane Centre The Cochrane Collaboration
Review Manager (RevMan) 50 Copenhagen The Nordic
Cochrane Centre The Cochrane Collaboration 2008
Royle 2003
Royle P Milne R Literature searching for randomized controlled
trials used in Cochrane reviews rapid versus exhaustive searches
International Journal of Technology Assessment in Health Care 2003
19(4)591ndash603
Schulz 1995
Schulz KF Chalmers I Hayer R Altman D Empirical evidence of
bias JAMA 1995273(5)408ndash12 [MEDLINE 7823387]
Sharara 1995
Sharara AI Camargo CA Clavien PA Ursodeoxycholic acid
prevents steroid resistant rejection in liver transplant recipients
Gastroenterology 1995108A1168
Sholmerich 1984
Sholmerich J Becher MS Schmidt KH Schubert R Kremer B
Felhaus S et alInfluence of hydroxylation and conjugation of bile
salts on their membrane damaging properties Hepatology 19844
(4)661ndash7 [MEDLINE 6745854]
Soderdahl 1998
Soderdahl G Nowak G Duraj F Wang FH Einarsson C Ericzon
BG Ursodeoxycholic acid increased bile flow and affects bile
composition in the early postoperative phase following liver
transplantation Transplantation International 199811(Suppl 1)
S231ndashS238 [MEDLINE 9664985]
Terasaki 1991
Terasaki S Nakanuma Y Ogino H Unoura M Kobayashi K
Hepatocellular and biliary expression of HLA antigens in primary
biliary cirrhosis before and after ursodeoxycholic acid therapy
American Journal of Gastroenterology 199186(9)1194ndash9
[MEDLINE 1882800]
Thalheimer 2002
Thalheimer U Capra F Liver transplantation making the best out
of what we have Digestive Diseases and Sciences 200247(5)
945ndash53 [MEDLINE 12018919]
Thorlund 2009
Thorlund K Devereaux PJ Wetterslev J Guyatt G Ioannidis JP
Thabane L et alCan trial sequential monitoring boundaries reduce
spurious inferences from meta-analyses International Journal of
Epidemiology 200938(1)276ndash86 [MEDLINE 18824467]
Thuluvath 2003
Thuluvath PJ Yoo HY Thompson RE A model to predict survival
at one month one year and five years after liver transplantation
based on pretransplant clinical characteristics Liver Transplantation
20039(5)527ndash32 [MEDLINE 12740799]
van den Berg 1998
van den Berg AP Twilhaar WN Mesander G van Son WJ van der
Bij W Klompmaker IJ et alQuantitation of immunosuppression
by flow cytometric measurement of the capacity of T cells for
interleukin-2 production Transplantation 199865(8)1066ndash71
[MEDLINE 9583867]
Vierling 1992
Vierling J Immunologic mechanisms of hepatic allograft rejection
Seminars in Liver Disease 199212(1)16ndash27 [MEDLINE
1570548]
Wetterslev 2008
Wetterslev J Thorlund K Brok J Gluud C Trial sequential
analysis may establish when firm evidence is reached in cumulative
meta-analysis Journal of Clinical Epidemiology 200861(1)64ndash75
[MEDLINE 18083463]
Wiesner 1992
Wiesner RH Acute cellular rejection following liver
transplantation incidence risk factors and outcome in the
NIDDK Liver Transplant Database (LTD) study Gastroenterology
1992102A910
Wood 2008
Wood L Egger M Gluud LL Schulz KF Juni P Altman DG et
alEmpirical evidence of bias in treatment effect estimates in
controlled trials with different interventions and outcomes meta-
epidemiological study BMJ (Clinical Research Ed) 2008336
(7644)601ndash5 [MEDLINE 18316340]
Yoshikawa 1998
Yoshikawa M Matsui Y Kawamoto H Toyohara M Matsumura
K Yamao J et alIntragastric administration of ursodeoxycholic
acid suppresses immunoglobulin secretion by lymphocytes from
liver but not from peripheral blood spleen or Peyerrsquos patches in
mice International Journal of Immunopharmacology 199820(1-3)
29ndash38 [MEDLINE 9717080]
References to other published versions of this review
17Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Chen 2003b
Chen W Gluud C Bile acids for liver transplanted patients
Cochrane Database of Systematic Reviews 2005 Issue 3 [DOI
10100214651858CD005442]lowast Indicates the major publication for the study
18Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
C H A R A C T E R I S T I C S O F S T U D I E S
Characteristics of included studies [ordered by study ID]
Angelico 1999
Methods Study design open-label randomised one-year pilot study
Participants Country Italy
Publication language English
Inclusion criteria
- patients who underwent liver transplantation from April 1994 to December 1994
Exclusion criteria
- not mentioned
Participants
Two patients in TUDCA group and two patients in control group were excluded from
the basic information of participants by the study due to withdrawal
- TUDCA group (n = 14)
Mean age (years +- SD)
467 +- 84
Ratio of sex (malefemale) 122
Origins of liver diseases
hepatitis C cirrhosis (9) hepatitis B cirrhosis (2) hepatitis B and C cirrhosis (1) cryp-
togenic cirrhosis (2) alcoholic cirrhosis (0) Wilson cirrhosis (0)
- Control group (n = 15)
Mean age (years +- SD)
474 +- 74
Ratio of sex (malefemale) 123
Origins of liver diseases
hepatitis C cirrhosis (7) hepatitis B cirrhosis (2) hepatitis B and C cirrhosis (2) cryp-
togenic cirrhosis (2) alcoholic cirrhosis (1) Wilson cirrhosis (1)
Interventions TUDCA group
- Dose 500 mgday in two divided doses
- Route orally
- Duration the treatment was started on day 5 after transplantation and continued for
one year
Control group
- no treatment
Co-interventions all patients received standard triple-drug regimens (steroids azathio-
prine and cyclosporine or tacrolimus)
Outcomes All cause mortality
Number of patients with rejection after liver transplantation
Notes Letter was sent to the authors in September 2009 A reply with additional information
was received shortly after
Risk of bias
19Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Angelico 1999 (Continued)
Item Authorsrsquo judgement Description
Adequate sequence generation Yes Computer generated table
Allocation concealment Unclear No information provided
Blinding No Not performed
Incomplete outcome data addressed
All outcomes
Yes Withdrawal two patients from the
TUDCA group and two patients from the
placebo group Three of them died due to
transplant non-function in the first postop-
erative week and one patient was regrafted
due to thrombosis of hepatic artery
Free of selective reporting Unclear Post-transplant cholestasis and liver bio-
chemistry specified as outcomes Differ-
ence reported as not significant but no ac-
tual data given
Sample size calculation No Not reported
Intention-to-treat analysis No Not stated and not used
Baseline imbalance Unclear Not enough information provided
Early stopping of trial Unclear Not enough information provided
Barnes 1997
Methods Study design randomised placebo-controlled double-blind trial
Participants Country United States
Publication language English
Inclusion criteria
- patients aged 18 years or older who underwent liver transplantation at the Cleveland
Clinic Foundation from April 1992 through June of 1994
Exclusion criteria
- patients who were found to have cancer at surgically resected margins of the biliary
tree
- patents who underwent retransplantation
Participants
- UDCA group (n = 28)
Mean age (years +- SD)
505 +- 116
Ratio of sex (malefemale) 1810
Child class A 7
20Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Barnes 1997 (Continued)
B 13
and C 8
Origins of liver diseases Laennecrsquos cirrhosis 4
PBC 3
cryptogenic cirrhosis 6
hepatitis Ccirrhosis 4
hepatitis Bcirrhosis 3
autoimmune hepatitis with cirrhosis 3
PSC 2
other 3
- Placebo group (n = 24)
Mean age (years +- SD)
507 +- 93
Ratio of sex (malefemale) 159
Child class A 6
B 14
and C 4
Origins of liver diseases Laennecrsquos cirrhosis 9
PBC 5
cryptogenic cirrhosis 1
hepatitis Ccirrhosis 1
hepatitis Bcirrhosis 1
autoimmune hepatitis with cirrhosis 1
PSC 2
other 4
Interventions UDCA group
- Dose 10-15 mgkg body weightday in divided doses
- Route orally
- Duration immediately after intestinal transit recovery usually between postoperative
days three and five and continue for three months
Placebo group
- identical-appearing capsules administered in the same quantity and manner
Co-interventions all patients received standard triple-drug regimens (steroids azathio-
prine and cyclosporine or tacrolimus)
Outcomes All cause mortality
Number of patients with acute cellular rejection
Number of patients with chronic rejection
Number of patients with steroid-resistant rejection
Number of days of hospitalisation
Adverse events
Notes Letter was sent to the authors in September 2009 A reply with additional information
was received shortly after
Risk of bias
Item Authorsrsquo judgement Description
21Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Barnes 1997 (Continued)
Adequate sequence generation Yes Computer generated table
Allocation concealment Unclear No information provided
Blinding Yes Quote ldquorandomised to receive either
UDCA or an identical placebo capsulerdquo
Incomplete outcome data addressed
All outcomes
Yes Mean follow-up time 18 months Ten pa-
tients withdrawn from study 6 in UDCA
group and 4 in placebo group Reasons
for withdrawal were reported Four patients
died in the placebo group
Free of selective reporting Yes All expected outcomes reported
Sample size calculation Unclear The trial reported the method of sample
size calculation but the actual number of
patients needed was not reported
Intention-to-treat analysis Yes Stated and used
Baseline imbalance Unclear Not enough information provided
Early stopping of trial Unclear The number of patients needed to gain the
actual power was not reported Whether
the trial was terminated early is not clear
Fleckenstein 1998
Methods Study design prospective randomised double-blind trial
Participants Country United States
Publication language English
Inclusion criteria
- patients who underwent liver transplantation at the Johns Hopkins Hospital
Exclusion criteria
- patients who were under 18 years old undergoing repeat transplantation had primary
graft nonfunction or refused consent
Participants
- UDCA group (n = 14)
Mean age (years +- SD)
443 +- 127
Ratio of sex (malefemale) 68
Origins of liver diseases hepatitis C 6
alcohol 2
autoimmune 1
PBC 2
22Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Fleckenstein 1998 (Continued)
PSC 1
autoimmune cholangiopathy 1
hepatitis B 1
- Placebo group (n = 16)
Mean age (years +- SD)
496 +- 109
Ratio of sex (malefemale) 124
Origins of liver diseases hepatitis C 3
alcohol 3
autoimmune 3
PBC 1
PSC 2
cryptogenic 2
hepatitis B 1
alpha1-antitrypsin deficiency 1
Interventions UDCA group
- Dose 15 mgkg body weightday in divided doses
- Route orally
- Duration immediately after intestinal transit recovery usually between postoperative
days three and five and continue for three months
Placebo group
- Identical-appearing capsules administered in the same quantity and manner
Co-interventions all patients received standard triple-drug regimens (steroids azathio-
prine and cyclosporine or tacrolimus)
Outcomes All cause mortality
Number with retransplantation
Number of patients with acute cellular rejection
Number of patients with chronic rejection
Serum bilirubin levels at the end of treatment
Notes Follow-up time nine months
Letter was sent to the authors in September 2009 No reply was received
Risk of bias
Item Authorsrsquo judgement Description
Adequate sequence generation Unclear No information provided
Allocation concealment Unclear No information provided
Blinding Yes Method of blinding not described but
probably adequate
Incomplete outcome data addressed
All outcomes
Yes Withdrawal one patient from the UDCA
group and two patients from the placebo
group because of capsule size
23Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Fleckenstein 1998 (Continued)
Free of selective reporting Unclear Outcomes were not completely described
Sample size calculation No Not reported
Intention-to-treat analysis Yes Quote ldquoThree patients withdrew after in-
clusionThey were included in the statis-
tical analysisrdquo
Baseline imbalance Unclear Not enough information provided
Early stopping of trial Unclear Not enough information provided
Keiding 1997
Methods Study design prospective randomised placebo-controlled multicenter study
Participants Country Denmark Finland Norway and Sweden
Publication language English
Inclusion criteria
- patients who underwent liver transplantation in Denmark Finland Norway and Swe-
den from September 1 1992 to May 31 1994
Exclusion criteria
- patients with malignant diseases
Participants
The age of the children ranged from 0 to 13 years (median 15) and the age of adults
ranged from 14 to 59 years old (median 44) MaleFemale ratio was 96 for children and
4344 for adults
- UDCA group (n = 54)
Origins of liver diseases
paracetamol intoxication 1 hepatitis B 1 autoimmune hepatitis 0 biliary atresia 2
metabolic diseases 7 neonatal hepatitis 2 PBC 13 post hepatitis cirrhosis 8 PSC 3
cryptogenic cirrhosis 7 alcoholic cirrhosis 2 other reasons 8
- Placebo group (n = 48)
Origins of liver diseases paracetamol intoxication 1 hepatitis B 0 autoimmune hepatitis
1 biliary atresia 3 metabolic diseases 11 neonatal hepatitis 0 PBC 7 post hepatitis
cirrhosis 5 PSC 7 cryptogenic cirrhosis 2 alcoholic cirrhosis 6 other reasons 5
Interventions UDCA group
- Dose 15 mgkg body weightday in two or three divided doses
- Route orally
- Duration immediately after intestinal transit recovery usually between postoperative
days three and five and continue for three months
Placebo group
- Identical-appearing capsules administered in the same quantity and manner
Co-interventions all patients received standard triple-drug regimens (steroids azathio-
prine and cyclosporine or tacrolimus)
24Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Keiding 1997 (Continued)
Outcomes All cause mortality
Number of deaths related to rejection
Number of patients with acute cellular rejection
Number of patients with chronic rejection
Number of patients with steroid-resistant rejection
Adverse events
Notes Letter was sent to the authors in September 2009 No reply was received
Risk of bias
Item Authorsrsquo judgement Description
Adequate sequence generation Unclear Patients were randomised at a ratio of 11
Allocation concealment Yes Quote ldquo The allocation was performed in
blocks of 10 patients using the sealed serial
envelope methodrdquo
Blinding Yes Quote ldquoThe UDCA and the placebo cap-
sules had identical appearance and tasterdquo
Incomplete outcome data addressed
All outcomes
Yes Follow-up time 12 months Five UDCA
patients and five placebo patients withdrew
from study Reasons were reported
Free of selective reporting Unclear Insufficient information
Sample size calculation Yes Performed and allowed for a difference in
the incidence of at least one episode of
acute rejection of 50 between the treat-
ment and placebo groups with 90 statisti-
cal power and a significance level of P value
less than 005 The calculated sample size
was 80 patients
Intention-to-treat analysis Yes Stated and used
Baseline imbalance Yes The study seems to be free of baseline im-
balance
Early stopping of trial Yes Study attained the pre-specified sample
size
25Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Koneru 1993
Methods Study design randomised controlled trial
Participants Country United States
Publication language English
Inclusion criteria
- patients who underwent liver transplantation
Exclusion criteria
- not mentioned
Participants
- UDCA group (n = 16)
Mean age (years +- SD)
no information
Ratio of sex (malefemale) no information
Origins of liver diseases
no information
- Control group (n = 16)
Mean age (years +- SD)
no information
Ratio of sex (malefemale) no information
Origins of liver diseases
no information
Interventions UDCA group
- Dose 900 mgday
- Route orally
- Duration immediately after intestinal transit recovery usually between postoperative
days three and five and continue for three months
Control group
- no treatment
Co-interventions all patients received standard triple-drug regimens (steroids azathio-
prine and cyclosporine)
Outcomes Number of patients with retransplantation due to rejection
Number of patients with rejection episodes
Notes Abstract
Letter was sent to the authors in September 2009 No reply was received
Risk of bias
Item Authorsrsquo judgement Description
Adequate sequence generation Unclear No information provided
Allocation concealment Unclear No information provided
Blinding No Not performed
26Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Koneru 1993 (Continued)
Incomplete outcome data addressed
All outcomes
Unclear The study gives the impression that there
were no withdrawals but this was not ex-
plicitly stated
Free of selective reporting Unclear Insufficient information provided
Sample size calculation No Not performed
Intention-to-treat analysis Unclear No information provided
Baseline imbalance Unclear Not enough information provided
Early stopping of trial Unclear Not enough information provided
Pageaux 1995
Methods Study design double-blind randomised study
Participants Country France
Publication language English
Inclusion criteria
- patients who underwent liver transplantation
Exclusion criteria
- not mentioned
Participants
- UDCA group (n=26)
Mean age (years +- SD)
47 +- 10
Ratio of sex (malefemale) 179
Origins of liver diseases alcoholic cirrhosis 14
post-hepatic B cirrhosis 2
post-hepatitis C cirrhosis 4
PBC 2
liver cancer 2
fulminant hepatitis 1
miscellaneous 1
- Placebo group (n = 24)
Mean age (years +- SD)
51+- 9
Ratio of sex (malefemale) 159
Origins of liver diseases alcoholic cirrhosis 10
post-hepatic B cirrhosis 0
post-hepatic C cirrhosis 6
PBC 3
liver cancer 4
fulminant hepatitis 0
miscellaneous 1
27Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Pageaux 1995 (Continued)
Interventions UDCA group
- Dose 600 mgday in three divided doses
- Route orally
- Duration immediately after intestinal transit recovery usually between postoperative
days three and five and continue for two months
Placebo group
- identical-appearing capsules administered in the same quantity and manner
Co-interventions all patients received standard triple-drug regimens (steroids azathio-
prine and cyclosporine or tacrolimus)
Outcomes Number of patients with acute cellular rejection
Number of patients with steroid-resistant rejection
Notes Letter was sent to the authors in September 2009 No reply was received
Risk of bias
Item Authorsrsquo judgement Description
Adequate sequence generation Unclear No information provided
Allocation concealment Unclear No information provided
Blinding Unclear Method of blinding not described
Incomplete outcome data addressed
All outcomes
Yes Five patients died from non-immunologi-
cal causes before the end of the first month
and were excluded from the study Reasons
were reported
Free of selective reporting Unclear Not enough information provided
Sample size calculation No Not performed
Intention-to-treat analysis No Not stated and not used
Baseline imbalance Unclear Not enough information provided
Early stopping of trial Unclear Not enough information provided
Sama 1991
Methods Study design randomised controlled trial
Participants Country Italy
Publication language English
Inclusion criteria
28Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Sama 1991 (Continued)
- patients who underwent liver transplantation
Exclusion criteria
- not mentioned
Participants
- UDCA group (n = 20)
Mean age (years +- SD)
no information
Ratio of sex (malefemale) no information
Origins of liver diseases
no information
- Control group (n = 20)
Mean age (years +- SD)
no information
Ratio of sex (malefemale) no information
Origins of liver diseases
no information
Interventions UDCA group
- Dose 600 mgday in two divided doses
- Route orally
- Duration immediately after intestinal transit recovery usually between postoperative
day five and day seven and continue for six months
Control group
- no treatment
Co-interventions all patients received standard immunosuppressive treatment (steroids
and cyclosporine)
Outcomes All cause mortality
Number of patients with acute cellular rejection
Notes Abstract
Letter was sent to the authors in September 2009 No reply was received
Risk of bias
Item Authorsrsquo judgement Description
Adequate sequence generation Unclear A randomisation list was performed before
patients were admitted to the trial (infor-
mation from principal author)
Allocation concealment Unclear No information provided
Blinding Unclear The principle author provided information
that the study was made according to a
single-blind randomised protocol The pri-
mary outcome was the occurrence of biopsy
proven rejection episodes The pathologists
were blind but the patients were not
29Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Sama 1991 (Continued)
Incomplete outcome data addressed
All outcomes
Unclear Five patients from the UDCA group and
six patients from the placebo group were
excluded Reasons for exclusion were not
fully stated
Free of selective reporting No Data about survival of patients were not
adequately reported
Sample size calculation No Not performed
Intention-to-treat analysis No Not stated and not used
Baseline imbalance Unclear Basic characteristics of patients not re-
ported
Early stopping of trial Unclear Not enough information provided
UDCA = ursodeoxycholic acid
TUDCA = tauroursodeoxycholic acid
PBC = primary biliary cirrhosis
PSC = primary sclerosing cholangitis
OKT3 = anti-CD3 monoclonal antibody
Characteristics of excluded studies [ordered by study ID]
Assy 2007 A randomised controlled trial that included only recipients of liver transplantation with stable graft function and
no episodes of rejection for at least 2 years that were then offered total immunosuppression withdrawal Fourteen
patients received UDCA (15 mgkg body weightday) and 12 received placebo Rejection occurred in 43 and
75 of patients respectively (no significant difference) None developed chronic rejection After follow-up two
patients were free of immunosuppression 80 were steroid free and 50 were able to reduce their dose of
cyclosporine
Clavien 1996 Case series Fifty consecutive liver-transplanted patients were treated with a standard cyclosporine immunosup-
pressive regimen Twenty three of the 43 survivors developed an episode of rejection and UDCA (10 mgkg
weightday) was initiated Only one patient had a second episode of rejection
Friman 1992 Observational study Thirty-three liver-transplanted patients received 10 mg UDCAkg body weightday for
median of 10 months (range four to 21 months) Eight historical liver-transplanted patients served as control
group The rejection incidence was significantly lower in the patients who received the treatment with UDCA
Biochemistry one month after transplantation demonstrated significantly lower average values of aminotrans-
ferases and alkaline phosphatases in patients treated with UDCA than in the control group
30Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
Heathcote 1999 Observational study From 1987 to 1996 37 UDCA treated and 53 placebo treated patients with primary biliary
cirrhosis were referred for transplantation Posttransplantation survival rates at one month were 939 in the
UDCA group and 884 in the placebo group and one year survival rates were 903 and 784 respectively
(no significant differences) However rejection (type not defined - a secondary outcome measure) occurred
significantly less often in the UDCA group (429) than in placebo group (688)
Henriksson 1991 Observational study All patients in this study were given sequential quadruple immunosuppression with anti-
lymphocyte globulin azathioprine steroids and cyclosporine All patients with primary graft function (n = 11)
were treated with 10 mg UDCAkg body weightday starting during the first postoperative week Patients who
received liver transplantation in the first 6 months of 1989 (n = 8) served as controls In the control group one
patient died after 9 months with chronic graft dysfunction and six patients had rejection episodes during the
first postoperative month All patients in the UDCA group were alive without rejection episodes
Persson 1990 Observational study All 11 adult patients transplanted between August 1989 and January 1990 with primary
graft function were treated with 10 mg UDCA kg body weightday Eight patients transplanted during the first
half of 1989 served as control UDCA was started during the first postoperative week and the treatment was
continued for six months All patients in the UDCA treated group survived with satisfactory graft function In
the control group six patients had at least one rejection episode needing treatment during the first postoperative
month
Rafael 1995 Observational study Seventeen patients who underwent liver transplantation between February 1990 and April
1993 and developed biliary complications after transplantation were retrospectively analysed regarding treatment
with UDCA UDCA was given in a dose of 500 to 1000 mgday Ten patients were treated for at least one year while
seven patients were treated for 14 to 250 days UDCA significantly improved gammaglutamyl transpeptidase in
liver graft recipients with biliary complications There was also a trend towards improvement in serum bilirubin
and alanine transaminase values
Sama 1998 Observational study Thirty-four patients who underwent liver transplantation between January 1995 and June
1996 were included in the study Seventeen were treated with UDCA 10 mgkg body weightday during 6
months while 17 served as controls on the basis of having undergone liver transplantation closest to UDCA
patients A significant decrease in serum bilirubin levels was observed in UDCA patients There was a significantly
higher incidence of recurrent hepatitis in the control group
UDCA ursodeoxycholic acid
31Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
D A T A A N D A N A L Y S E S
Comparison 1 Bile acids for liver-transplanted patients
Outcome or subgroup titleNo of
studies
No of
participants Statistical method Effect size
1 All-cause mortality at maximum
follow-up
5 257 Risk Ratio (M-H Fixed 95 CI) 085 [053 136]
11 UDCA versus placebo or
no treatment
4 224 Risk Ratio (M-H Fixed 95 CI) 080 [049 130]
12 TUDCA versus no
treatment
1 33 Risk Ratio (M-H Fixed 95 CI) 159 [030 833]
2 All-cause mortality worst-best
case and best-worst case
scenarios
5 Risk Ratio (M-H Fixed 95 CI) Subtotals only
21 Worst-best case scenario 5 257 Risk Ratio (M-H Fixed 95 CI) 130 [086 196]
22 Best-worst case scenario 5 257 Risk Ratio (M-H Fixed 95 CI) 058 [038 090]
3 Subgroup analyses all-cause
mortality at maximum
follow-up according to time of
start of bile acids
5 257 Risk Ratio (M-H Fixed 95 CI) 085 [053 136]
31 Less than three days after
transplantation
1 102 Risk Ratio (M-H Fixed 95 CI) 124 [061 254]
32 Three days or more after
transplantation
4 155 Risk Ratio (M-H Fixed 95 CI) 063 [033 120]
4 Subgroup analyses all cause
mortality at maximum
follow-up according to
treatment duration
5 257 Risk Ratio (M-H Fixed 95 CI) 085 [053 136]
41 Less than six months 3 184 Risk Ratio (M-H Fixed 95 CI) 078 [045 138]
42 Six months or more 2 73 Risk Ratio (M-H Fixed 95 CI) 102 [043 240]
5 Number of deaths related
to rejection at maximum
follow-up
1 102 Risk Ratio (M-H Fixed 95 CI) 030 [001 712]
51 UDCA versus placebo 1 102 Risk Ratio (M-H Fixed 95 CI) 030 [001 712]
6 Number of retransplantations at
maximum follow-up
2 132 Risk Ratio (M-H Fixed 95 CI) 076 [020 286]
7 Number of patients with acute
cellular rejection at maximum
follow-up
7 339 Risk Ratio (M-H Fixed 95 CI) 089 [074 106]
71 UDCA versus placebo or
no treatment
6 306 Risk Ratio (M-H Fixed 95 CI) 089 [074 108]
72 TUDCA versus no
treatment
1 33 Risk Ratio (M-H Fixed 95 CI) 085 [045 160]
8 Subgroup analysis number of
patients with acute cellular
rejection according to time of
start of bile acid
7 339 Risk Ratio (M-H Fixed 95 CI) 089 [074 106]
32Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
81 Less than three days after
transplantation
2 134 Risk Ratio (M-H Fixed 95 CI) 084 [063 111]
82 Three days or more after
liver transplantation
5 205 Risk Ratio (M-H Fixed 95 CI) 092 [072 117]
9 Subgroup analysis number
of patients with acute
cellular rejection according to
treatment duration
7 339 Risk Ratio (M-H Fixed 95 CI) 089 [074 106]
91 Less than six months 5 266 Risk Ratio (M-H Fixed 95 CI) 087 [071 107]
92 Six months or more 2 73 Risk Ratio (M-H Fixed 95 CI) 094 [065 136]
10 Number of patients with
chronic rejection at maximum
follow-up
3 184 Risk Ratio (M-H Fixed 95 CI) 028 [008 095]
11 Number of patients with
steroid-resistant rejection at
maximum follow-up
4 234 Risk Ratio (M-H Fixed 95 CI) 077 [047 127]
12 Serum bilirubin (mgdl) at the
end of treatment
1 30 Mean Difference (IV Fixed 95 CI) 26 [-096 616]
13 Number of days of
hospitalisation after liver
transplantation
1 52 Mean Difference (IV Fixed 95 CI) -85 [-1667 -033]
14 Adverse events 3 187 Risk Ratio (M-H Fixed 95 CI) 088 [030 260]
Analysis 11 Comparison 1 Bile acids for liver-transplanted patients Outcome 1 All-cause mortality at
maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 1 All-cause mortality at maximum follow-up
Study or subgroup Favours bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 UDCA versus placebo or no treatment
Barnes 1997 228 724 253 024 [ 006 107 ]
Fleckenstein 1998 214 416 125 057 [ 012 266 ]
Keiding 1997 1454 1048 355 124 [ 061 254 ]
Sama 1991 520 620 201 083 [ 030 229 ]
Subtotal (95 CI) 116 108 935 080 [ 049 130 ]
Total events 23 (Favours bile acids) 27 (Control)
Heterogeneity Chi2 = 416 df = 3 (P = 025) I2 =28
Test for overall effect Z = 091 (P = 036)
01 02 05 1 2 5 10
Favours bile acids Favours control
(Continued )
33Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Favours bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
2 TUDCA versus no treatment
Angelico 1999 316 217 65 159 [ 030 833 ]
Subtotal (95 CI) 16 17 65 159 [ 030 833 ]
Total events 3 (Favours bile acids) 2 (Control)
Heterogeneity not applicable
Test for overall effect Z = 055 (P = 058)
Total (95 CI) 132 125 1000 085 [ 053 136 ]
Total events 26 (Favours bile acids) 29 (Control)
Heterogeneity Chi2 = 466 df = 4 (P = 032) I2 =14
Test for overall effect Z = 069 (P = 049)
01 02 05 1 2 5 10
Favours bile acids Favours control
Analysis 12 Comparison 1 Bile acids for liver-transplanted patients Outcome 2 All-cause mortality worst-
best case and best-worst case scenarios
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 2 All-cause mortality worst-best case and best-worst case scenarios
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 Worst-best case scenario
Angelico 1999 516 217 65 266 [ 060 1180 ]
Barnes 1997 828 724 253 098 [ 042 230 ]
Fleckenstein 1998 314 416 125 086 [ 023 319 ]
Keiding 1997 1954 1048 355 169 [ 087 327 ]
Sama 1991 520 620 201 083 [ 030 229 ]
Subtotal (95 CI) 132 125 1000 130 [ 086 196 ]
Total events 40 (Bile acids) 29 (Control)
Heterogeneity Chi2 = 303 df = 4 (P = 055) I2 =00
Test for overall effect Z = 123 (P = 022)
2 Best-worst case scenario
005 02 1 5 20
Favours bile acids Favours control
(Continued )
34Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Angelico 1999 316 417 90 080 [ 021 302 ]
Barnes 1997 228 1124 274 016 [ 004 063 ]
Fleckenstein 1998 214 616 130 038 [ 009 159 ]
Keiding 1997 1454 1548 368 083 [ 045 154 ]
Sama 1991 520 620 139 083 [ 030 229 ]
Subtotal (95 CI) 132 125 1000 058 [ 038 090 ]
Total events 26 (Bile acids) 42 (Control)
Heterogeneity Chi2 = 567 df = 4 (P = 023) I2 =29
Test for overall effect Z = 247 (P = 0014)
005 02 1 5 20
Favours bile acids Favours control
Analysis 13 Comparison 1 Bile acids for liver-transplanted patients Outcome 3 Subgroup analyses all-
cause mortality at maximum follow-up according to time of start of bile acids
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 3 Subgroup analyses all-cause mortality at maximum follow-up according to time of start of bile acids
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 Less than three days after transplantation
Keiding 1997 1454 1048 355 124 [ 061 254 ]
Subtotal (95 CI) 54 48 355 124 [ 061 254 ]
Total events 14 (Bile acids) 10 (Control)
Heterogeneity not applicable
Test for overall effect Z = 060 (P = 055)
2 Three days or more after transplantation
Angelico 1999 316 217 65 159 [ 030 833 ]
Barnes 1997 228 724 253 024 [ 006 107 ]
Fleckenstein 1998 214 416 125 057 [ 012 266 ]
Sama 1991 520 620 201 083 [ 030 229 ]
005 02 1 5 20
Favours bile acids Favours control
(Continued )
35Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Subtotal (95 CI) 78 77 645 063 [ 033 120 ]
Total events 12 (Bile acids) 19 (Control)
Heterogeneity Chi2 = 310 df = 3 (P = 038) I2 =3
Test for overall effect Z = 141 (P = 016)
Total (95 CI) 132 125 1000 085 [ 053 136 ]
Total events 26 (Bile acids) 29 (Control)
Heterogeneity Chi2 = 466 df = 4 (P = 032) I2 =14
Test for overall effect Z = 069 (P = 049)
005 02 1 5 20
Favours bile acids Favours control
Analysis 14 Comparison 1 Bile acids for liver-transplanted patients Outcome 4 Subgroup analyses all
cause mortality at maximum follow-up according to treatment duration
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 4 Subgroup analyses all cause mortality at maximum follow-up according to treatment duration
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 Less than six months
Barnes 1997 228 724 253 024 [ 006 107 ]
Fleckenstein 1998 214 416 125 057 [ 012 266 ]
Keiding 1997 1454 1048 355 124 [ 061 254 ]
Subtotal (95 CI) 96 88 734 078 [ 045 138 ]
Total events 18 (Bile acids) 21 (Control)
Heterogeneity Chi2 = 417 df = 2 (P = 012) I2 =52
Test for overall effect Z = 084 (P = 040)
2 Six months or more
Angelico 1999 316 217 65 159 [ 030 833 ]
Sama 1991 520 620 201 083 [ 030 229 ]
Subtotal (95 CI) 36 37 266 102 [ 043 240 ]
Total events 8 (Bile acids) 8 (Control)
Heterogeneity Chi2 = 043 df = 1 (P = 051) I2 =00
005 02 1 5 20
Favours bile acids Favours control
(Continued )
36Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Test for overall effect Z = 004 (P = 097)
Total (95 CI) 132 125 1000 085 [ 053 136 ]
Total events 26 (Bile acids) 29 (Control)
Heterogeneity Chi2 = 466 df = 4 (P = 032) I2 =14
Test for overall effect Z = 069 (P = 049)
005 02 1 5 20
Favours bile acids Favours control
Analysis 15 Comparison 1 Bile acids for liver-transplanted patients Outcome 5 Number of deaths related
to rejection at maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 5 Number of deaths related to rejection at maximum follow-up
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 UDCA versus placebo
Keiding 1997 054 148 1000 030 [ 001 712 ]
Total (95 CI) 54 48 1000 030 [ 001 712 ]
Total events 0 (Bile acids) 1 (Control)
Heterogeneity not applicable
Test for overall effect Z = 075 (P = 045)
0001 001 01 1 10 100 1000
Favours bile acids Favours control
37Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 16 Comparison 1 Bile acids for liver-transplanted patients Outcome 6 Number of
retransplantations at maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 6 Number of retransplantations at maximum follow-up
Study or subgroup Bile acids Placebo Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Fleckenstein 1998 214 016 100 567 [ 029 10891 ]
Keiding 1997 154 448 900 022 [ 003 192 ]
Total (95 CI) 68 64 1000 076 [ 020 286 ]
Total events 3 (Bile acids) 4 (Placebo)
Heterogeneity Chi2 = 303 df = 1 (P = 008) I2 =67
Test for overall effect Z = 040 (P = 069)
0001 001 01 1 10 100 1000
Favours bile acids Favours placebo
Analysis 17 Comparison 1 Bile acids for liver-transplanted patients Outcome 7 Number of patients with
acute cellular rejection at maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 7 Number of patients with acute cellular rejection at maximum follow-up
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 UDCA versus placebo or no treatment
Barnes 1997 1728 1724 180 086 [ 058 127 ]
Fleckenstein 1998 814 916 83 102 [ 054 190 ]
Keiding 1997 3554 3248 333 097 [ 073 129 ]
Koneru 1993 316 916 89 033 [ 011 101 ]
Pageaux 1995 926 924 92 092 [ 044 193 ]
Sama 1991 1320 1320 128 100 [ 063 158 ]
Subtotal (95 CI) 158 148 905 089 [ 074 108 ]
01 02 05 1 2 5 10
Favours bile acids Favours control
(Continued )
38Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Total events 85 (Bile acids) 89 (Control)
Heterogeneity Chi2 = 387 df = 5 (P = 057) I2 =00
Test for overall effect Z = 120 (P = 023)
2 TUDCA versus no treatment
Angelico 1999 816 1017 95 085 [ 045 160 ]
Subtotal (95 CI) 16 17 95 085 [ 045 160 ]
Total events 8 (Bile acids) 10 (Control)
Heterogeneity not applicable
Test for overall effect Z = 050 (P = 061)
Total (95 CI) 174 165 1000 089 [ 074 106 ]
Total events 93 (Bile acids) 99 (Control)
Heterogeneity Chi2 = 392 df = 6 (P = 069) I2 =00
Test for overall effect Z = 130 (P = 019)
01 02 05 1 2 5 10
Favours bile acids Favours control
Analysis 18 Comparison 1 Bile acids for liver-transplanted patients Outcome 8 Subgroup analysis
number of patients with acute cellular rejection according to time of start of bile acid
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 8 Subgroup analysis number of patients with acute cellular rejection according to time of start of bile acid
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 Less than three days after transplantation
Keiding 1997 3554 3248 333 097 [ 073 129 ]
Koneru 1993 316 916 89 033 [ 011 101 ]
Subtotal (95 CI) 70 64 422 084 [ 063 111 ]
Total events 38 (Bile acids) 41 (Control)
Heterogeneity Chi2 = 374 df = 1 (P = 005) I2 =73
Test for overall effect Z = 124 (P = 022)
2 Three days or more after liver transplantation
Angelico 1999 816 1017 95 085 [ 045 160 ]
01 02 05 1 2 5 10
Favours bile acids Favours control
(Continued )
39Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Barnes 1997 1728 1724 180 086 [ 058 127 ]
Fleckenstein 1998 814 916 83 102 [ 054 190 ]
Pageaux 1995 926 924 92 092 [ 044 193 ]
Sama 1991 1320 1320 128 100 [ 063 158 ]
Subtotal (95 CI) 104 101 578 092 [ 072 117 ]
Total events 55 (Bile acids) 58 (Control)
Heterogeneity Chi2 = 041 df = 4 (P = 098) I2 =00
Test for overall effect Z = 067 (P = 050)
Total (95 CI) 174 165 1000 089 [ 074 106 ]
Total events 93 (Bile acids) 99 (Control)
Heterogeneity Chi2 = 392 df = 6 (P = 069) I2 =00
Test for overall effect Z = 130 (P = 019)
01 02 05 1 2 5 10
Favours bile acids Favours control
40Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 19 Comparison 1 Bile acids for liver-transplanted patients Outcome 9 Subgroup analysis
number of patients with acute cellular rejection according to treatment duration
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 9 Subgroup analysis number of patients with acute cellular rejection according to treatment duration
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 Less than six months
Barnes 1997 1728 1724 180 086 [ 058 127 ]
Fleckenstein 1998 814 916 83 102 [ 054 190 ]
Keiding 1997 3554 3248 333 097 [ 073 129 ]
Koneru 1993 316 916 89 033 [ 011 101 ]
Pageaux 1995 926 924 92 092 [ 044 193 ]
Subtotal (95 CI) 138 128 777 087 [ 071 107 ]
Total events 72 (Bile acids) 76 (Control)
Heterogeneity Chi2 = 374 df = 4 (P = 044) I2 =00
Test for overall effect Z = 129 (P = 020)
2 Six months or more
Angelico 1999 816 1017 95 085 [ 045 160 ]
Sama 1991 1320 1320 128 100 [ 063 158 ]
Subtotal (95 CI) 36 37 223 094 [ 065 136 ]
Total events 21 (Bile acids) 23 (Control)
Heterogeneity Chi2 = 017 df = 1 (P = 068) I2 =00
Test for overall effect Z = 035 (P = 073)
Total (95 CI) 174 165 1000 089 [ 074 106 ]
Total events 93 (Bile acids) 99 (Control)
Heterogeneity Chi2 = 392 df = 6 (P = 069) I2 =00
Test for overall effect Z = 130 (P = 019)
01 02 05 1 2 5 10
Favours bile acids Favours control
41Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 110 Comparison 1 Bile acids for liver-transplanted patients Outcome 10 Number of patients
with chronic rejection at maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 10 Number of patients with chronic rejection at maximum follow-up
Study or subgroup Bile acids Placebo Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Barnes 1997 128 624 611 014 [ 002 110 ]
Fleckenstein 1998 114 116 88 114 [ 008 1663 ]
Keiding 1997 154 348 300 030 [ 003 275 ]
Total (95 CI) 96 88 1000 028 [ 008 095 ]
Total events 3 (Bile acids) 10 (Placebo)
Heterogeneity Chi2 = 148 df = 2 (P = 048) I2 =00
Test for overall effect Z = 204 (P = 0041)
0001 001 01 1 10 100 1000
Favours bile acids Favours placebo
Analysis 111 Comparison 1 Bile acids for liver-transplanted patients Outcome 11 Number of patients
with steroid-resistant rejection at maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 11 Number of patients with steroid-resistant rejection at maximum follow-up
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Barnes 1997 328 724 277 037 [ 011 127 ]
Fleckenstein 1998 314 316 103 114 [ 027 478 ]
Keiding 1997 1454 1548 583 083 [ 045 154 ]
Pageaux 1995 226 124 38 185 [ 018 1908 ]
Total (95 CI) 122 112 1000 077 [ 047 127 ]
Total events 22 (Bile acids) 26 (Control)
Heterogeneity Chi2 = 226 df = 3 (P = 052) I2 =00
Test for overall effect Z = 102 (P = 031)
001 01 1 10 100
Favours bile acids Favours placebo
42Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 112 Comparison 1 Bile acids for liver-transplanted patients Outcome 12 Serum bilirubin (mgdl)
at the end of treatment
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 12 Serum bilirubin (mgdl) at the end of treatment
Study or subgroup Bile acids Placebo Mean Difference Weight Mean Difference
N Mean(SD) N Mean(SD) IVFixed95 CI IVFixed95 CI
Fleckenstein 1998 14 319 (68) 16 059 (022) 1000 260 [ -096 616 ]
Total (95 CI) 14 16 1000 260 [ -096 616 ]
Heterogeneity not applicable
Test for overall effect Z = 143 (P = 015)
-10 -5 0 5 10
Favours bile acids Favours placebo
Analysis 113 Comparison 1 Bile acids for liver-transplanted patients Outcome 13 Number of days of
hospitalisation after liver transplantation
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 13 Number of days of hospitalisation after liver transplantation
Study or subgroup Bile acids Placebo Mean Difference Weight Mean Difference
N Mean(SD) N Mean(SD) IVFixed95 CI IVFixed95 CI
Barnes 1997 28 25 (17) 24 335 (13) 1000 -850 [ -1667 -033 ]
Total (95 CI) 28 24 1000 -850 [ -1667 -033 ]
Heterogeneity not applicable
Test for overall effect Z = 204 (P = 0041)
-100 -50 0 50 100
Favours bile acids Favours placebo
43Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 114 Comparison 1 Bile acids for liver-transplanted patients Outcome 14 Adverse events
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 14 Adverse events
Study or subgroup Bile acids Placebo Risk Ratio Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Angelico 1999 016 017 00 [ 00 00 ]
Barnes 1997 128 124 086 [ 006 1298 ]
Keiding 1997 554 548 089 [ 027 288 ]
Total (95 CI) 98 89 088 [ 030 260 ]
Total events 6 (Bile acids) 6 (Placebo)
Heterogeneity Chi2 = 000 df = 1 (P = 098) I2 =00
Test for overall effect Z = 022 (P = 082)
001 01 1 10 100
Favours bile acids Favours placebo
A P P E N D I C E S
Appendix 1 Search strategies
Data Base Date of Search Search Strategy
The Cochrane Hepato-Biliary Group Con-
trolled Trials Register
September 2009 1 rsquoliver transplantationrsquo and rsquochenodeoxy-
cholicrsquo
2 rsquoliver transplantationrsquo and rsquocholicrsquo
3 rsquoliver transplantationrsquo and rsquodeoxycholicrsquo
4 rsquoliver transplantationrsquo and rsquoglycochen-
odeoxycholicrsquo
5 rsquoliver transplantationrsquo and rsquoglycocholicrsquo
6 rsquoliver transplantationrsquo and rsquoglycodeoxy-
cholicrsquo
7 rsquoliver transplantationrsquo and rsquoglycolitho-
cholicrsquo
8 rsquoliver transplantationrsquo and rsquohyodeoxy-
cholicrsquo
9 rsquoliver transplantationrsquo and rsquolithocholicrsquo
10 rsquoliver transplantationrsquo and rsquotaurochen-
odeoxycholicrsquo
44Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
11 rsquoliver transplantationrsquo and rsquotauro-
cholicrsquo
12 rsquoliver transplantationrsquo and rsquotaurodehy-
drocholicrsquo
13 rsquoliver transplantationrsquo and rsquotau-
rodeoxycholicrsquo
14 rsquoliver transplantationrsquo and rsquotauroglyco-
cholicrsquo
15 rsquoliver transplantationrsquo and rsquotaurolitho-
cholicrsquo
16 rsquoliver transplantationrsquo and rsquotaurosel-
cholicrsquo
17 rsquoliver transplantationrsquo and rsquotaurourso-
cholicrsquo
18 rsquoliver transplantationrsquo and rsquotaurour-
sodeoxycholicrsquo
19 rsquoliver transplantationrsquo and rsquoursocholicrsquo
20 rsquoliver transplantationrsquo and rsquoursodeoxy-
cholicrsquo
The Cochrane Central Register of Con-
trolled Trials in The Cochrane Library
Issue 3 2009 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
6 3 or 4
7 5 and 6
MEDLINE September 2009 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
45Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
6 3 or 4
7 5 and 6
8 RANDOMIZED-CONTROLLED-
TRIAL ME
9 RANDOM
10 8 or 9
11 7 and 10
EMBASE September 2009 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
6 3 or 4
7 5 and 6
8 RANDOMIZED-CONTROLLED-
TRIAL ME
9 RANDOM
10 8 or 9
11 7 and 10
46Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
Science Citation Index Expanded September 2009 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
6 3 or 4
7 5 and 6
8 RANDOMIZED-CONTROLLED-
TRIAL ME
9 RANDOM
10 8 or 9
11 7 and 10
The Chinese Biomedical Database Searched from January 1980 to April 2002 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
47Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
6 3 or 4
7 5 and 6
8 RANDOMIZED-CONTROLLED-
TRIAL ME
9 RANDOM
10 8 or 9
11 7 and 10
W H A T rsquo S N E W
Last assessed as up-to-date 8 February 2010
18 September 2009 New citation required but conclusions have not
changed
This review is an updated version of a review that was
published for the first time in Issue 3 2005 of TheCochrane Library by Chen 2003b
18 September 2009 New search has been performed No new studies fulfilled the inclusion criteria
H I S T O R Y
Protocol first published Issue 3 2003
Review first published Issue 3 2005
C O N T R I B U T I O N S O F A U T H O R S
GP and VG independently performed searches of relevant databases GP validated the search selected trials for inclusion contacted
the authors of the trials performed data extraction and data analysis and drafted the systematic review VG revised the review update
CG and DS revised the review update solved discrepancies of data extraction validated data analyses and provided consultation
D E C L A R A T I O N S O F I N T E R E S T
None known
48Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
S O U R C E S O F S U P P O R T
Internal sources
bull Copenhagen Trial Unit Denmark
External sources
bull Danish Medical Research Councilrsquos Grant on Getting Research into Practice (GRIP) Denmark
D I F F E R E N C E S B E T W E E N P R O T O C O L A N D R E V I E W
We assessed the risk of bias in the included studies for another four domains that were added to the review protocol (incomplete
outcome data selective outcome reporting baseline imbalance and early stopping of trial) In general the text of the risk of bias
domains were updated following Higgins 2008 Trials were considered at low risk of bias when judged as adequate in all domains
Quasi-randomised studies observational and case-control studies were included for the report of adverse events
We performed trial sequential analysis for outcomes demonstrating a statistically significant result
I N D E X T E R M S
Medical Subject Headings (MeSH)
lowastLiver Transplantation Cholagogues and Choleretics [lowasttherapeutic use] Graft Rejection [lowastprevention amp control] Randomized Con-
trolled Trials as Topic Taurochenodeoxycholic Acid [lowasttherapeutic use] Ursodeoxycholic Acid [lowasttherapeutic use]
MeSH check words
Humans
49Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
fore the bile duct epithelium and central vein endothelium are
the primary targets attacked by cytotoxic T cells during rejection
Impairment of the bile flow in the grafted liver may also cause re-
jection (Ericzon 1990) Mild cholestasis is a common finding after
liver transplantation and its association with clinically significant
pathology is unlikely Nevertheless severe cholestasis should be
treated as a potential cause of allograft rejection (Corbani 2008)
In the study by Fusai 2006 the development of cholestasis was sig-
nificantly related to prolonged warm ischaemia of the liver trans-
plant Cholestasis can induce hyper-expression of major histocom-
patibility complex class I molecules by hepatocytes and thereby
lymphocyte CD8+-dependent cytotoxicity (Calmus 1992)
Bile acids include chenodeoxycholic acid deoxycholic acid litho-
cholic acid and ursodeoxycholic acid (UDCA) (Fuchs 1999)
In the course of cholestasis intrahepatic accumulation of chen-
odeoxycholic acid and deoxycholic acid is thought to induce liver
damage (Palmer 1972) In fact the direct damage of membrane
phospholipids and cholesterol components caused by the deter-
gent-like properties of hydrophobic bile acids results in hepato-
cyte necrosis (Sholmerich 1984 Perez 2009) It is also suggested
that oxidative stress induced by hydrophobic bile acids plays an
important role in liver damage during cholestasis These effects
can be prevented by the addition of UDCA which modifies the
bile acid pool resulting in an increase of the hydrophilic frac-
tion and stabilisation of the cell membranes (Armstrong 1982
Perez 2009) Several studies on animal models showed evidence
of potential immunomodulatory beneficial effects of UDCA and
tauro-ursodeoxycholic acid (TUDCA) by suppressing cytokine
and immunoglobulin production and T-cell mediated cytotoxic-
ity (Yoshikawa 1998) In the study by Calmus 1990 it has been
observed that UDCA down-regulates the expression of abnormal
major histocompatibility complex class I molecules in periportal
hepatocytes in patients with primary biliary cirrhosis Treatment
with UDCA has been reported to have potential beneficial ef-
fects in various cholestatic liver conditions including primary bil-
iary cirrhosis (Gong 2008) primary sclerosing cholangitis (Chen
2003a) and cystic fibrosis (Cheng 2002)
It has previously been suggested that UDCA and perhaps tauro-
UDCA (TUDCA) may reduce the incidence of acute rejection
and steroid-resistant rejection in liver-transplanted patients when
administered with combination of immunosuppressive treatment
There are several potential mechanisms by which UDCA may in-
hibit allograft rejection in liver transplant recipients (Okolicsanyi
1986 Merion 1989 Calmus 1990 Terasaki 1991 Heuman 1993
Al-Quaiz 1994 Friman 1994 Soderdahl 1998 Yoshikawa 1998
Assy 2007 Perez 2009) However most of these studies included
a relatively small number of patients were not randomised and
often did not include histological information (Persson 1990
Friman 1992 Koneru 1993 Sharara 1995)
The previous version of this review by Chen 2003b stated that
there was no convincing beneficial effects from the use of bile acids
in liver-transplanted patients the risk of bias in the seven included
trials was high The review also found that there was a low occur-
rence of adverse events and hence the use of bile acids could be
considered safe It should be noted however that this observation
is based on reports from four trials with few patients We have
been unable to identify any other meta-analyses or systematic re-
views either This review represents an update of the Chen 2003b
Cochrane hepato-Biliary Group review
O B J E C T I V E S
To evaluate the beneficial and harmful effects of bile acids for liver-
transplanted patients by comparing bile acids versus placebo no
intervention or another intervention in randomised clinical trials
M E T H O D S
Criteria for considering studies for this review
Types of studies
We included randomised clinical trials irrespective of blinding
publication status year of publication or language We assessed
both included and excluded studies for the report of adverse events
We listed all studies reporting on adverse events in an additional
table (Table 1) However only data from the included trials were
used in the statistical analysis
Table 1 Adverse events
Study Pts in experimental
group
Patients in control
group
AE in experimental
group
AE in control group Authorrsquos conclusion
Barnes 1997 28 24 Diarrhoea (1 pt) Diarrhoea (1 pt) Adverse
reactions attributable
to study medication
were rare
3Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Table 1 Adverse events (Continued)
Keiding 1997 54 48 Diarrhoea and diffi-
culties in swallowing
capsules (5 pts)
Diarrhoea and diffi-
culties in swallowing
capsules (5 pts)
No other presumed
drug-induced side ef-
fects were observed
Angelico 1999 16 17 No AE No AE TUDCA administra-
tion was well tol-
erated in all pa-
tients and no drug-
related side effects
were recorded
Assy 2007 14 12 Mild diarrhoea (1 pt) No AE No dose reduction
was required
pt(s) = patient(s)
AE = adverse events
Types of participants
Patients who underwent liver transplantation
Types of interventions
Any dose of a bile acid or duration of treatment versus placebo
no intervention or another intervention
We allowed co-interventions if received equally by the intervention
groups within a trial
Types of outcome measures
The primary outcome measures were
1 All-cause mortality
2 Death due to allograft rejection (acute cellular rejection or
chronic rejection or liver retransplantation because of rejection)
Acute cellular rejection was diagnosed by the combination of ab-
normal liver biochemical variables (bilirubin aspartate transam-
inase alanine transaminase alkaline phosphatases andor gam-
maglutamyl transpeptidase) clinical signs such as fever and liver
histological changes including mononuclear portal inflammation
bile duct damage and subendothelial inflammation of portal or
terminal hepatic veins (IWP 1995) Chronic rejection was charac-
terised by liver histological changes including the progressive loss
of interlobular bile ducts and arteriopathy characterised by foam
cell infiltration of the arterial intima
The secondary outcome measures were
3 Number of patients who experienced rejection - irrespective of
the type acute cellular rejection chronic rejection or both types
of rejections
4 Number of patients with acute cellular rejection
5 Number of patients with chronic rejection
6 Number of patients with steroid-resistant rejection
7 Biochemical responses serum activities of alkaline phos-
phatases gammaglutamyl transpeptidase alanine aminotrans-
ferase and aspartate aminotransferase and serum bilirubin con-
centration andor number of patients with abnormal liver bio-
chemical variables mentioned above
8 Adverse events Adverse events were defined as any untoward
medical occurrence not necessarily having a causal relationship
with the treatment but resulting in a dose reduction or discontin-
uation of treatment (ICH-GCP 1997)
9 Quality of life
10 Cost-effectiveness
Search methods for identification of studies
We performed searches of The Cochrane Hepato-Biliary GroupControlled Trials Register (September 2009)(Gluud 2010) and TheCochrane Central Register of Controlled Trials (CENTRAL) in TheCochrane Library (Issue 3 2009) by combining the terms rsquoliverrsquo
and rsquotransplantationrsquo with the individual bile acid name (litho-
cholic acid chenodeoxycholic acid ursodeoxycholic acid deoxy-
cholic acid dehydrocholic acid and tauro-ursodeoxycholic acid)
We searched MEDLINE (January 1966 to September 2009) EM-BASE (January 1980 to September 2009) and Science Citation In-dex Expanded (1945 to September 2009) by using the terms rsquoliverrsquo
4Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
and rsquotransplantationrsquo in combination with the bile acids mentioned
above (Royle 2003) The search strategies with the time span of
the searches are given in Appendix 1 We contacted the Chinese
Cochrane Centre regarding the search of The Chinese BiomedicalDatabase and received a reply that they are unable to help us with
this search Therefore the latter database could not be included
in the search strategy of this update
Further trials were identified by reading the reference lists of the
identified studies We wrote to the principal authors of the reports
of the identified randomised clinical trials in September 2009 and
enquired about additional trials which they might know of The
first team of authors had also written to pharmaceutical companies
involved in the production of bile acids to obtain information on
published or unpublished randomised clinical trials in 2002 but
no information had been received at that time
Data collection and analysis
The update of this review was conducted according to the proto-
col previously published in The Cochrane Library (Chen 2003b)
and following the recommendations given by the Cochrane Hand-book for Systematic Reviews of Interventions (Higgins 2008) and the
Cochrane Hepato-Biliary Group Module (Gluud 2010)
Trial identification
Identified trials were listed and the two review authors evaluated
whether the trials fulfilled the inclusion criteria Excluded trials
were listed with the reasons for exclusion
Data extraction
GP and VG extracted the data independently and disagreements
were resolved by discussion or by CG We extracted the following
characteristics from each trial primary author number of patients
randomised patient inclusion and exclusion criteria methodolog-
ical quality follow-up (number and reasons for withdrawal) sam-
ple size calculation intention-to-treat analysis intervention reg-
imens mean age proportion of males and females aetiology of
liver disease origin of allograft matching criteria between donor
and recipient time to follow-up number of outcomes and num-
ber and type of adverse events in both the intervention and the
control groups Additional information was sought by correspon-
dence with the principal investigator or co-investigators of the trial
in cases where the relevant data were not published
Assessment of risk of bias
Risk of bias was defined as the confidence that the study design and
reporting restricted bias in the intervention comparison (Schulz
1995 Moher 1998 Kjaergard 2001 Wood 2008) Due to the risk
of overestimation of intervention effects in randomised trials with
unclear or inadequate components we assessed the risk of bias by
separate domains
Allocation sequence generation
bull Adequate if the allocation sequence was generated by a
computer or random number table Drawing of lots tossing of a
coin shuffling of cards or throwing dice was considered as
adequate if a person who was not otherwise involved in the
recruitment of participants performed the procedure
bull Unclear if the trial was described as randomised but the
method used for the allocation sequence generation was not
described
bull Inadequate if a system involving dates names or
admittance numbers were used for the allocation of patients
Such quasi-randomised studies were excluded
Allocation concealment
bull Adequate if the allocation of patients involved a central
independent unit on-site locked computer identically appearing
numbered drug bottles or containers prepared by an
independent pharmacist or investigator or serially numbered
sealed and opaque envelopes
bull Unclear if the trial was described as randomised but the
method used to conceal the allocation was not described
bull Inadequate if the allocation sequence was known to the
investigators who assigned participants or if the study was quasi-
randomised The latter studies were excluded
Blinding
bull Adequate the trial was described as blinded the parties that
were blinded and the method of blinding was described so that
knowledge of allocation was adequately prevented during the
trial
bull Unclear the trial was described as double blind but the
method of blinding was not described so that knowledge of
allocation was possible during the trial
bull Not performed the trial was not blinded so that the
allocation was known during the trial
Incomplete outcome data
bull Adequate if the numbers and reasons for dropouts and
withdrawals in all intervention groups were described or if it was
specified that there were no dropouts or withdrawals
bull Unclear if the report gave the impression that there had
been no dropouts or withdrawals but this was not specifically
stated
bull Inadequate if the number or reasons for dropouts and
withdrawals were not described
Selective outcome reporting
bull Adequate if study protocol is available and all pre-specified
outcomes are reported in the manuscript or if the study protocol
is not available but it is clear that the report includes all expected
outcomes
bull Unclear if there are no sufficient information to permit
judgement
bull Inadequate if not all of the pre-specified outcomes were
reported andor were reported incompletely or one or more
reported outcomes were not pre-specified
Baseline imbalance
5Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
bull Adequate if there is no baseline imbalance in the main
characteristics
bull Unclear if there is no sufficient information to assess
baseline characteristics
bull Inadequate if there was a baseline imbalance due to chance
or due to imbalanced exclusion after randomisation
Early stopping
bull Adequate if sample size calculation was reported and the
trial was not stopped or the trial was stopped early by formal
stopping rules at a point where the likelihood of observing an
extreme intervention effect due to chance was low
bull Unclear if sample size calculation was not reported and it is
not clear whether the trial was stopped early or not
bull Inadequate if the trial was stopped early due to informal
stopping rules or the trial was stopped early by a formal stopping
rule at a point where the likelihood of observing an extreme
intervention effect due to chance was high
Furthermore we registered whether the randomised clinical trials
had used an intention-to-treat analysis (Gluud 2001) and had
calculated a sample size estimate
Statistical methods
We performed the analyses in RevMan 5 (RevMan 2008) Anal-
yses included all patients irrespective of compliance or follow-up
according to the intention-to-treat principle and using the last
reported observed response (rsquocarry forwardrsquo) Regarding death
both a worst-best-case scenario analysis considering all dropped-
out patients in the bile acid group as dead and the dropped-out
patients in the control group as alive and a best-worst-case sce-
nario analysis considering all dropped-out patients in the bile acid
group as alive and the dropped-out patients in the control group as
dead were performed Both a random-effects model (DerSimonian
1986) and a fixed-effect model (DeMets 1987) were used The re-
sults of the fixed-effect model were reported if there were no differ-
ences between the results produced by the two models otherwise
we reported the results produced by both models We presented
binary outcome measures as relative risks (RR) with 95 confi-
dence intervals (CI) and continuous outcome measures as mean
differences (MD) with 95 CI
The risk of type I errors increases in single trials with interim anal-
yses To avoid type I errors group sequential monitoring bound-
aries (Lan 1983) can be performed when deciding to terminate the
trial earlier than planned This requires analyses at different time
intervals to record when the P-value has become sufficiently small
that is when the cumulative Z-curve will cross the monitoring
boundaries Sequential monitoring boundaries the so called rsquotrial
sequential monitoring boundariesrsquo can also be applied to meta-
analyses In a trial sequential analysis (TSA) every trial that is
added in a cumulative meta-analysis is regarded as an interim meta-
analysis and the information it adds on helps on deciding if more
trials need to be included
The interpretation of the TSA is as follows if the cumulative Z-
curve has crossed the boundary a sufficient level of evidence is
reached and no further trials may be needed If the Z-curve has
not crossed the boundary then the evidence is insufficient in order
to reach a conclusion To construct the trial sequential monitor-
ing boundaries information size is needed It is calculated as the
minimum number of participants needed in a well-powered single
trial (Pogue 1997 Pogue 1998 Brok 2008 Wetterslev 2008) We
applied TSA since it prevents an increase of the risk of type I error
due to sparse and multiple updating in a cumulative meta-analysis
and provides us with important information in order to estimate
the level of evidence of the experimental intervention Addition-
ally TSA provides us with important information regarding the
need for additional trials and the required information size We
applied trial sequential monitoring boundaries according to an in-
formation size suggested by the trials with low risk of bias and a
50 relative risk reduction (RRR)
Subgroup analyses
We planned to perform the following subgroup analyses on the
main outcome measures (all-cause mortality and number of pa-
tients with acute rejection)
1 Risk of bias of the trials comparing the intervention effect for
trials with low risk of bias components to the intervention effect
in trials with unclear or high risk of bias components
2 Dose and duration of treatment with bile acids comparing the
intervention effect in trials administrating bile acid at or above the
median dose multiplied by duration to the intervention effect of
trials administrating bile acid at less than the median dose multi-
plied by duration
3 Time between transplantation and the start of bile acids com-
paring the intervention effect of trials having less than three days
between transplantation and starting bile acid intake to the inter-
vention effect of trials with a duration of three days or more be-
tween transplantation and the start of bile acid intake (Neuberger
1999)
4 Co-interventions comparing the intervention effect of trials
with co-interventions to the intervention effect of trials without
co-interventions
Funnel plot analysis
We planned to explore bias by funnel plot analysis (Egger 1997)
R E S U L T S
Description of studies
See Characteristics of included studies Characteristics of excluded
studies
The performed electronic searches resulted in a total of 378 ref-
erences We excluded 362 duplicates or irrelevant references by
reading abstracts We excluded eight of the 16 further assessed ref-
erences because they were observational studies case series or ran-
6Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
domised clinical trials with a different reason for exclusion They
are listed under rsquoCharacteristic of excluded studiesrsquo with reasons
for exclusion Seven references already included in the previous
version of this review and one new reference referring to an al-
ready included trial (Barnes 1997) were included in this review
We were not able to identify more trials by reading the reference
lists of the identified studies contacting the principle authors of
the identified trials or approaching pharmaceutical companies for
unpublished trials
Seven publications included in the review (five full publications
and two abstracts) were randomised clinical trials that reported
the random allocation of liver-transplanted patients into groups
receiving bile acid placebo or no treatment We listed these trials
in the table of Characteristics of included studies All seven trials
were published in English Three randomised clinical trials were
from the United States (Koneru 1993 Barnes 1997 Fleckenstein
1998) two from Italy (Sama 1991 Angelico 1999) one from
France (Pageaux 1995) and one from Denmark (Keiding 1997)
Patients
In the included trials all patients received blood group-compatible
grafts The median size of the seven trials was 40 patients (range
29 to 102 patients) In total 335 patients were randomised
Five trials were published as full publications (Pageaux 1995
Barnes 1997 Keiding 1997 Fleckenstein 1998 Angelico 1999)
which allowed us to extract detailed information on 263 of the
patients The mean age of the patients ranged from 44 to 51 years
One trial (Keiding 1997) also enrolled children ranging in age
from 0 to 13 years (median 15 years) The male to female ratio in
these five trials was 159104 The diseases that led to liver trans-
plantation were alcoholic cirrhosis in 51 patients (194) cirrho-
sis caused by chronic hepatitis C in 40 patients (152) primary
biliary cirrhosis in 36 patients (137) cryptogenic cirrhosis in
22 patients (84) metabolic diseases in 19 patients (72) pri-
mary sclerosing cholangitis in 17 patients (65) non-specified
post-hepatitis cirrhosis in 17 patients (65) cirrhosis caused by
chronic hepatitis B in 13 patients (49) 9 with autoimmune
hepatitis and cirrhosis (34) six with liver cancer (23) five
with biliary atresia (19) and 28 with other diseases (106)
Only one trial reported the severity of liver function according to
the Child-Pugh class (Barnes 1997)
Bile acids and collateral interventions
Six trials (Sama 1991 Koneru 1993 Pageaux 1995 Barnes
1997 Keiding 1997 Fleckenstein 1998) compared UDCA versus
placebo or no intervention One trial (Angelico 1999) compared
TUDCA versus no intervention Bile acid treatment began one
day after transplantation in the Keiding 1997 trial three days after
transplantation in the Koneru 1993 trial three or five days in the
Fleckenstein 1998 and Pageaux 1995 trials five days after trans-
plantation in the Barnes 1997 and Angelico 1999 trials and five
or seven days after transplantation in the Sama 1991 trial
Patients received UCDA (10 to 15 mgkg body weightday) for
two months in the Pageaux 1995 trial for three months in the
Koneru 1993 Barnes 1997 Keiding 1997 and Fleckenstein 1998
trials and for six months in the Sama 1991 trial In the Barnes
1997 trial patients were followed up for 18 months Patients in the
Fleckenstein 1998 trial and the Keiding 1997 trial were followed
up for nine months There was no post-treatment follow-up in
three trials (Sama 1991 Koneru 1993 Pageaux 1995) Patients
received TUDCA (500 mgday) for one year and no follow-up
was conducted in the Angelico 1999 trial
In addition to the bile acids or control intervention all patients
in the seven trials received standard triple-drug regimens (steroids
azathioprine and cyclosporine or tacrolimus) The patients who
had steroid-resistant rejection received treatment with immuno-
suppressive antibodies (OKT3)
Outcome measures
The outcome measures reported by most trials were all-cause mor-
tality and acute cellular rejection Three trials reported on death
related to rejection (Barnes 1997 Keiding 1997 Angelico 1999)
two trials reported the number of patients who received retrans-
plantation due to rejection (Keiding 1997 Fleckenstein 1998)
three trials reported the number of patients with chronic rejection
(Barnes 1997 Keiding 1997 Fleckenstein 1998) and four trials
reported the number of patients with steroid-resistant rejection
(Pageaux 1995 Barnes 1997 Keiding 1997 Fleckenstein 1998)
Four trials had adverse events as outcome measures (Barnes 1997
Keiding 1997 Fleckenstein 1998 Angelico 1999) Serum biliru-
bin level was only reported by the Fleckenstein 1998 trial No tri-
als provided data on other liver biochemical parameters quality
of life or cost-effectiveness
Risk of bias in included studies
Two trials reported adequate allocation sequence generation by
using computer-generated random tables (Barnes 1997 Angelico
1999) One trial (Keiding 1997) reported adequate allocation con-
cealment by using sealed serially numbered envelopes Three tri-
als (Barnes 1997 Keiding 1997 Fleckenstein 1998) reported ad-
equate blinding by using placebo with an identical appearance
and taste Five trials (Pageaux 1995 Barnes 1997 Keiding 1997
Fleckenstein 1998 Angelico 1999) reported adequate description
of incomplete outcome data by the number of withdrawals the
reasons for withdrawal or no patients dropped out The trial by
Keiding 1997 is the only one free of selective reporting since all
the pre-specified outcomes were fairly reported Two trials (Barnes
1997 Keiding 1997) performed sample-size calculations Only
the trial by Keiding 1997 seemed to be free of baseline imbalance
and it is the only trial achieving the calculated sample size and
therefore probably the only that was not terminated early Other
trials did not perform sample size calculation or the authors did
not report whether the calculated sample size was achieved The
lack of this information made it unclear for us to judge whether
7Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
a trial was terminated early that is before an adequate number
of patients was included in the trial Three trials (Barnes 1997
Keiding 1997 Fleckenstein 1998) stated that intention-to-treat
analyses were used (Figure 1 Figure 2)
Figure 1 Methodological quality graph review authorsrsquo judgements about each methodological quality
item presented as percentages across all included studies
8Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Figure 2 Methodological quality summary review authorsrsquo judgements about each methodological quality
item for each included study
9Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Following the assessment of risk of bias domains none of the seven
trials were considered to have low risk of bias that is having all
the nine domains for risk of bias assessed as adequate
Effects of interventions
We were able to include seven randomised clinical trials in this
review Six trials with 306 liver-transplanted patients compared
ursodeoxycholic acid (UDCA) with placebo or no intervention
and one trial with 29 liver-transplanted patients compared tauro-
UDCA (TUDCA) with no intervention
All-cause mortality
Five trials including 257 liver-transplanted patients reported on
all-cause mortality at the end of treatment or at maximum follow-
up Bile acids did not significantly reduce all-cause mortality (RR
085 95 CI 053 to 136) there were 26 deaths among 132
patients treated with bile acids (197) versus 29 deaths among
125 patients in the control groups (232) (Analysis 11) There
was no statistically significant heterogeneity (I2 = 141)
Four trials (Sama 1991 Barnes 1997 Keiding 1997 Fleckenstein
1998) showed that UDCA did not significantly reduce all-cause
mortality (RR 080 95 CI 049 to 130) 23 deaths among 116
patients treated with UCDA (198) versus 27 deaths among
108 patients in the control groups (250) The Angelico 1999
trial demonstrated that TUDCA was not able to reduce all-cause
mortality (RR 159 95 CI 030 to 833) there were 3 deaths
among 16 patients (188) versus 2 deaths among 17 patients
(118)
The Fleckenstein 1998 trial and the Sama 1991 trial did not report
the causes of deaths In the three other trials the deaths were
considered to be caused by infections (n = 11) hepatic failure (n =
7) abdominal bleeding (n = 3) renal failure (n = 2) multiple organ
failure (n = 2) hepatitis B virus fibrosis (n = 2) acute rejection
(n = 1) hepatic artery thrombosis (n = 1) encephalitis (n = 1)
lymphoproliferative disorder (n = 1) cerebral haemorrhage (n =
1) or other reasons (n = 6)
Worst-best case and best-worst case scenario analyses
In the worst-best case scenario analysis bile acids did not signif-
icantly reduce all-cause mortality when compared with placebo
or no intervention (RR 130 95 CI 086 to 196) 40 deaths
among 132 patients on bile acids (303) versus 29 deaths among
125 patients in the control groups (232) However all-cause
mortality was significantly reduced by bile acids in the best-worst
case scenario analysis (RR 058 95 CI 038 to 090) 26 deaths
among 132 patients (197) versus 42 deaths among 125 patients
in the control groups (336) (Analysis 12)
Subgroup analyses
We performed subgroup analyses regarding the time that bile acid
intake was started The Keiding 1997 trial started bile acid intake
less than three days after liver transplantation and demonstrated
no significant effect of UDCA on all-cause mortality (RR 124
95 CI 061 to 254) 14 deaths out of 54 patients (259)
versus 10 out of 48 control patients (208) The same effect
was noticed in the four other trials (Sama 1991 Barnes 1997
Fleckenstein 1998 Angelico 1999) which started bile acids three
days or more after liver transplantation (RR 063 95 CI 033
to 120) 12 deaths among 78 patients (154) versus 9 deaths
among 77 control patients (247) (Analysis 13) There were no
statistically significant differences between the two estimates
We also performed subgroup analyses regarding the duration of
bile acid treatment Bile acids were administrated for less than six
months in three trials (Barnes 1997 Keiding 1997 Fleckenstein
1998) and were not able to significantly decrease all-cause mor-
tality (RR 078 95 CI 045 to 138) 18 deaths in a group of
96 treated patients (188) versus 21 deaths among 88 control
patients (239) In the other two trials (Sama 1991 Angelico
1999) patients were treated with bile acids for six months or more
The treatment did not show statistically significant decrease in all-
cause mortality (RR 102 95 CI 043 to 24) 8 deaths in a
group of 36 treated patients (222) versus 8 deaths in a group
of 37 control patients (216) (Analysis 14) There were no sta-
tistically significant differences between the two estimates
Mortality related to allograft rejection
We did not find statistically significant reduction in mortality re-
lated to allograft rejection at maximum follow-up in the three tri-
als reporting cause of death (Barnes 1997 Keiding 1997 Angelico
1999) (RR 030 95 CI 001 to 712) 098 (0) versus 189
(11)) (Analysis 15) The only death due to acute rejection was
found in the placebo group of the Keiding 1997 trial
Number of liver retransplantations
Two trials (Fleckenstein 1998 Keiding 1997) including 132 liver-
transplanted patients reported the number of liver retransplan-
tations UDCA did not significantly reduce the risk of liver re-
transplantation at maximum follow-up (RR 076 95 CI 020
to 286) 368 (44) versus 464 (63)) (Analysis 16) In the
Keiding 1997 trial one patient in the UDCA group was retrans-
planted due to chronic rejection and four patients in the placebo
group were retransplanted either due to chronic rejection (three
cases) or acute rejection (one case) In the Fleckenstein 1998 trial
two patients in the UDCA group were retransplanted due to acute
rejection (one case) and chronic rejection (one case) respectively
Number of patients with acute cellular rejection
Seven trials reported the number of patients who had acute cellu-
lar rejection after liver transplantation Bile acids did not signifi-
cantly reduce the number of patients who experienced acute cel-
lular rejection (RR 089 95 CI 074 to 106) 93174(535)
versus 99165 (600)) There was no significant heterogeneity
(I2 = 0)
Six trials (Sama 1991 Koneru 1993 Pageaux 1995 Barnes 1997
10Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Keiding 1997 Fleckenstein 1998) compared UDCA with placebo
or no intervention and demonstrated that UDCA did not signifi-
cantly reduce the number of patients with acute cellular rejection
after liver transplantation (RR 089 95 CI 074 to 108 85
158 (538) versus 89148 (601)) Neither did the Angelico
1999 trial demonstrate significant reduction of the number of pa-
tients with acute cellular rejection with TUDCA (RR 085 95
CI 045 to 160) 816 (500) versus 1017 (588) (Analysis
17)
Subgroup analyses
Two trials (Koneru 1993 Keiding 1997) in which the patients
started bile acids intake less than three days after liver transplan-
tation did not demonstrate any significant reduction of the risk
of acute cellular rejection by bile acids (RR 084 95 CI 063 to
111) 3870 (543) versus 4164 (641) The other five tri-
als (Sama 1991 Pageaux 1995 Barnes 1997 Fleckenstein 1998
Angelico 1999) in which the patients were started on bile acid
intake three days or more after liver transplantation did not find
a significant reduction of the risk of acute cellular rejection by bile
acids (RR 092 95 CI 072 to 117) 55104 (529) versus 58
101 (574) (Analysis 18) There was no significant difference
between the two estimates
Bile acids did not significantly reduce the risk of acute cellular
rejection in the five trials (Koneru 1993 Pageaux 1995 Barnes
1997 Keiding 1997 Fleckenstein 1998) in which the patients
received treatment with bile acids less than six months (RR 087
95 CI 071 to 107) 72138 (522) versus 76128 (594)
Neither did bile acids in the two other trials (Sama 1991 Angelico
1999) in which the patients received bile acids for more than six
months (RR 094 95 CI 065 to 136) 2136 (583) versus
2337 (622) (Analysis 19) There were no significant difference
between the two estimates
Number of patients with chronic rejection
Three trials comparing UDCA versus placebo (Barnes 1997
Keiding 1997 Fleckenstein 1998) reported the number of patients
with chronic rejection after liver transplantation UDCA signifi-
cantly reduced the number of patients with chronic rejection in
the fixed-effect model analysis (RR 028 95 CI 008 to 095)
396 (31) versus 1088 (114) (Analysis 110) but not in the
random-effects model analysis (RR 030 95 CI 008 to 113) 3
96 (31) versus 1088 (114) There was no statistically signifi-
cant heterogeneity (I2 0) We performed trial sequential analysis
for the available data from three trials (Figure 3) with heterogene-
ity corrected required information size based on proportion of this
outcome of 12 in the control group a relative risk reduction of
50 in the intervention group at a type I error of 5 and a type
II error of 10 We obtained a required information size of 957
patients UDCA was not able to reach or break the trial sequential
monitoring boundary and only 183 out of 957 (19) patients
were randomised regarding this outcome
11Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Figure 3 Trial sequential analysis for the number of patients with chronic rejection at maximum follow-up
We calculated the heterogeneity-corrected required information size (HCRIS) based on a proportion of 12 of
the patients in the placebo group with chronic rejection at maximum follow-up a 50 risk ratio reduction in
the bile acid group an alpha of 5 a beta of 10 and a heterogeneity of 0 Only 184 patients have been
randomised reporting this outcome which is only 19 of the HCRIS of 957 patients The cumulative Z-score
crosses the conventional boundaries for P 005 but not the monitoring boundaries
Number of patients with steroid-resistant rejection
Four trials (Pageaux 1995 Barnes 1997 Keiding 1997
Fleckenstein 1998) reported the number of patients with steroid-
resistant rejection These trials demonstrated that UDCA did not
significantly reduce the number of patients with steroid-resistant
rejection when compared with placebo (22122 (18) versus 26
112 (232) (RR 077 95 CI 047 to 127) (Analysis 111)
There was no significant heterogeneity (I2 0)
Liver biochemistry
The Fleckenstein 1998 trial reported serum bilirubin levels after
a three-month-treatment period in 30 liver-transplanted patients
There was no statistically significant difference in serum bilirubin
levels between the UDCA group and the placebo group (MD 260
mgdl 95 CI -096 to 616 mgdl) (Analysis 112)
No data were available for other liver biochemical variables
Cost-effectiveness
One trial (Barnes 1997) with 52 liver-transplanted patients re-
ported the days of hospitalisation after liver transplantation
UDCA significantly decreased the number of days of hospitali-
sation when compared with placebo (MD -850 days 95 CI -
1667 to -033 days) (Analysis 113) We were not able to extract
other medical cost from the trials
Adverse events
Among all the included and excluded trials only four reported on
adverse events however adverse events only occurred in two of
the included trials (Barnes 1997 Keiding 1997) There were no
significant differences regarding adverse events (RR 088 95 CI
030 to 260) 6112 (54) versus 6105 (57) (Analysis 114)
In the Barnes 1997 trial diarrhoea was reported by two patients
(one in the UDCA group and one in the placebo group) In the
Keiding 1997 trial five UDCA patients and five placebo patients
stopped intake of the trial medicine because of diarrhoea or dif-
ficulties in swallowing the capsules The remaining included trial
by Angelico 1999 stated that no adverse events occurred during
the study period The excluded trial by Assy 2007 was the only
one reporting on a case of mild diarrhoea in one patient in the
12Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
intervention group No other excluded studies reported on adverse
events (see Table 1)
Quality of life
None of the included studies assessed quality of life as an outcome
Other subgroup analyses
We planned to perform subgroup analyses regarding the risk of
bias of trials the dosage of bile acid and any co-intervention
However none of the trials were considered to be of low risk of
bias they all used a similar dosage of bile acid and patients in all
trials received similar immunosuppressive treatment as co-inter-
ventions (steroids azathioprine and cyclosporine or tacrolimus)
after liver transplantation Therefore we were not able to perform
the planned subgroup analyses
Funnel plot asymmetry
We did not draw a funnel plot analysis due to the limited number
of trials included in the present review
D I S C U S S I O N
In the update of this review we included no new trials assessing
the use of bile acids for liver-transplanted patients The analyses
of the seven previously included trials showed that bile acids did
not significantly affect mortality acute cellular rejection steroid-
resistant rejection retransplantation or serum bilirubin Bile acids
might significantly decrease the length of hospital stay and the
number of patients with chronic rejection included in these tri-
als but more supportive evidence is needed The number of pa-
tients with chronic rejection was not significantly influenced by
bile acids when a random-effects model was used and length of
stay was assessed in one single trial Furthermore none of the trials
were considered to be of low risk of bias and few patients were en-
rolled Therefore our positive findings may be due to bias (Schulz
1995 Moher 1998 Kjaergard 2001 Wood 2008) or random er-
rors (Wetterslev 2008 Brok 2009 Thorlund 2009) On the other
hand we are not able to exclude type II errors (that is finding
no significant differences when in fact they exist) due to the low
number of participants Therefore this topic could be of potential
interest in future large randomised trials with adequate control of
bias
All-cause mortality at one year after liver transplantation is re-
ported to be about 20 (Thuluvath 2003) which we also ob-
served for the patients included in the present review According to
our subgroup analyses neither UDCA nor TUDCA significantly
decreased all-cause mortality We also performed a subgroup anal-
ysis regarding treatment duration but we were not able to find any
difference between short (less than six months) and long treatment
duration (six months or more) Thus bile acids do not seem to
have statistically significant effects in reducing all-cause mortal-
ity after liver transplantation We performed both worst-best-case
scenario and best-worst-case scenario analyses In the worst-best-
case scenario bile acids did not differ significantly from placebo or
no intervention regarding all-cause mortality However bile acids
significantly decreased all-cause mortality in the best-worst-case
scenario analysis However such an analysis is very extreme and
may not be realistic We have also found that UDCA may be able
to decrease the risk of chronic rejection in liver-transplanted pa-
tients but trial sequential analysis could not confirm this result
Due to a limited number of patients (Ioannidis 2001) we are not
able to exclude the possibility that it may be relevant to perform
placebo-controlled trials with low risk of bias on the use of bile
acids for liver-transplanted patients
We looked into the causes of deaths that were reported by the trials
and only one trial reported one death related to rejection At the
same time the number of retransplantations was 3 among 68 liver-
transplanted patients who received treatment with UDCA and 4
among 64 liver-transplanted patients who received treatment with
placebo We noticed that all patients in the included trials received
co-interventions of standard triple-drug regimens (steroids aza-
thioprine and cyclosporine or tacrolimus) which were able to
control the possible acute or chronic rejection and prevent deaths
due to allograft rejection (FK506 1994)
The assumption that UDCA might reduce the incidence of acute
graft rejection came from the findings that UDCA could regulate
major histocompatibility complex antigen expression in bile ducts
and liver endothelia and inhibit lymphocyte activity (Calmus
1990 Terasaki 1991 Perez 2009) However in the present review
bile acids did not significantly reduce the risk of acute cellular re-
jection in liver-transplanted patients Considering that acute cellu-
lar rejection is commonly found within a few days after liver trans-
plantation (Vierling 1992) some might argue that the adminis-
tration of bile acids was started too late to prevent acute cellular
rejection We performed subgroup analyses regarding the time bile
acids were started and no statistically significant difference was
found Furthermore bile acids were not able to decrease the risk
of steroid-resistant rejection Therefore the lack of effects of bile
acids does not seem to be due to a delayed start to bile acid ad-
ministration after liver transplantation However it is a possibility
that one should start bile acids intake before liver transplantation
A retrospective study found that rejection rates differed signifi-
cantly between patients with primary biliary cirrhosis treated with
or without UDCA before liver transplantation (Heathcote 1999)
One could argue whether UDCA-induced delay in transplantation
has an adverse effect on post-transplantation outcome Since we
did not find any prospective randomised clinical trials addressing
this issue further research might be needed Furthermore some
studies may provide an explanation why UDCA was not able to
prevent acute cellular rejection These studies found that UDCA
did not appear to change the expression of major histocompatibil-
ity complex class II antigens but rather major histocompatibility
complex class I antigens (Calmus 1990) The initial mechanism
of acute rejection is thought to be recognition of MHC class II
13Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
antigens by CD4+ T cells (Vierling 1992) Moreover the inhibi-
tion of the production of interleukin-2 by peripheral blood lym-
phocytes with UDCA (Heuman 1993) might be negated by the
immunosuppressive treatment after liver transplantation (van den
Berg 1998) so that UDCA is unable to demonstrate effects on
graft rejection In a recent study by Assy 2007 a significant re-
duction in the mean dose of immunosuppressive medications was
achieved in stable liver graft recipients treated with UDCA indi-
cating a possible influence of UDCA on rejection mechanisms
In accordance with previous systematic reviews (Chen 2003a
Chen 2007 Gong 2008) bile acids were not associated with the
occurrence of serious adverse events or any major occurrence of
adverse events
In summary our results do not support or refute the use of bile
acids (UDCA and TUDCA) additional to standard immunosup-
pressive treatment in liver-transplanted patients
A U T H O R S rsquo C O N C L U S I O N SImplications for practice
There seems to be no evidence to support or refute the use of bile
acids for liver-transplanted patients receiving standard immuno-
suppressive treatment
Implications for research
We need more randomised placebo-controlled clinical trials with
enough statistical power and low risk of bias to explore the poten-
tial effects of bile acids on chronic rejection and mortality in liver-
transplanted patients Such trials should also consider evaluation
of quality of life and length of hospitalisation Such trials may
consider starting bile acid and placebo interventions before liver
transplantation we were not able to identify any randomised trials
addressing this regimen Such trials ought to be reported accord-
ing to the CONSORT statement (wwwconsort-statementorg)
However before embarking on such trials the effects of bile acids
in other patient groups should be scrutinised as they may have
small or negative effects
A C K N O W L E D G E M E N T S
We thank all the patients and investigators who were involved in
the clinical trials mentioned in this review We thank Wendong
Chen for his work and contribution on the previous version of this
review We thank the staff of The Cochrane Hepato-Biliary Group
Editorial Team especially Dimitrinka Nikolova and Sarah Louise
Klingenberg for excellent collaboration and assistance during the
update of this review
Peer Reviewers Carlo Merkel Italy M Tomikawa Japan
Contact Editor Bodil Als-Nielsen Denmark
R E F E R E N C E S
References to studies included in this review
Angelico 1999 published data only
Angelico M Tisone G Baiocchi L Palmieri G Pisani F Negrini S
et alOne-year pilot study on tauroursodeoxycholic acid as an
adjuvant treatment after liver transplantation Italian Journal of
Gastroenterology and Hepatology 199931(6)462ndash8 [MEDLINE
10575563]
Barnes 1997 published data onlylowast Barnes D Talenti D Cammell G Goormastic M Farquhar L
Henderson M et alA randomized clinical trial of ursodeoxycholic
acid as adjuvant treatment to prevent liver transplant rejection
Hepatology 199726(4)853ndash7 [MEDLINE 9328304]
Barnes D Talenti D Goormastic M Farquhar L Cammell G
Henderson M et alUrsodeoxycholic acid (UDCA) reduces hepatic
allograft rejection after orthotopic liver transplantation (OLT) - a
prospective randomized placebo-controlled double-blind trial
Hepatology 199522149A
Fleckenstein 1998 published data only
Fleckenstein JF Paredes M Thuluvath PJ A prospective
randomized double-blind trial evaluating the efficacy of
ursodeoxycholic acid in prevention of liver transplant rejection
Liver Transplantation and Surgery 19984(4)276ndash9 [MEDLINE
9649640]
Keiding 1997 published data only
Keiding S Hockerstedt K Bjoro K Bondesen S Hjortrup A
Isoniemi H et alThe Nordic multicenter double-blind randomized
controlled trial of prophylactic ursodeoxycholic acid in liver
transplant patients Transplantation 199763(11)1591ndash4
[MEDLINE 9197351]
Koneru 1993 published data only
Koneru B Tint GS Wilson DJ Leevy CB Salen F Randomised
prospective trial of ursodeoxycholic acid in liver transplant
recipients Hepatology 199318336A
Pageaux 1995 published data only
Pageaux GP Blanc P Perrigault PF Navarro F Fabre JM Souche B
et alFailure of ursodeoxycholic acid to prevent acute cellular
rejection after liver transplantation Journal of Hepatology 199523
(2)119ndash22 [MEDLINE 7499781]
Sama 1991 published data only
Sama C Mazziotti A Grigioni W Morselli AM Chianura A
Stefanini GF et alUrsodeoxycholic acid administration does not
14Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
prevent rejection after OLT Journal of Hepatology 199113(Suppl
2)68
References to studies excluded from this review
Assy 2007 published data only
Assy N Adams PC Myers P Simon V Minuk GY Wall W et
alRandomized controlled trial of total immunosuppression
withdrawal in liver transplant recipients role of ursodeoxycholic
acid Transplantation 200783(12)1571ndash6 [MEDLINE
17589339]
Clavien 1996 published data only
Clavien PA Sharara AI Camargo CA Jr Harland RC Fitz JG
Evidence that ursodeoxycholic acid prevents steroid-resistant
rejection in adult liver transplantation Clinical Transplantation
199610(6 Pt 2)658ndash62 [MEDLINE 8996761]
Friman 1992 published data only
Friman S Persson H Schersten T Svanvik J Karlberg I Adjuvant
treatment with ursodeoxycholic acid reduces acute rejection after
liver transplantation Transplantation Proceedings 199224(1)
389ndash90 [MEDLINE 1539328]
Heathcote 1999 published data onlylowast Heathcote EJ Stone J Cauch-Dudek K Poupon R Chazouilleres
O Lindor KD et alEffect of pretransplantation ursodeoxycholic
acid therapy on the outcome of liver transplantation in patients
with primary biliary cirrhosis Liver Transplantation and Surgery
19995(4)269ndash74 [MEDLINE 10388499]
Henriksson 1991 published data only
Henriksson BA Persson H Friman S Wangberg B Svanvik J
Karlberg I Adjuvant ursodeoxycholic acid prevents acute rejection
in liver transplant recipients Transplantation Proceedings 199123
(3)1971 [MEDLINE 2063453]
Persson 1990 published data only
Persson H Friman S Schersten T Svanvik J Karlberg I
Ursodeoxycholic acid for prevention of acute rejection in liver
transplant recipients Lancet 1990336(8706)52ndash3 [MEDLINE
1973232]
Rafael 1995 published data only
Rafael E Duraj F Rudstrom H Wilczek H Ericzon B Effect of
ursodeoxycholic acid treatment for cholestasis in liver transplant
recipients Transplantation Proceedings 199527(6)3501ndash2
[MEDLINE 8540069]
Sama 1998 published data only
Sama C Morselli-Labate AM Grazi GL Mastroianni A Danesi G
Pianta P et alUrsodeoxycholic acid in liver transplantation effect
on cholestasis and rejection Gastroenterology 1998114(4 Suppl)
A1332
Additional references
Adams 1990
Adams DH Neuberger JM Patterns of graft rejection following
liver transplantation Journal of Hepatology 199010(1)113ndash9
[MEDLINE 2407770]
Al-Quaiz 1994
Al-Quaiz M OrsquoGrady J Tredger J Williams R Variable effect of
ursodeoxycholic acid on cyclosporin absorption after orthotopic
liver transplantation Transplant International 19947(3)190ndash4
[MEDLINE 8060468]
Armstrong 1982
Armstrong MJ Carey MC The hydrophobic-hydrophilic balance
of bile salt Inverse correlation between reverse phase high
performance liquid chromatographic mobilities and micellar
cholesterol-solubilizing capacities Journal of Lipid Research 1982
23(1)70ndash80 [MEDLINE 7057113]
Ascher 1988
Ascher NL Stock PG Baumgardner GL Payne WD Najarian JS
Infection and rejection of primary hepatic transplant in 93
consecutive patients treated with triple immunosuppressive therapy
Surgery Gynecology amp Obstetrics 1988167(6)474ndash84
[MEDLINE 3055368]
Brok 2008
Brok J Thorlund K Gluud C Wetterslev J Trial sequential
analysis reveals insufficient information size and potentially false
positive results in many meta-analyses Journal of Clinical
Epidemiology 200861(8)763ndash9 [MEDLINE 18411040]
Brok 2009
Brok J Thorlund K Wetterslev J Gluud C Apparently conclusive
meta-analysis may be inconclusive - Trial sequential analysis
adjustment of random error risk due to repetitive testing of
accumulating data in apparently conclusive neonatal meta-analysis
International Journal of Epidemiology 200938(1)298ndash303
[MEDLINE 18824466]
Calmus 1990
Calmus Y Gane P Rouger P Poupon R Hepatic expression of class
I and class II major histocompatibility complex molecules in
primary biliary cirrhosis effect of ursodeoxycholic acid Hepatology
199011(1)12ndash5 [MEDLINE 2403961]
Calmus 1992
Calmus Y Arvieux C Gane P Boucher E Nordlinger B Rouger P
et alCholestasis induces major histocompatibility complex class I
expression in hepatocytes Gastroenterology 1992102(4 Pt 1)
1371ndash7 [MEDLINE 1551542]
Chen 2003a
Chen W Gluud C Bile acids for primary sclerosing cholangitis
Cochrane Database of Systematic Reviews 2003 Issue 2 [DOI
10100214651858CD003626]
Chen 2007
Chen W Liu J Gluud C Bile acids for viral hepatitis Cochrane
Database of Systematic Reviews 2007 Issue 4 [DOI 101002
14651858CD003181pub2]
Cheng 2002
Cheng K Ashby D Smyth R Ursodeoxycholic acid for cystic
fibrosis-related liver disease Cochrane Database of Systematic
Reviews 2002 Issue 2 [DOI 10100214651858CD000222]
Corbani 2008
Corbani A Burroughs AK Intrahepatic cholestasis after liver
transplantation Clinics in Liver Disease 200812(1)111ndash29
[MEDLINE 18242500]
DeMets 1987
DeMets DL Methods for combining randomised clinical trials
strengths and limitations Statistics in Medicine 19876(3)341ndash50
[MEDLINE 3616287]
15Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
DerSimonian 1986
DerSimonian R Laird N Meta-analysis in clinical trials Controlled
Clinical Trials 19867(3)177ndash88 [MEDLINE 3802833]
Egger 1997
Egger M Davey Smith G Schneider M Minder C Bias in meta-
analysis detected by a simple graphical test BMJ (Clinical Research
Ed) 1997315(7109)629ndash34 [MEDLINE 9310563]
Ericzon 1990
Ericzon BG Eusufzai S Kubota K Einarsson K Angelin B
Characteristics of biliary lipid metabolism after liver
transplantation Hepatology 199012(5)1222ndash8 [MEDLINE
2227822]
FK506 1994
The US Multicenter FK506 Liver Study Group A comparison of
tacrolimus (FK506) and cyclosporine for immunosuppression in
liver transplantation New England Journal of Medicine 1994331
(17)1110ndash5 [MEDLINE 7523946]
Friman 1994
Friman S Svanvik J A possible role of ursodeoxycholic acid in liver
transplantation Scandinavian Journal of Gastroenterology 1994204
62ndash4 [MEDLINE 7824880]
Fuchs 1999
Fuchs M Stange EF Metabolism of bile acids In Johannes
Bircher Jean-Pierre Benhamou Neil McIntyre Mario Rizzetto
Juan Rodes editor(s) Oxford Textbook of Clinical Hepatology 2
Vol 1 Oxford Oxford University Press 1999223ndash56
Fusai 2006
Fusai G Dhaliwal P Rolando N Sabin CA Patch D Davidson BR
et alIncidence and risk factors for the development of prolonged
and severe intrahepatic cholestasis after liver transplantation Liver
Transplantation 200612(11)1626ndash33 [DOI 101002lt20870]
Gluud 2001
Gluud C Alcoholic hepatitis no glucocorticosteroids In
Leuschner U James OFW Dancygier H editor(s) Steatohepatitis
(NASH and ASH) Falk Symposium 121 Lancaster Kluwer
Academic Publisher 2001322ndash42
Gluud 2010
Gluud C Nikolova D Klingenberg SL Alexakis N Als-Nielsen B
Colli A et alCochrane Hepato-Biliary Group About The
Cochrane Collaboration (Cochrane Review Groups (CRGs))
2010 Issue 1 Art No LIVER
Gong 2008
Gong Y Huang ZB Christiansen E Gluud C Ursodeoxycholic
acid for primary biliary cirrhosis Cochrane Database of Systematic
Reviews 2008 Issue 3 [DOI 101002
14651858CD000551pub2]
Haddad 2006
Haddad EM McAlister VC Renouf E Malthaner R Kjaer MS
Gluud LL Cyclosporin versus tacrolimus for liver transplanted
patients Cochrane Database of Systematic Reviews 2006 Issue 4
[DOI 10100214651858CD005161pub2]
Heuman 1993
Heuman DM Hepatoprotective properties of ursodeoxycholic acid
Gastroenterology 1993104(6)1865ndash9 [MEDLINE 8500748]
Higgins 2008
Higgins PTJ Green S editors Cochrane Handbook for Systematic
Reviews of Interventions West Sussex England Wiley-Blackwell
2008
Hirschfield 2009
Hirschfield GM Gibbs P Griffiths WJH Adult liver
transplantation what non-specialists need to know BMJ (Clinical
Research Ed) 2009338(b1670)1321ndash7 [DOI 101136
bmjb1670]
Hussain 2002
Hussain HK Nghiem HV Imaging of hepatic transplantation
Clinics in Liver Disease 20026(1)247ndash70 [MEDLINE
11933592]
ICH-GCP 1997
International Conference on Harmonisation Expert Working
Group Code of Federal Regulations amp International Conference on
Harmonization Guidelines Media Parexel Barnett 1997
Ioannidis 2001
Ioannidis JPA Lau J Evolution of treatment effects over time
Empirical insight from recursive cumulative meta analyses
Proceedings of the National Academy of Sciences 200198(3)831ndash6
IWP 1995
International Working Party Terminology for hepatic allograft
rejection Hepatology 199522(2)648ndash54 [MEDLINE 7635435]
Kjaergard 2001
Kjaergard LL Villumsen J Gluud C Reported methodological
quality and discrepancies between large and small randomised trials
in meta-analyses Annals of Internal Medicine 2001135(11)982ndash9
[MEDLINE 11730399]
Klintmalm 1989
Klintmalm GB Nery JR Husberg BS Gonwa TA Tillery GW
Rejection in liver transplantation Hepatology 198910(6)978ndash85
[MEDLINE 2583691]
Knechtle 2009
Knechtle SJ Kwun J Unique aspects of rejection and tolerance in
liver transplantation Seminars in Liver Disease 200929(1)91ndash101
[MEDLINE 19235662]
Krams 1993
Krams SM Ascher NL Martinez OM New immunologic insights
into mechanisms of allograft rejection Gastroenterology Clinics of
North America 199318(2)374ndash7 [MEDLINE 8509176]
Lan 1983
Lan KKG DeMets DL Discrete sequential boundaries for clinical
trials Biometrika 198370659ndash63
Merion 1989
Merion RM Gorski DH Burtch GD Turcotte JG Colletti LM
Campbell DA Jr Bile refeeding after liver transplantation and
avoidance of intravenous cyclosporine Surgery 1989106(4)
604ndash9 [MEDLINE 2799635]
Moher 1998
Moher D Pham B Jones A Cook DJ Jadad AR Moher M et
alDoes quality of reports of randomised trials affect estimates of
intervention efficacy reported in meta-analyses Lancet 1998352
(9128)609ndash13 [MEDLINE 9746022]
16Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Neuberger 1999
Neuberger J Incidence timing and risk factors for acute and
chronic rejection Liver Transplantation and Surgery 19995(4 Suppl
1)S30ndashS36 [MEDLINE 10431015]
Okolicsanyi 1986
Okolicsanyi L Lirussi F Strazzabosco M Jemmolo RM Orlando R
Nassuato G et alThe effect of drugs on bile flow and composition
An overview Drugs 198631(5)430ndash48 [MEDLINE 2872047]
Palmer 1972
Palmer RH Bile acids liver injury and liver disease Archives of
Internal Medicine 1972130(4)606ndash17 [MEDLINE 4627840]
Perez 2009
Perez MJ Briz O Bile-acid-induced cell injury and protection
World Journal of Gastroenterology 200915(14)1677ndash89
[MEDLINE 19360911]
Pogue 1997
Pogue JM Yusuf S Cumulating evidence from randomized trials
Utilizing sequential monitoring boundaries for cumulative meta-
analysis Controlled Clinical Trials 199718(6)580ndash93
[MEDLINE 9408720]
Pogue 1998
Pogue J Yusuf S Overcoming the limitations of current meta-
analysis of randomised controlled trials Lancet 1998351(9095)
45ndash52 [MEDLINE 9433436]
RevMan 2008
The Nordic Cochrane Centre The Cochrane Collaboration
Review Manager (RevMan) 50 Copenhagen The Nordic
Cochrane Centre The Cochrane Collaboration 2008
Royle 2003
Royle P Milne R Literature searching for randomized controlled
trials used in Cochrane reviews rapid versus exhaustive searches
International Journal of Technology Assessment in Health Care 2003
19(4)591ndash603
Schulz 1995
Schulz KF Chalmers I Hayer R Altman D Empirical evidence of
bias JAMA 1995273(5)408ndash12 [MEDLINE 7823387]
Sharara 1995
Sharara AI Camargo CA Clavien PA Ursodeoxycholic acid
prevents steroid resistant rejection in liver transplant recipients
Gastroenterology 1995108A1168
Sholmerich 1984
Sholmerich J Becher MS Schmidt KH Schubert R Kremer B
Felhaus S et alInfluence of hydroxylation and conjugation of bile
salts on their membrane damaging properties Hepatology 19844
(4)661ndash7 [MEDLINE 6745854]
Soderdahl 1998
Soderdahl G Nowak G Duraj F Wang FH Einarsson C Ericzon
BG Ursodeoxycholic acid increased bile flow and affects bile
composition in the early postoperative phase following liver
transplantation Transplantation International 199811(Suppl 1)
S231ndashS238 [MEDLINE 9664985]
Terasaki 1991
Terasaki S Nakanuma Y Ogino H Unoura M Kobayashi K
Hepatocellular and biliary expression of HLA antigens in primary
biliary cirrhosis before and after ursodeoxycholic acid therapy
American Journal of Gastroenterology 199186(9)1194ndash9
[MEDLINE 1882800]
Thalheimer 2002
Thalheimer U Capra F Liver transplantation making the best out
of what we have Digestive Diseases and Sciences 200247(5)
945ndash53 [MEDLINE 12018919]
Thorlund 2009
Thorlund K Devereaux PJ Wetterslev J Guyatt G Ioannidis JP
Thabane L et alCan trial sequential monitoring boundaries reduce
spurious inferences from meta-analyses International Journal of
Epidemiology 200938(1)276ndash86 [MEDLINE 18824467]
Thuluvath 2003
Thuluvath PJ Yoo HY Thompson RE A model to predict survival
at one month one year and five years after liver transplantation
based on pretransplant clinical characteristics Liver Transplantation
20039(5)527ndash32 [MEDLINE 12740799]
van den Berg 1998
van den Berg AP Twilhaar WN Mesander G van Son WJ van der
Bij W Klompmaker IJ et alQuantitation of immunosuppression
by flow cytometric measurement of the capacity of T cells for
interleukin-2 production Transplantation 199865(8)1066ndash71
[MEDLINE 9583867]
Vierling 1992
Vierling J Immunologic mechanisms of hepatic allograft rejection
Seminars in Liver Disease 199212(1)16ndash27 [MEDLINE
1570548]
Wetterslev 2008
Wetterslev J Thorlund K Brok J Gluud C Trial sequential
analysis may establish when firm evidence is reached in cumulative
meta-analysis Journal of Clinical Epidemiology 200861(1)64ndash75
[MEDLINE 18083463]
Wiesner 1992
Wiesner RH Acute cellular rejection following liver
transplantation incidence risk factors and outcome in the
NIDDK Liver Transplant Database (LTD) study Gastroenterology
1992102A910
Wood 2008
Wood L Egger M Gluud LL Schulz KF Juni P Altman DG et
alEmpirical evidence of bias in treatment effect estimates in
controlled trials with different interventions and outcomes meta-
epidemiological study BMJ (Clinical Research Ed) 2008336
(7644)601ndash5 [MEDLINE 18316340]
Yoshikawa 1998
Yoshikawa M Matsui Y Kawamoto H Toyohara M Matsumura
K Yamao J et alIntragastric administration of ursodeoxycholic
acid suppresses immunoglobulin secretion by lymphocytes from
liver but not from peripheral blood spleen or Peyerrsquos patches in
mice International Journal of Immunopharmacology 199820(1-3)
29ndash38 [MEDLINE 9717080]
References to other published versions of this review
17Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Chen 2003b
Chen W Gluud C Bile acids for liver transplanted patients
Cochrane Database of Systematic Reviews 2005 Issue 3 [DOI
10100214651858CD005442]lowast Indicates the major publication for the study
18Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
C H A R A C T E R I S T I C S O F S T U D I E S
Characteristics of included studies [ordered by study ID]
Angelico 1999
Methods Study design open-label randomised one-year pilot study
Participants Country Italy
Publication language English
Inclusion criteria
- patients who underwent liver transplantation from April 1994 to December 1994
Exclusion criteria
- not mentioned
Participants
Two patients in TUDCA group and two patients in control group were excluded from
the basic information of participants by the study due to withdrawal
- TUDCA group (n = 14)
Mean age (years +- SD)
467 +- 84
Ratio of sex (malefemale) 122
Origins of liver diseases
hepatitis C cirrhosis (9) hepatitis B cirrhosis (2) hepatitis B and C cirrhosis (1) cryp-
togenic cirrhosis (2) alcoholic cirrhosis (0) Wilson cirrhosis (0)
- Control group (n = 15)
Mean age (years +- SD)
474 +- 74
Ratio of sex (malefemale) 123
Origins of liver diseases
hepatitis C cirrhosis (7) hepatitis B cirrhosis (2) hepatitis B and C cirrhosis (2) cryp-
togenic cirrhosis (2) alcoholic cirrhosis (1) Wilson cirrhosis (1)
Interventions TUDCA group
- Dose 500 mgday in two divided doses
- Route orally
- Duration the treatment was started on day 5 after transplantation and continued for
one year
Control group
- no treatment
Co-interventions all patients received standard triple-drug regimens (steroids azathio-
prine and cyclosporine or tacrolimus)
Outcomes All cause mortality
Number of patients with rejection after liver transplantation
Notes Letter was sent to the authors in September 2009 A reply with additional information
was received shortly after
Risk of bias
19Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Angelico 1999 (Continued)
Item Authorsrsquo judgement Description
Adequate sequence generation Yes Computer generated table
Allocation concealment Unclear No information provided
Blinding No Not performed
Incomplete outcome data addressed
All outcomes
Yes Withdrawal two patients from the
TUDCA group and two patients from the
placebo group Three of them died due to
transplant non-function in the first postop-
erative week and one patient was regrafted
due to thrombosis of hepatic artery
Free of selective reporting Unclear Post-transplant cholestasis and liver bio-
chemistry specified as outcomes Differ-
ence reported as not significant but no ac-
tual data given
Sample size calculation No Not reported
Intention-to-treat analysis No Not stated and not used
Baseline imbalance Unclear Not enough information provided
Early stopping of trial Unclear Not enough information provided
Barnes 1997
Methods Study design randomised placebo-controlled double-blind trial
Participants Country United States
Publication language English
Inclusion criteria
- patients aged 18 years or older who underwent liver transplantation at the Cleveland
Clinic Foundation from April 1992 through June of 1994
Exclusion criteria
- patients who were found to have cancer at surgically resected margins of the biliary
tree
- patents who underwent retransplantation
Participants
- UDCA group (n = 28)
Mean age (years +- SD)
505 +- 116
Ratio of sex (malefemale) 1810
Child class A 7
20Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Barnes 1997 (Continued)
B 13
and C 8
Origins of liver diseases Laennecrsquos cirrhosis 4
PBC 3
cryptogenic cirrhosis 6
hepatitis Ccirrhosis 4
hepatitis Bcirrhosis 3
autoimmune hepatitis with cirrhosis 3
PSC 2
other 3
- Placebo group (n = 24)
Mean age (years +- SD)
507 +- 93
Ratio of sex (malefemale) 159
Child class A 6
B 14
and C 4
Origins of liver diseases Laennecrsquos cirrhosis 9
PBC 5
cryptogenic cirrhosis 1
hepatitis Ccirrhosis 1
hepatitis Bcirrhosis 1
autoimmune hepatitis with cirrhosis 1
PSC 2
other 4
Interventions UDCA group
- Dose 10-15 mgkg body weightday in divided doses
- Route orally
- Duration immediately after intestinal transit recovery usually between postoperative
days three and five and continue for three months
Placebo group
- identical-appearing capsules administered in the same quantity and manner
Co-interventions all patients received standard triple-drug regimens (steroids azathio-
prine and cyclosporine or tacrolimus)
Outcomes All cause mortality
Number of patients with acute cellular rejection
Number of patients with chronic rejection
Number of patients with steroid-resistant rejection
Number of days of hospitalisation
Adverse events
Notes Letter was sent to the authors in September 2009 A reply with additional information
was received shortly after
Risk of bias
Item Authorsrsquo judgement Description
21Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Barnes 1997 (Continued)
Adequate sequence generation Yes Computer generated table
Allocation concealment Unclear No information provided
Blinding Yes Quote ldquorandomised to receive either
UDCA or an identical placebo capsulerdquo
Incomplete outcome data addressed
All outcomes
Yes Mean follow-up time 18 months Ten pa-
tients withdrawn from study 6 in UDCA
group and 4 in placebo group Reasons
for withdrawal were reported Four patients
died in the placebo group
Free of selective reporting Yes All expected outcomes reported
Sample size calculation Unclear The trial reported the method of sample
size calculation but the actual number of
patients needed was not reported
Intention-to-treat analysis Yes Stated and used
Baseline imbalance Unclear Not enough information provided
Early stopping of trial Unclear The number of patients needed to gain the
actual power was not reported Whether
the trial was terminated early is not clear
Fleckenstein 1998
Methods Study design prospective randomised double-blind trial
Participants Country United States
Publication language English
Inclusion criteria
- patients who underwent liver transplantation at the Johns Hopkins Hospital
Exclusion criteria
- patients who were under 18 years old undergoing repeat transplantation had primary
graft nonfunction or refused consent
Participants
- UDCA group (n = 14)
Mean age (years +- SD)
443 +- 127
Ratio of sex (malefemale) 68
Origins of liver diseases hepatitis C 6
alcohol 2
autoimmune 1
PBC 2
22Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Fleckenstein 1998 (Continued)
PSC 1
autoimmune cholangiopathy 1
hepatitis B 1
- Placebo group (n = 16)
Mean age (years +- SD)
496 +- 109
Ratio of sex (malefemale) 124
Origins of liver diseases hepatitis C 3
alcohol 3
autoimmune 3
PBC 1
PSC 2
cryptogenic 2
hepatitis B 1
alpha1-antitrypsin deficiency 1
Interventions UDCA group
- Dose 15 mgkg body weightday in divided doses
- Route orally
- Duration immediately after intestinal transit recovery usually between postoperative
days three and five and continue for three months
Placebo group
- Identical-appearing capsules administered in the same quantity and manner
Co-interventions all patients received standard triple-drug regimens (steroids azathio-
prine and cyclosporine or tacrolimus)
Outcomes All cause mortality
Number with retransplantation
Number of patients with acute cellular rejection
Number of patients with chronic rejection
Serum bilirubin levels at the end of treatment
Notes Follow-up time nine months
Letter was sent to the authors in September 2009 No reply was received
Risk of bias
Item Authorsrsquo judgement Description
Adequate sequence generation Unclear No information provided
Allocation concealment Unclear No information provided
Blinding Yes Method of blinding not described but
probably adequate
Incomplete outcome data addressed
All outcomes
Yes Withdrawal one patient from the UDCA
group and two patients from the placebo
group because of capsule size
23Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Fleckenstein 1998 (Continued)
Free of selective reporting Unclear Outcomes were not completely described
Sample size calculation No Not reported
Intention-to-treat analysis Yes Quote ldquoThree patients withdrew after in-
clusionThey were included in the statis-
tical analysisrdquo
Baseline imbalance Unclear Not enough information provided
Early stopping of trial Unclear Not enough information provided
Keiding 1997
Methods Study design prospective randomised placebo-controlled multicenter study
Participants Country Denmark Finland Norway and Sweden
Publication language English
Inclusion criteria
- patients who underwent liver transplantation in Denmark Finland Norway and Swe-
den from September 1 1992 to May 31 1994
Exclusion criteria
- patients with malignant diseases
Participants
The age of the children ranged from 0 to 13 years (median 15) and the age of adults
ranged from 14 to 59 years old (median 44) MaleFemale ratio was 96 for children and
4344 for adults
- UDCA group (n = 54)
Origins of liver diseases
paracetamol intoxication 1 hepatitis B 1 autoimmune hepatitis 0 biliary atresia 2
metabolic diseases 7 neonatal hepatitis 2 PBC 13 post hepatitis cirrhosis 8 PSC 3
cryptogenic cirrhosis 7 alcoholic cirrhosis 2 other reasons 8
- Placebo group (n = 48)
Origins of liver diseases paracetamol intoxication 1 hepatitis B 0 autoimmune hepatitis
1 biliary atresia 3 metabolic diseases 11 neonatal hepatitis 0 PBC 7 post hepatitis
cirrhosis 5 PSC 7 cryptogenic cirrhosis 2 alcoholic cirrhosis 6 other reasons 5
Interventions UDCA group
- Dose 15 mgkg body weightday in two or three divided doses
- Route orally
- Duration immediately after intestinal transit recovery usually between postoperative
days three and five and continue for three months
Placebo group
- Identical-appearing capsules administered in the same quantity and manner
Co-interventions all patients received standard triple-drug regimens (steroids azathio-
prine and cyclosporine or tacrolimus)
24Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Keiding 1997 (Continued)
Outcomes All cause mortality
Number of deaths related to rejection
Number of patients with acute cellular rejection
Number of patients with chronic rejection
Number of patients with steroid-resistant rejection
Adverse events
Notes Letter was sent to the authors in September 2009 No reply was received
Risk of bias
Item Authorsrsquo judgement Description
Adequate sequence generation Unclear Patients were randomised at a ratio of 11
Allocation concealment Yes Quote ldquo The allocation was performed in
blocks of 10 patients using the sealed serial
envelope methodrdquo
Blinding Yes Quote ldquoThe UDCA and the placebo cap-
sules had identical appearance and tasterdquo
Incomplete outcome data addressed
All outcomes
Yes Follow-up time 12 months Five UDCA
patients and five placebo patients withdrew
from study Reasons were reported
Free of selective reporting Unclear Insufficient information
Sample size calculation Yes Performed and allowed for a difference in
the incidence of at least one episode of
acute rejection of 50 between the treat-
ment and placebo groups with 90 statisti-
cal power and a significance level of P value
less than 005 The calculated sample size
was 80 patients
Intention-to-treat analysis Yes Stated and used
Baseline imbalance Yes The study seems to be free of baseline im-
balance
Early stopping of trial Yes Study attained the pre-specified sample
size
25Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Koneru 1993
Methods Study design randomised controlled trial
Participants Country United States
Publication language English
Inclusion criteria
- patients who underwent liver transplantation
Exclusion criteria
- not mentioned
Participants
- UDCA group (n = 16)
Mean age (years +- SD)
no information
Ratio of sex (malefemale) no information
Origins of liver diseases
no information
- Control group (n = 16)
Mean age (years +- SD)
no information
Ratio of sex (malefemale) no information
Origins of liver diseases
no information
Interventions UDCA group
- Dose 900 mgday
- Route orally
- Duration immediately after intestinal transit recovery usually between postoperative
days three and five and continue for three months
Control group
- no treatment
Co-interventions all patients received standard triple-drug regimens (steroids azathio-
prine and cyclosporine)
Outcomes Number of patients with retransplantation due to rejection
Number of patients with rejection episodes
Notes Abstract
Letter was sent to the authors in September 2009 No reply was received
Risk of bias
Item Authorsrsquo judgement Description
Adequate sequence generation Unclear No information provided
Allocation concealment Unclear No information provided
Blinding No Not performed
26Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Koneru 1993 (Continued)
Incomplete outcome data addressed
All outcomes
Unclear The study gives the impression that there
were no withdrawals but this was not ex-
plicitly stated
Free of selective reporting Unclear Insufficient information provided
Sample size calculation No Not performed
Intention-to-treat analysis Unclear No information provided
Baseline imbalance Unclear Not enough information provided
Early stopping of trial Unclear Not enough information provided
Pageaux 1995
Methods Study design double-blind randomised study
Participants Country France
Publication language English
Inclusion criteria
- patients who underwent liver transplantation
Exclusion criteria
- not mentioned
Participants
- UDCA group (n=26)
Mean age (years +- SD)
47 +- 10
Ratio of sex (malefemale) 179
Origins of liver diseases alcoholic cirrhosis 14
post-hepatic B cirrhosis 2
post-hepatitis C cirrhosis 4
PBC 2
liver cancer 2
fulminant hepatitis 1
miscellaneous 1
- Placebo group (n = 24)
Mean age (years +- SD)
51+- 9
Ratio of sex (malefemale) 159
Origins of liver diseases alcoholic cirrhosis 10
post-hepatic B cirrhosis 0
post-hepatic C cirrhosis 6
PBC 3
liver cancer 4
fulminant hepatitis 0
miscellaneous 1
27Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Pageaux 1995 (Continued)
Interventions UDCA group
- Dose 600 mgday in three divided doses
- Route orally
- Duration immediately after intestinal transit recovery usually between postoperative
days three and five and continue for two months
Placebo group
- identical-appearing capsules administered in the same quantity and manner
Co-interventions all patients received standard triple-drug regimens (steroids azathio-
prine and cyclosporine or tacrolimus)
Outcomes Number of patients with acute cellular rejection
Number of patients with steroid-resistant rejection
Notes Letter was sent to the authors in September 2009 No reply was received
Risk of bias
Item Authorsrsquo judgement Description
Adequate sequence generation Unclear No information provided
Allocation concealment Unclear No information provided
Blinding Unclear Method of blinding not described
Incomplete outcome data addressed
All outcomes
Yes Five patients died from non-immunologi-
cal causes before the end of the first month
and were excluded from the study Reasons
were reported
Free of selective reporting Unclear Not enough information provided
Sample size calculation No Not performed
Intention-to-treat analysis No Not stated and not used
Baseline imbalance Unclear Not enough information provided
Early stopping of trial Unclear Not enough information provided
Sama 1991
Methods Study design randomised controlled trial
Participants Country Italy
Publication language English
Inclusion criteria
28Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Sama 1991 (Continued)
- patients who underwent liver transplantation
Exclusion criteria
- not mentioned
Participants
- UDCA group (n = 20)
Mean age (years +- SD)
no information
Ratio of sex (malefemale) no information
Origins of liver diseases
no information
- Control group (n = 20)
Mean age (years +- SD)
no information
Ratio of sex (malefemale) no information
Origins of liver diseases
no information
Interventions UDCA group
- Dose 600 mgday in two divided doses
- Route orally
- Duration immediately after intestinal transit recovery usually between postoperative
day five and day seven and continue for six months
Control group
- no treatment
Co-interventions all patients received standard immunosuppressive treatment (steroids
and cyclosporine)
Outcomes All cause mortality
Number of patients with acute cellular rejection
Notes Abstract
Letter was sent to the authors in September 2009 No reply was received
Risk of bias
Item Authorsrsquo judgement Description
Adequate sequence generation Unclear A randomisation list was performed before
patients were admitted to the trial (infor-
mation from principal author)
Allocation concealment Unclear No information provided
Blinding Unclear The principle author provided information
that the study was made according to a
single-blind randomised protocol The pri-
mary outcome was the occurrence of biopsy
proven rejection episodes The pathologists
were blind but the patients were not
29Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Sama 1991 (Continued)
Incomplete outcome data addressed
All outcomes
Unclear Five patients from the UDCA group and
six patients from the placebo group were
excluded Reasons for exclusion were not
fully stated
Free of selective reporting No Data about survival of patients were not
adequately reported
Sample size calculation No Not performed
Intention-to-treat analysis No Not stated and not used
Baseline imbalance Unclear Basic characteristics of patients not re-
ported
Early stopping of trial Unclear Not enough information provided
UDCA = ursodeoxycholic acid
TUDCA = tauroursodeoxycholic acid
PBC = primary biliary cirrhosis
PSC = primary sclerosing cholangitis
OKT3 = anti-CD3 monoclonal antibody
Characteristics of excluded studies [ordered by study ID]
Assy 2007 A randomised controlled trial that included only recipients of liver transplantation with stable graft function and
no episodes of rejection for at least 2 years that were then offered total immunosuppression withdrawal Fourteen
patients received UDCA (15 mgkg body weightday) and 12 received placebo Rejection occurred in 43 and
75 of patients respectively (no significant difference) None developed chronic rejection After follow-up two
patients were free of immunosuppression 80 were steroid free and 50 were able to reduce their dose of
cyclosporine
Clavien 1996 Case series Fifty consecutive liver-transplanted patients were treated with a standard cyclosporine immunosup-
pressive regimen Twenty three of the 43 survivors developed an episode of rejection and UDCA (10 mgkg
weightday) was initiated Only one patient had a second episode of rejection
Friman 1992 Observational study Thirty-three liver-transplanted patients received 10 mg UDCAkg body weightday for
median of 10 months (range four to 21 months) Eight historical liver-transplanted patients served as control
group The rejection incidence was significantly lower in the patients who received the treatment with UDCA
Biochemistry one month after transplantation demonstrated significantly lower average values of aminotrans-
ferases and alkaline phosphatases in patients treated with UDCA than in the control group
30Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
Heathcote 1999 Observational study From 1987 to 1996 37 UDCA treated and 53 placebo treated patients with primary biliary
cirrhosis were referred for transplantation Posttransplantation survival rates at one month were 939 in the
UDCA group and 884 in the placebo group and one year survival rates were 903 and 784 respectively
(no significant differences) However rejection (type not defined - a secondary outcome measure) occurred
significantly less often in the UDCA group (429) than in placebo group (688)
Henriksson 1991 Observational study All patients in this study were given sequential quadruple immunosuppression with anti-
lymphocyte globulin azathioprine steroids and cyclosporine All patients with primary graft function (n = 11)
were treated with 10 mg UDCAkg body weightday starting during the first postoperative week Patients who
received liver transplantation in the first 6 months of 1989 (n = 8) served as controls In the control group one
patient died after 9 months with chronic graft dysfunction and six patients had rejection episodes during the
first postoperative month All patients in the UDCA group were alive without rejection episodes
Persson 1990 Observational study All 11 adult patients transplanted between August 1989 and January 1990 with primary
graft function were treated with 10 mg UDCA kg body weightday Eight patients transplanted during the first
half of 1989 served as control UDCA was started during the first postoperative week and the treatment was
continued for six months All patients in the UDCA treated group survived with satisfactory graft function In
the control group six patients had at least one rejection episode needing treatment during the first postoperative
month
Rafael 1995 Observational study Seventeen patients who underwent liver transplantation between February 1990 and April
1993 and developed biliary complications after transplantation were retrospectively analysed regarding treatment
with UDCA UDCA was given in a dose of 500 to 1000 mgday Ten patients were treated for at least one year while
seven patients were treated for 14 to 250 days UDCA significantly improved gammaglutamyl transpeptidase in
liver graft recipients with biliary complications There was also a trend towards improvement in serum bilirubin
and alanine transaminase values
Sama 1998 Observational study Thirty-four patients who underwent liver transplantation between January 1995 and June
1996 were included in the study Seventeen were treated with UDCA 10 mgkg body weightday during 6
months while 17 served as controls on the basis of having undergone liver transplantation closest to UDCA
patients A significant decrease in serum bilirubin levels was observed in UDCA patients There was a significantly
higher incidence of recurrent hepatitis in the control group
UDCA ursodeoxycholic acid
31Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
D A T A A N D A N A L Y S E S
Comparison 1 Bile acids for liver-transplanted patients
Outcome or subgroup titleNo of
studies
No of
participants Statistical method Effect size
1 All-cause mortality at maximum
follow-up
5 257 Risk Ratio (M-H Fixed 95 CI) 085 [053 136]
11 UDCA versus placebo or
no treatment
4 224 Risk Ratio (M-H Fixed 95 CI) 080 [049 130]
12 TUDCA versus no
treatment
1 33 Risk Ratio (M-H Fixed 95 CI) 159 [030 833]
2 All-cause mortality worst-best
case and best-worst case
scenarios
5 Risk Ratio (M-H Fixed 95 CI) Subtotals only
21 Worst-best case scenario 5 257 Risk Ratio (M-H Fixed 95 CI) 130 [086 196]
22 Best-worst case scenario 5 257 Risk Ratio (M-H Fixed 95 CI) 058 [038 090]
3 Subgroup analyses all-cause
mortality at maximum
follow-up according to time of
start of bile acids
5 257 Risk Ratio (M-H Fixed 95 CI) 085 [053 136]
31 Less than three days after
transplantation
1 102 Risk Ratio (M-H Fixed 95 CI) 124 [061 254]
32 Three days or more after
transplantation
4 155 Risk Ratio (M-H Fixed 95 CI) 063 [033 120]
4 Subgroup analyses all cause
mortality at maximum
follow-up according to
treatment duration
5 257 Risk Ratio (M-H Fixed 95 CI) 085 [053 136]
41 Less than six months 3 184 Risk Ratio (M-H Fixed 95 CI) 078 [045 138]
42 Six months or more 2 73 Risk Ratio (M-H Fixed 95 CI) 102 [043 240]
5 Number of deaths related
to rejection at maximum
follow-up
1 102 Risk Ratio (M-H Fixed 95 CI) 030 [001 712]
51 UDCA versus placebo 1 102 Risk Ratio (M-H Fixed 95 CI) 030 [001 712]
6 Number of retransplantations at
maximum follow-up
2 132 Risk Ratio (M-H Fixed 95 CI) 076 [020 286]
7 Number of patients with acute
cellular rejection at maximum
follow-up
7 339 Risk Ratio (M-H Fixed 95 CI) 089 [074 106]
71 UDCA versus placebo or
no treatment
6 306 Risk Ratio (M-H Fixed 95 CI) 089 [074 108]
72 TUDCA versus no
treatment
1 33 Risk Ratio (M-H Fixed 95 CI) 085 [045 160]
8 Subgroup analysis number of
patients with acute cellular
rejection according to time of
start of bile acid
7 339 Risk Ratio (M-H Fixed 95 CI) 089 [074 106]
32Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
81 Less than three days after
transplantation
2 134 Risk Ratio (M-H Fixed 95 CI) 084 [063 111]
82 Three days or more after
liver transplantation
5 205 Risk Ratio (M-H Fixed 95 CI) 092 [072 117]
9 Subgroup analysis number
of patients with acute
cellular rejection according to
treatment duration
7 339 Risk Ratio (M-H Fixed 95 CI) 089 [074 106]
91 Less than six months 5 266 Risk Ratio (M-H Fixed 95 CI) 087 [071 107]
92 Six months or more 2 73 Risk Ratio (M-H Fixed 95 CI) 094 [065 136]
10 Number of patients with
chronic rejection at maximum
follow-up
3 184 Risk Ratio (M-H Fixed 95 CI) 028 [008 095]
11 Number of patients with
steroid-resistant rejection at
maximum follow-up
4 234 Risk Ratio (M-H Fixed 95 CI) 077 [047 127]
12 Serum bilirubin (mgdl) at the
end of treatment
1 30 Mean Difference (IV Fixed 95 CI) 26 [-096 616]
13 Number of days of
hospitalisation after liver
transplantation
1 52 Mean Difference (IV Fixed 95 CI) -85 [-1667 -033]
14 Adverse events 3 187 Risk Ratio (M-H Fixed 95 CI) 088 [030 260]
Analysis 11 Comparison 1 Bile acids for liver-transplanted patients Outcome 1 All-cause mortality at
maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 1 All-cause mortality at maximum follow-up
Study or subgroup Favours bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 UDCA versus placebo or no treatment
Barnes 1997 228 724 253 024 [ 006 107 ]
Fleckenstein 1998 214 416 125 057 [ 012 266 ]
Keiding 1997 1454 1048 355 124 [ 061 254 ]
Sama 1991 520 620 201 083 [ 030 229 ]
Subtotal (95 CI) 116 108 935 080 [ 049 130 ]
Total events 23 (Favours bile acids) 27 (Control)
Heterogeneity Chi2 = 416 df = 3 (P = 025) I2 =28
Test for overall effect Z = 091 (P = 036)
01 02 05 1 2 5 10
Favours bile acids Favours control
(Continued )
33Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Favours bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
2 TUDCA versus no treatment
Angelico 1999 316 217 65 159 [ 030 833 ]
Subtotal (95 CI) 16 17 65 159 [ 030 833 ]
Total events 3 (Favours bile acids) 2 (Control)
Heterogeneity not applicable
Test for overall effect Z = 055 (P = 058)
Total (95 CI) 132 125 1000 085 [ 053 136 ]
Total events 26 (Favours bile acids) 29 (Control)
Heterogeneity Chi2 = 466 df = 4 (P = 032) I2 =14
Test for overall effect Z = 069 (P = 049)
01 02 05 1 2 5 10
Favours bile acids Favours control
Analysis 12 Comparison 1 Bile acids for liver-transplanted patients Outcome 2 All-cause mortality worst-
best case and best-worst case scenarios
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 2 All-cause mortality worst-best case and best-worst case scenarios
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 Worst-best case scenario
Angelico 1999 516 217 65 266 [ 060 1180 ]
Barnes 1997 828 724 253 098 [ 042 230 ]
Fleckenstein 1998 314 416 125 086 [ 023 319 ]
Keiding 1997 1954 1048 355 169 [ 087 327 ]
Sama 1991 520 620 201 083 [ 030 229 ]
Subtotal (95 CI) 132 125 1000 130 [ 086 196 ]
Total events 40 (Bile acids) 29 (Control)
Heterogeneity Chi2 = 303 df = 4 (P = 055) I2 =00
Test for overall effect Z = 123 (P = 022)
2 Best-worst case scenario
005 02 1 5 20
Favours bile acids Favours control
(Continued )
34Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Angelico 1999 316 417 90 080 [ 021 302 ]
Barnes 1997 228 1124 274 016 [ 004 063 ]
Fleckenstein 1998 214 616 130 038 [ 009 159 ]
Keiding 1997 1454 1548 368 083 [ 045 154 ]
Sama 1991 520 620 139 083 [ 030 229 ]
Subtotal (95 CI) 132 125 1000 058 [ 038 090 ]
Total events 26 (Bile acids) 42 (Control)
Heterogeneity Chi2 = 567 df = 4 (P = 023) I2 =29
Test for overall effect Z = 247 (P = 0014)
005 02 1 5 20
Favours bile acids Favours control
Analysis 13 Comparison 1 Bile acids for liver-transplanted patients Outcome 3 Subgroup analyses all-
cause mortality at maximum follow-up according to time of start of bile acids
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 3 Subgroup analyses all-cause mortality at maximum follow-up according to time of start of bile acids
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 Less than three days after transplantation
Keiding 1997 1454 1048 355 124 [ 061 254 ]
Subtotal (95 CI) 54 48 355 124 [ 061 254 ]
Total events 14 (Bile acids) 10 (Control)
Heterogeneity not applicable
Test for overall effect Z = 060 (P = 055)
2 Three days or more after transplantation
Angelico 1999 316 217 65 159 [ 030 833 ]
Barnes 1997 228 724 253 024 [ 006 107 ]
Fleckenstein 1998 214 416 125 057 [ 012 266 ]
Sama 1991 520 620 201 083 [ 030 229 ]
005 02 1 5 20
Favours bile acids Favours control
(Continued )
35Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Subtotal (95 CI) 78 77 645 063 [ 033 120 ]
Total events 12 (Bile acids) 19 (Control)
Heterogeneity Chi2 = 310 df = 3 (P = 038) I2 =3
Test for overall effect Z = 141 (P = 016)
Total (95 CI) 132 125 1000 085 [ 053 136 ]
Total events 26 (Bile acids) 29 (Control)
Heterogeneity Chi2 = 466 df = 4 (P = 032) I2 =14
Test for overall effect Z = 069 (P = 049)
005 02 1 5 20
Favours bile acids Favours control
Analysis 14 Comparison 1 Bile acids for liver-transplanted patients Outcome 4 Subgroup analyses all
cause mortality at maximum follow-up according to treatment duration
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 4 Subgroup analyses all cause mortality at maximum follow-up according to treatment duration
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 Less than six months
Barnes 1997 228 724 253 024 [ 006 107 ]
Fleckenstein 1998 214 416 125 057 [ 012 266 ]
Keiding 1997 1454 1048 355 124 [ 061 254 ]
Subtotal (95 CI) 96 88 734 078 [ 045 138 ]
Total events 18 (Bile acids) 21 (Control)
Heterogeneity Chi2 = 417 df = 2 (P = 012) I2 =52
Test for overall effect Z = 084 (P = 040)
2 Six months or more
Angelico 1999 316 217 65 159 [ 030 833 ]
Sama 1991 520 620 201 083 [ 030 229 ]
Subtotal (95 CI) 36 37 266 102 [ 043 240 ]
Total events 8 (Bile acids) 8 (Control)
Heterogeneity Chi2 = 043 df = 1 (P = 051) I2 =00
005 02 1 5 20
Favours bile acids Favours control
(Continued )
36Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Test for overall effect Z = 004 (P = 097)
Total (95 CI) 132 125 1000 085 [ 053 136 ]
Total events 26 (Bile acids) 29 (Control)
Heterogeneity Chi2 = 466 df = 4 (P = 032) I2 =14
Test for overall effect Z = 069 (P = 049)
005 02 1 5 20
Favours bile acids Favours control
Analysis 15 Comparison 1 Bile acids for liver-transplanted patients Outcome 5 Number of deaths related
to rejection at maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 5 Number of deaths related to rejection at maximum follow-up
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 UDCA versus placebo
Keiding 1997 054 148 1000 030 [ 001 712 ]
Total (95 CI) 54 48 1000 030 [ 001 712 ]
Total events 0 (Bile acids) 1 (Control)
Heterogeneity not applicable
Test for overall effect Z = 075 (P = 045)
0001 001 01 1 10 100 1000
Favours bile acids Favours control
37Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 16 Comparison 1 Bile acids for liver-transplanted patients Outcome 6 Number of
retransplantations at maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 6 Number of retransplantations at maximum follow-up
Study or subgroup Bile acids Placebo Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Fleckenstein 1998 214 016 100 567 [ 029 10891 ]
Keiding 1997 154 448 900 022 [ 003 192 ]
Total (95 CI) 68 64 1000 076 [ 020 286 ]
Total events 3 (Bile acids) 4 (Placebo)
Heterogeneity Chi2 = 303 df = 1 (P = 008) I2 =67
Test for overall effect Z = 040 (P = 069)
0001 001 01 1 10 100 1000
Favours bile acids Favours placebo
Analysis 17 Comparison 1 Bile acids for liver-transplanted patients Outcome 7 Number of patients with
acute cellular rejection at maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 7 Number of patients with acute cellular rejection at maximum follow-up
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 UDCA versus placebo or no treatment
Barnes 1997 1728 1724 180 086 [ 058 127 ]
Fleckenstein 1998 814 916 83 102 [ 054 190 ]
Keiding 1997 3554 3248 333 097 [ 073 129 ]
Koneru 1993 316 916 89 033 [ 011 101 ]
Pageaux 1995 926 924 92 092 [ 044 193 ]
Sama 1991 1320 1320 128 100 [ 063 158 ]
Subtotal (95 CI) 158 148 905 089 [ 074 108 ]
01 02 05 1 2 5 10
Favours bile acids Favours control
(Continued )
38Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Total events 85 (Bile acids) 89 (Control)
Heterogeneity Chi2 = 387 df = 5 (P = 057) I2 =00
Test for overall effect Z = 120 (P = 023)
2 TUDCA versus no treatment
Angelico 1999 816 1017 95 085 [ 045 160 ]
Subtotal (95 CI) 16 17 95 085 [ 045 160 ]
Total events 8 (Bile acids) 10 (Control)
Heterogeneity not applicable
Test for overall effect Z = 050 (P = 061)
Total (95 CI) 174 165 1000 089 [ 074 106 ]
Total events 93 (Bile acids) 99 (Control)
Heterogeneity Chi2 = 392 df = 6 (P = 069) I2 =00
Test for overall effect Z = 130 (P = 019)
01 02 05 1 2 5 10
Favours bile acids Favours control
Analysis 18 Comparison 1 Bile acids for liver-transplanted patients Outcome 8 Subgroup analysis
number of patients with acute cellular rejection according to time of start of bile acid
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 8 Subgroup analysis number of patients with acute cellular rejection according to time of start of bile acid
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 Less than three days after transplantation
Keiding 1997 3554 3248 333 097 [ 073 129 ]
Koneru 1993 316 916 89 033 [ 011 101 ]
Subtotal (95 CI) 70 64 422 084 [ 063 111 ]
Total events 38 (Bile acids) 41 (Control)
Heterogeneity Chi2 = 374 df = 1 (P = 005) I2 =73
Test for overall effect Z = 124 (P = 022)
2 Three days or more after liver transplantation
Angelico 1999 816 1017 95 085 [ 045 160 ]
01 02 05 1 2 5 10
Favours bile acids Favours control
(Continued )
39Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Barnes 1997 1728 1724 180 086 [ 058 127 ]
Fleckenstein 1998 814 916 83 102 [ 054 190 ]
Pageaux 1995 926 924 92 092 [ 044 193 ]
Sama 1991 1320 1320 128 100 [ 063 158 ]
Subtotal (95 CI) 104 101 578 092 [ 072 117 ]
Total events 55 (Bile acids) 58 (Control)
Heterogeneity Chi2 = 041 df = 4 (P = 098) I2 =00
Test for overall effect Z = 067 (P = 050)
Total (95 CI) 174 165 1000 089 [ 074 106 ]
Total events 93 (Bile acids) 99 (Control)
Heterogeneity Chi2 = 392 df = 6 (P = 069) I2 =00
Test for overall effect Z = 130 (P = 019)
01 02 05 1 2 5 10
Favours bile acids Favours control
40Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 19 Comparison 1 Bile acids for liver-transplanted patients Outcome 9 Subgroup analysis
number of patients with acute cellular rejection according to treatment duration
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 9 Subgroup analysis number of patients with acute cellular rejection according to treatment duration
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 Less than six months
Barnes 1997 1728 1724 180 086 [ 058 127 ]
Fleckenstein 1998 814 916 83 102 [ 054 190 ]
Keiding 1997 3554 3248 333 097 [ 073 129 ]
Koneru 1993 316 916 89 033 [ 011 101 ]
Pageaux 1995 926 924 92 092 [ 044 193 ]
Subtotal (95 CI) 138 128 777 087 [ 071 107 ]
Total events 72 (Bile acids) 76 (Control)
Heterogeneity Chi2 = 374 df = 4 (P = 044) I2 =00
Test for overall effect Z = 129 (P = 020)
2 Six months or more
Angelico 1999 816 1017 95 085 [ 045 160 ]
Sama 1991 1320 1320 128 100 [ 063 158 ]
Subtotal (95 CI) 36 37 223 094 [ 065 136 ]
Total events 21 (Bile acids) 23 (Control)
Heterogeneity Chi2 = 017 df = 1 (P = 068) I2 =00
Test for overall effect Z = 035 (P = 073)
Total (95 CI) 174 165 1000 089 [ 074 106 ]
Total events 93 (Bile acids) 99 (Control)
Heterogeneity Chi2 = 392 df = 6 (P = 069) I2 =00
Test for overall effect Z = 130 (P = 019)
01 02 05 1 2 5 10
Favours bile acids Favours control
41Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 110 Comparison 1 Bile acids for liver-transplanted patients Outcome 10 Number of patients
with chronic rejection at maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 10 Number of patients with chronic rejection at maximum follow-up
Study or subgroup Bile acids Placebo Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Barnes 1997 128 624 611 014 [ 002 110 ]
Fleckenstein 1998 114 116 88 114 [ 008 1663 ]
Keiding 1997 154 348 300 030 [ 003 275 ]
Total (95 CI) 96 88 1000 028 [ 008 095 ]
Total events 3 (Bile acids) 10 (Placebo)
Heterogeneity Chi2 = 148 df = 2 (P = 048) I2 =00
Test for overall effect Z = 204 (P = 0041)
0001 001 01 1 10 100 1000
Favours bile acids Favours placebo
Analysis 111 Comparison 1 Bile acids for liver-transplanted patients Outcome 11 Number of patients
with steroid-resistant rejection at maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 11 Number of patients with steroid-resistant rejection at maximum follow-up
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Barnes 1997 328 724 277 037 [ 011 127 ]
Fleckenstein 1998 314 316 103 114 [ 027 478 ]
Keiding 1997 1454 1548 583 083 [ 045 154 ]
Pageaux 1995 226 124 38 185 [ 018 1908 ]
Total (95 CI) 122 112 1000 077 [ 047 127 ]
Total events 22 (Bile acids) 26 (Control)
Heterogeneity Chi2 = 226 df = 3 (P = 052) I2 =00
Test for overall effect Z = 102 (P = 031)
001 01 1 10 100
Favours bile acids Favours placebo
42Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 112 Comparison 1 Bile acids for liver-transplanted patients Outcome 12 Serum bilirubin (mgdl)
at the end of treatment
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 12 Serum bilirubin (mgdl) at the end of treatment
Study or subgroup Bile acids Placebo Mean Difference Weight Mean Difference
N Mean(SD) N Mean(SD) IVFixed95 CI IVFixed95 CI
Fleckenstein 1998 14 319 (68) 16 059 (022) 1000 260 [ -096 616 ]
Total (95 CI) 14 16 1000 260 [ -096 616 ]
Heterogeneity not applicable
Test for overall effect Z = 143 (P = 015)
-10 -5 0 5 10
Favours bile acids Favours placebo
Analysis 113 Comparison 1 Bile acids for liver-transplanted patients Outcome 13 Number of days of
hospitalisation after liver transplantation
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 13 Number of days of hospitalisation after liver transplantation
Study or subgroup Bile acids Placebo Mean Difference Weight Mean Difference
N Mean(SD) N Mean(SD) IVFixed95 CI IVFixed95 CI
Barnes 1997 28 25 (17) 24 335 (13) 1000 -850 [ -1667 -033 ]
Total (95 CI) 28 24 1000 -850 [ -1667 -033 ]
Heterogeneity not applicable
Test for overall effect Z = 204 (P = 0041)
-100 -50 0 50 100
Favours bile acids Favours placebo
43Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 114 Comparison 1 Bile acids for liver-transplanted patients Outcome 14 Adverse events
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 14 Adverse events
Study or subgroup Bile acids Placebo Risk Ratio Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Angelico 1999 016 017 00 [ 00 00 ]
Barnes 1997 128 124 086 [ 006 1298 ]
Keiding 1997 554 548 089 [ 027 288 ]
Total (95 CI) 98 89 088 [ 030 260 ]
Total events 6 (Bile acids) 6 (Placebo)
Heterogeneity Chi2 = 000 df = 1 (P = 098) I2 =00
Test for overall effect Z = 022 (P = 082)
001 01 1 10 100
Favours bile acids Favours placebo
A P P E N D I C E S
Appendix 1 Search strategies
Data Base Date of Search Search Strategy
The Cochrane Hepato-Biliary Group Con-
trolled Trials Register
September 2009 1 rsquoliver transplantationrsquo and rsquochenodeoxy-
cholicrsquo
2 rsquoliver transplantationrsquo and rsquocholicrsquo
3 rsquoliver transplantationrsquo and rsquodeoxycholicrsquo
4 rsquoliver transplantationrsquo and rsquoglycochen-
odeoxycholicrsquo
5 rsquoliver transplantationrsquo and rsquoglycocholicrsquo
6 rsquoliver transplantationrsquo and rsquoglycodeoxy-
cholicrsquo
7 rsquoliver transplantationrsquo and rsquoglycolitho-
cholicrsquo
8 rsquoliver transplantationrsquo and rsquohyodeoxy-
cholicrsquo
9 rsquoliver transplantationrsquo and rsquolithocholicrsquo
10 rsquoliver transplantationrsquo and rsquotaurochen-
odeoxycholicrsquo
44Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
11 rsquoliver transplantationrsquo and rsquotauro-
cholicrsquo
12 rsquoliver transplantationrsquo and rsquotaurodehy-
drocholicrsquo
13 rsquoliver transplantationrsquo and rsquotau-
rodeoxycholicrsquo
14 rsquoliver transplantationrsquo and rsquotauroglyco-
cholicrsquo
15 rsquoliver transplantationrsquo and rsquotaurolitho-
cholicrsquo
16 rsquoliver transplantationrsquo and rsquotaurosel-
cholicrsquo
17 rsquoliver transplantationrsquo and rsquotaurourso-
cholicrsquo
18 rsquoliver transplantationrsquo and rsquotaurour-
sodeoxycholicrsquo
19 rsquoliver transplantationrsquo and rsquoursocholicrsquo
20 rsquoliver transplantationrsquo and rsquoursodeoxy-
cholicrsquo
The Cochrane Central Register of Con-
trolled Trials in The Cochrane Library
Issue 3 2009 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
6 3 or 4
7 5 and 6
MEDLINE September 2009 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
45Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
6 3 or 4
7 5 and 6
8 RANDOMIZED-CONTROLLED-
TRIAL ME
9 RANDOM
10 8 or 9
11 7 and 10
EMBASE September 2009 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
6 3 or 4
7 5 and 6
8 RANDOMIZED-CONTROLLED-
TRIAL ME
9 RANDOM
10 8 or 9
11 7 and 10
46Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
Science Citation Index Expanded September 2009 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
6 3 or 4
7 5 and 6
8 RANDOMIZED-CONTROLLED-
TRIAL ME
9 RANDOM
10 8 or 9
11 7 and 10
The Chinese Biomedical Database Searched from January 1980 to April 2002 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
47Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
6 3 or 4
7 5 and 6
8 RANDOMIZED-CONTROLLED-
TRIAL ME
9 RANDOM
10 8 or 9
11 7 and 10
W H A T rsquo S N E W
Last assessed as up-to-date 8 February 2010
18 September 2009 New citation required but conclusions have not
changed
This review is an updated version of a review that was
published for the first time in Issue 3 2005 of TheCochrane Library by Chen 2003b
18 September 2009 New search has been performed No new studies fulfilled the inclusion criteria
H I S T O R Y
Protocol first published Issue 3 2003
Review first published Issue 3 2005
C O N T R I B U T I O N S O F A U T H O R S
GP and VG independently performed searches of relevant databases GP validated the search selected trials for inclusion contacted
the authors of the trials performed data extraction and data analysis and drafted the systematic review VG revised the review update
CG and DS revised the review update solved discrepancies of data extraction validated data analyses and provided consultation
D E C L A R A T I O N S O F I N T E R E S T
None known
48Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
S O U R C E S O F S U P P O R T
Internal sources
bull Copenhagen Trial Unit Denmark
External sources
bull Danish Medical Research Councilrsquos Grant on Getting Research into Practice (GRIP) Denmark
D I F F E R E N C E S B E T W E E N P R O T O C O L A N D R E V I E W
We assessed the risk of bias in the included studies for another four domains that were added to the review protocol (incomplete
outcome data selective outcome reporting baseline imbalance and early stopping of trial) In general the text of the risk of bias
domains were updated following Higgins 2008 Trials were considered at low risk of bias when judged as adequate in all domains
Quasi-randomised studies observational and case-control studies were included for the report of adverse events
We performed trial sequential analysis for outcomes demonstrating a statistically significant result
I N D E X T E R M S
Medical Subject Headings (MeSH)
lowastLiver Transplantation Cholagogues and Choleretics [lowasttherapeutic use] Graft Rejection [lowastprevention amp control] Randomized Con-
trolled Trials as Topic Taurochenodeoxycholic Acid [lowasttherapeutic use] Ursodeoxycholic Acid [lowasttherapeutic use]
MeSH check words
Humans
49Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Table 1 Adverse events (Continued)
Keiding 1997 54 48 Diarrhoea and diffi-
culties in swallowing
capsules (5 pts)
Diarrhoea and diffi-
culties in swallowing
capsules (5 pts)
No other presumed
drug-induced side ef-
fects were observed
Angelico 1999 16 17 No AE No AE TUDCA administra-
tion was well tol-
erated in all pa-
tients and no drug-
related side effects
were recorded
Assy 2007 14 12 Mild diarrhoea (1 pt) No AE No dose reduction
was required
pt(s) = patient(s)
AE = adverse events
Types of participants
Patients who underwent liver transplantation
Types of interventions
Any dose of a bile acid or duration of treatment versus placebo
no intervention or another intervention
We allowed co-interventions if received equally by the intervention
groups within a trial
Types of outcome measures
The primary outcome measures were
1 All-cause mortality
2 Death due to allograft rejection (acute cellular rejection or
chronic rejection or liver retransplantation because of rejection)
Acute cellular rejection was diagnosed by the combination of ab-
normal liver biochemical variables (bilirubin aspartate transam-
inase alanine transaminase alkaline phosphatases andor gam-
maglutamyl transpeptidase) clinical signs such as fever and liver
histological changes including mononuclear portal inflammation
bile duct damage and subendothelial inflammation of portal or
terminal hepatic veins (IWP 1995) Chronic rejection was charac-
terised by liver histological changes including the progressive loss
of interlobular bile ducts and arteriopathy characterised by foam
cell infiltration of the arterial intima
The secondary outcome measures were
3 Number of patients who experienced rejection - irrespective of
the type acute cellular rejection chronic rejection or both types
of rejections
4 Number of patients with acute cellular rejection
5 Number of patients with chronic rejection
6 Number of patients with steroid-resistant rejection
7 Biochemical responses serum activities of alkaline phos-
phatases gammaglutamyl transpeptidase alanine aminotrans-
ferase and aspartate aminotransferase and serum bilirubin con-
centration andor number of patients with abnormal liver bio-
chemical variables mentioned above
8 Adverse events Adverse events were defined as any untoward
medical occurrence not necessarily having a causal relationship
with the treatment but resulting in a dose reduction or discontin-
uation of treatment (ICH-GCP 1997)
9 Quality of life
10 Cost-effectiveness
Search methods for identification of studies
We performed searches of The Cochrane Hepato-Biliary GroupControlled Trials Register (September 2009)(Gluud 2010) and TheCochrane Central Register of Controlled Trials (CENTRAL) in TheCochrane Library (Issue 3 2009) by combining the terms rsquoliverrsquo
and rsquotransplantationrsquo with the individual bile acid name (litho-
cholic acid chenodeoxycholic acid ursodeoxycholic acid deoxy-
cholic acid dehydrocholic acid and tauro-ursodeoxycholic acid)
We searched MEDLINE (January 1966 to September 2009) EM-BASE (January 1980 to September 2009) and Science Citation In-dex Expanded (1945 to September 2009) by using the terms rsquoliverrsquo
4Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
and rsquotransplantationrsquo in combination with the bile acids mentioned
above (Royle 2003) The search strategies with the time span of
the searches are given in Appendix 1 We contacted the Chinese
Cochrane Centre regarding the search of The Chinese BiomedicalDatabase and received a reply that they are unable to help us with
this search Therefore the latter database could not be included
in the search strategy of this update
Further trials were identified by reading the reference lists of the
identified studies We wrote to the principal authors of the reports
of the identified randomised clinical trials in September 2009 and
enquired about additional trials which they might know of The
first team of authors had also written to pharmaceutical companies
involved in the production of bile acids to obtain information on
published or unpublished randomised clinical trials in 2002 but
no information had been received at that time
Data collection and analysis
The update of this review was conducted according to the proto-
col previously published in The Cochrane Library (Chen 2003b)
and following the recommendations given by the Cochrane Hand-book for Systematic Reviews of Interventions (Higgins 2008) and the
Cochrane Hepato-Biliary Group Module (Gluud 2010)
Trial identification
Identified trials were listed and the two review authors evaluated
whether the trials fulfilled the inclusion criteria Excluded trials
were listed with the reasons for exclusion
Data extraction
GP and VG extracted the data independently and disagreements
were resolved by discussion or by CG We extracted the following
characteristics from each trial primary author number of patients
randomised patient inclusion and exclusion criteria methodolog-
ical quality follow-up (number and reasons for withdrawal) sam-
ple size calculation intention-to-treat analysis intervention reg-
imens mean age proportion of males and females aetiology of
liver disease origin of allograft matching criteria between donor
and recipient time to follow-up number of outcomes and num-
ber and type of adverse events in both the intervention and the
control groups Additional information was sought by correspon-
dence with the principal investigator or co-investigators of the trial
in cases where the relevant data were not published
Assessment of risk of bias
Risk of bias was defined as the confidence that the study design and
reporting restricted bias in the intervention comparison (Schulz
1995 Moher 1998 Kjaergard 2001 Wood 2008) Due to the risk
of overestimation of intervention effects in randomised trials with
unclear or inadequate components we assessed the risk of bias by
separate domains
Allocation sequence generation
bull Adequate if the allocation sequence was generated by a
computer or random number table Drawing of lots tossing of a
coin shuffling of cards or throwing dice was considered as
adequate if a person who was not otherwise involved in the
recruitment of participants performed the procedure
bull Unclear if the trial was described as randomised but the
method used for the allocation sequence generation was not
described
bull Inadequate if a system involving dates names or
admittance numbers were used for the allocation of patients
Such quasi-randomised studies were excluded
Allocation concealment
bull Adequate if the allocation of patients involved a central
independent unit on-site locked computer identically appearing
numbered drug bottles or containers prepared by an
independent pharmacist or investigator or serially numbered
sealed and opaque envelopes
bull Unclear if the trial was described as randomised but the
method used to conceal the allocation was not described
bull Inadequate if the allocation sequence was known to the
investigators who assigned participants or if the study was quasi-
randomised The latter studies were excluded
Blinding
bull Adequate the trial was described as blinded the parties that
were blinded and the method of blinding was described so that
knowledge of allocation was adequately prevented during the
trial
bull Unclear the trial was described as double blind but the
method of blinding was not described so that knowledge of
allocation was possible during the trial
bull Not performed the trial was not blinded so that the
allocation was known during the trial
Incomplete outcome data
bull Adequate if the numbers and reasons for dropouts and
withdrawals in all intervention groups were described or if it was
specified that there were no dropouts or withdrawals
bull Unclear if the report gave the impression that there had
been no dropouts or withdrawals but this was not specifically
stated
bull Inadequate if the number or reasons for dropouts and
withdrawals were not described
Selective outcome reporting
bull Adequate if study protocol is available and all pre-specified
outcomes are reported in the manuscript or if the study protocol
is not available but it is clear that the report includes all expected
outcomes
bull Unclear if there are no sufficient information to permit
judgement
bull Inadequate if not all of the pre-specified outcomes were
reported andor were reported incompletely or one or more
reported outcomes were not pre-specified
Baseline imbalance
5Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
bull Adequate if there is no baseline imbalance in the main
characteristics
bull Unclear if there is no sufficient information to assess
baseline characteristics
bull Inadequate if there was a baseline imbalance due to chance
or due to imbalanced exclusion after randomisation
Early stopping
bull Adequate if sample size calculation was reported and the
trial was not stopped or the trial was stopped early by formal
stopping rules at a point where the likelihood of observing an
extreme intervention effect due to chance was low
bull Unclear if sample size calculation was not reported and it is
not clear whether the trial was stopped early or not
bull Inadequate if the trial was stopped early due to informal
stopping rules or the trial was stopped early by a formal stopping
rule at a point where the likelihood of observing an extreme
intervention effect due to chance was high
Furthermore we registered whether the randomised clinical trials
had used an intention-to-treat analysis (Gluud 2001) and had
calculated a sample size estimate
Statistical methods
We performed the analyses in RevMan 5 (RevMan 2008) Anal-
yses included all patients irrespective of compliance or follow-up
according to the intention-to-treat principle and using the last
reported observed response (rsquocarry forwardrsquo) Regarding death
both a worst-best-case scenario analysis considering all dropped-
out patients in the bile acid group as dead and the dropped-out
patients in the control group as alive and a best-worst-case sce-
nario analysis considering all dropped-out patients in the bile acid
group as alive and the dropped-out patients in the control group as
dead were performed Both a random-effects model (DerSimonian
1986) and a fixed-effect model (DeMets 1987) were used The re-
sults of the fixed-effect model were reported if there were no differ-
ences between the results produced by the two models otherwise
we reported the results produced by both models We presented
binary outcome measures as relative risks (RR) with 95 confi-
dence intervals (CI) and continuous outcome measures as mean
differences (MD) with 95 CI
The risk of type I errors increases in single trials with interim anal-
yses To avoid type I errors group sequential monitoring bound-
aries (Lan 1983) can be performed when deciding to terminate the
trial earlier than planned This requires analyses at different time
intervals to record when the P-value has become sufficiently small
that is when the cumulative Z-curve will cross the monitoring
boundaries Sequential monitoring boundaries the so called rsquotrial
sequential monitoring boundariesrsquo can also be applied to meta-
analyses In a trial sequential analysis (TSA) every trial that is
added in a cumulative meta-analysis is regarded as an interim meta-
analysis and the information it adds on helps on deciding if more
trials need to be included
The interpretation of the TSA is as follows if the cumulative Z-
curve has crossed the boundary a sufficient level of evidence is
reached and no further trials may be needed If the Z-curve has
not crossed the boundary then the evidence is insufficient in order
to reach a conclusion To construct the trial sequential monitor-
ing boundaries information size is needed It is calculated as the
minimum number of participants needed in a well-powered single
trial (Pogue 1997 Pogue 1998 Brok 2008 Wetterslev 2008) We
applied TSA since it prevents an increase of the risk of type I error
due to sparse and multiple updating in a cumulative meta-analysis
and provides us with important information in order to estimate
the level of evidence of the experimental intervention Addition-
ally TSA provides us with important information regarding the
need for additional trials and the required information size We
applied trial sequential monitoring boundaries according to an in-
formation size suggested by the trials with low risk of bias and a
50 relative risk reduction (RRR)
Subgroup analyses
We planned to perform the following subgroup analyses on the
main outcome measures (all-cause mortality and number of pa-
tients with acute rejection)
1 Risk of bias of the trials comparing the intervention effect for
trials with low risk of bias components to the intervention effect
in trials with unclear or high risk of bias components
2 Dose and duration of treatment with bile acids comparing the
intervention effect in trials administrating bile acid at or above the
median dose multiplied by duration to the intervention effect of
trials administrating bile acid at less than the median dose multi-
plied by duration
3 Time between transplantation and the start of bile acids com-
paring the intervention effect of trials having less than three days
between transplantation and starting bile acid intake to the inter-
vention effect of trials with a duration of three days or more be-
tween transplantation and the start of bile acid intake (Neuberger
1999)
4 Co-interventions comparing the intervention effect of trials
with co-interventions to the intervention effect of trials without
co-interventions
Funnel plot analysis
We planned to explore bias by funnel plot analysis (Egger 1997)
R E S U L T S
Description of studies
See Characteristics of included studies Characteristics of excluded
studies
The performed electronic searches resulted in a total of 378 ref-
erences We excluded 362 duplicates or irrelevant references by
reading abstracts We excluded eight of the 16 further assessed ref-
erences because they were observational studies case series or ran-
6Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
domised clinical trials with a different reason for exclusion They
are listed under rsquoCharacteristic of excluded studiesrsquo with reasons
for exclusion Seven references already included in the previous
version of this review and one new reference referring to an al-
ready included trial (Barnes 1997) were included in this review
We were not able to identify more trials by reading the reference
lists of the identified studies contacting the principle authors of
the identified trials or approaching pharmaceutical companies for
unpublished trials
Seven publications included in the review (five full publications
and two abstracts) were randomised clinical trials that reported
the random allocation of liver-transplanted patients into groups
receiving bile acid placebo or no treatment We listed these trials
in the table of Characteristics of included studies All seven trials
were published in English Three randomised clinical trials were
from the United States (Koneru 1993 Barnes 1997 Fleckenstein
1998) two from Italy (Sama 1991 Angelico 1999) one from
France (Pageaux 1995) and one from Denmark (Keiding 1997)
Patients
In the included trials all patients received blood group-compatible
grafts The median size of the seven trials was 40 patients (range
29 to 102 patients) In total 335 patients were randomised
Five trials were published as full publications (Pageaux 1995
Barnes 1997 Keiding 1997 Fleckenstein 1998 Angelico 1999)
which allowed us to extract detailed information on 263 of the
patients The mean age of the patients ranged from 44 to 51 years
One trial (Keiding 1997) also enrolled children ranging in age
from 0 to 13 years (median 15 years) The male to female ratio in
these five trials was 159104 The diseases that led to liver trans-
plantation were alcoholic cirrhosis in 51 patients (194) cirrho-
sis caused by chronic hepatitis C in 40 patients (152) primary
biliary cirrhosis in 36 patients (137) cryptogenic cirrhosis in
22 patients (84) metabolic diseases in 19 patients (72) pri-
mary sclerosing cholangitis in 17 patients (65) non-specified
post-hepatitis cirrhosis in 17 patients (65) cirrhosis caused by
chronic hepatitis B in 13 patients (49) 9 with autoimmune
hepatitis and cirrhosis (34) six with liver cancer (23) five
with biliary atresia (19) and 28 with other diseases (106)
Only one trial reported the severity of liver function according to
the Child-Pugh class (Barnes 1997)
Bile acids and collateral interventions
Six trials (Sama 1991 Koneru 1993 Pageaux 1995 Barnes
1997 Keiding 1997 Fleckenstein 1998) compared UDCA versus
placebo or no intervention One trial (Angelico 1999) compared
TUDCA versus no intervention Bile acid treatment began one
day after transplantation in the Keiding 1997 trial three days after
transplantation in the Koneru 1993 trial three or five days in the
Fleckenstein 1998 and Pageaux 1995 trials five days after trans-
plantation in the Barnes 1997 and Angelico 1999 trials and five
or seven days after transplantation in the Sama 1991 trial
Patients received UCDA (10 to 15 mgkg body weightday) for
two months in the Pageaux 1995 trial for three months in the
Koneru 1993 Barnes 1997 Keiding 1997 and Fleckenstein 1998
trials and for six months in the Sama 1991 trial In the Barnes
1997 trial patients were followed up for 18 months Patients in the
Fleckenstein 1998 trial and the Keiding 1997 trial were followed
up for nine months There was no post-treatment follow-up in
three trials (Sama 1991 Koneru 1993 Pageaux 1995) Patients
received TUDCA (500 mgday) for one year and no follow-up
was conducted in the Angelico 1999 trial
In addition to the bile acids or control intervention all patients
in the seven trials received standard triple-drug regimens (steroids
azathioprine and cyclosporine or tacrolimus) The patients who
had steroid-resistant rejection received treatment with immuno-
suppressive antibodies (OKT3)
Outcome measures
The outcome measures reported by most trials were all-cause mor-
tality and acute cellular rejection Three trials reported on death
related to rejection (Barnes 1997 Keiding 1997 Angelico 1999)
two trials reported the number of patients who received retrans-
plantation due to rejection (Keiding 1997 Fleckenstein 1998)
three trials reported the number of patients with chronic rejection
(Barnes 1997 Keiding 1997 Fleckenstein 1998) and four trials
reported the number of patients with steroid-resistant rejection
(Pageaux 1995 Barnes 1997 Keiding 1997 Fleckenstein 1998)
Four trials had adverse events as outcome measures (Barnes 1997
Keiding 1997 Fleckenstein 1998 Angelico 1999) Serum biliru-
bin level was only reported by the Fleckenstein 1998 trial No tri-
als provided data on other liver biochemical parameters quality
of life or cost-effectiveness
Risk of bias in included studies
Two trials reported adequate allocation sequence generation by
using computer-generated random tables (Barnes 1997 Angelico
1999) One trial (Keiding 1997) reported adequate allocation con-
cealment by using sealed serially numbered envelopes Three tri-
als (Barnes 1997 Keiding 1997 Fleckenstein 1998) reported ad-
equate blinding by using placebo with an identical appearance
and taste Five trials (Pageaux 1995 Barnes 1997 Keiding 1997
Fleckenstein 1998 Angelico 1999) reported adequate description
of incomplete outcome data by the number of withdrawals the
reasons for withdrawal or no patients dropped out The trial by
Keiding 1997 is the only one free of selective reporting since all
the pre-specified outcomes were fairly reported Two trials (Barnes
1997 Keiding 1997) performed sample-size calculations Only
the trial by Keiding 1997 seemed to be free of baseline imbalance
and it is the only trial achieving the calculated sample size and
therefore probably the only that was not terminated early Other
trials did not perform sample size calculation or the authors did
not report whether the calculated sample size was achieved The
lack of this information made it unclear for us to judge whether
7Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
a trial was terminated early that is before an adequate number
of patients was included in the trial Three trials (Barnes 1997
Keiding 1997 Fleckenstein 1998) stated that intention-to-treat
analyses were used (Figure 1 Figure 2)
Figure 1 Methodological quality graph review authorsrsquo judgements about each methodological quality
item presented as percentages across all included studies
8Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Figure 2 Methodological quality summary review authorsrsquo judgements about each methodological quality
item for each included study
9Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Following the assessment of risk of bias domains none of the seven
trials were considered to have low risk of bias that is having all
the nine domains for risk of bias assessed as adequate
Effects of interventions
We were able to include seven randomised clinical trials in this
review Six trials with 306 liver-transplanted patients compared
ursodeoxycholic acid (UDCA) with placebo or no intervention
and one trial with 29 liver-transplanted patients compared tauro-
UDCA (TUDCA) with no intervention
All-cause mortality
Five trials including 257 liver-transplanted patients reported on
all-cause mortality at the end of treatment or at maximum follow-
up Bile acids did not significantly reduce all-cause mortality (RR
085 95 CI 053 to 136) there were 26 deaths among 132
patients treated with bile acids (197) versus 29 deaths among
125 patients in the control groups (232) (Analysis 11) There
was no statistically significant heterogeneity (I2 = 141)
Four trials (Sama 1991 Barnes 1997 Keiding 1997 Fleckenstein
1998) showed that UDCA did not significantly reduce all-cause
mortality (RR 080 95 CI 049 to 130) 23 deaths among 116
patients treated with UCDA (198) versus 27 deaths among
108 patients in the control groups (250) The Angelico 1999
trial demonstrated that TUDCA was not able to reduce all-cause
mortality (RR 159 95 CI 030 to 833) there were 3 deaths
among 16 patients (188) versus 2 deaths among 17 patients
(118)
The Fleckenstein 1998 trial and the Sama 1991 trial did not report
the causes of deaths In the three other trials the deaths were
considered to be caused by infections (n = 11) hepatic failure (n =
7) abdominal bleeding (n = 3) renal failure (n = 2) multiple organ
failure (n = 2) hepatitis B virus fibrosis (n = 2) acute rejection
(n = 1) hepatic artery thrombosis (n = 1) encephalitis (n = 1)
lymphoproliferative disorder (n = 1) cerebral haemorrhage (n =
1) or other reasons (n = 6)
Worst-best case and best-worst case scenario analyses
In the worst-best case scenario analysis bile acids did not signif-
icantly reduce all-cause mortality when compared with placebo
or no intervention (RR 130 95 CI 086 to 196) 40 deaths
among 132 patients on bile acids (303) versus 29 deaths among
125 patients in the control groups (232) However all-cause
mortality was significantly reduced by bile acids in the best-worst
case scenario analysis (RR 058 95 CI 038 to 090) 26 deaths
among 132 patients (197) versus 42 deaths among 125 patients
in the control groups (336) (Analysis 12)
Subgroup analyses
We performed subgroup analyses regarding the time that bile acid
intake was started The Keiding 1997 trial started bile acid intake
less than three days after liver transplantation and demonstrated
no significant effect of UDCA on all-cause mortality (RR 124
95 CI 061 to 254) 14 deaths out of 54 patients (259)
versus 10 out of 48 control patients (208) The same effect
was noticed in the four other trials (Sama 1991 Barnes 1997
Fleckenstein 1998 Angelico 1999) which started bile acids three
days or more after liver transplantation (RR 063 95 CI 033
to 120) 12 deaths among 78 patients (154) versus 9 deaths
among 77 control patients (247) (Analysis 13) There were no
statistically significant differences between the two estimates
We also performed subgroup analyses regarding the duration of
bile acid treatment Bile acids were administrated for less than six
months in three trials (Barnes 1997 Keiding 1997 Fleckenstein
1998) and were not able to significantly decrease all-cause mor-
tality (RR 078 95 CI 045 to 138) 18 deaths in a group of
96 treated patients (188) versus 21 deaths among 88 control
patients (239) In the other two trials (Sama 1991 Angelico
1999) patients were treated with bile acids for six months or more
The treatment did not show statistically significant decrease in all-
cause mortality (RR 102 95 CI 043 to 24) 8 deaths in a
group of 36 treated patients (222) versus 8 deaths in a group
of 37 control patients (216) (Analysis 14) There were no sta-
tistically significant differences between the two estimates
Mortality related to allograft rejection
We did not find statistically significant reduction in mortality re-
lated to allograft rejection at maximum follow-up in the three tri-
als reporting cause of death (Barnes 1997 Keiding 1997 Angelico
1999) (RR 030 95 CI 001 to 712) 098 (0) versus 189
(11)) (Analysis 15) The only death due to acute rejection was
found in the placebo group of the Keiding 1997 trial
Number of liver retransplantations
Two trials (Fleckenstein 1998 Keiding 1997) including 132 liver-
transplanted patients reported the number of liver retransplan-
tations UDCA did not significantly reduce the risk of liver re-
transplantation at maximum follow-up (RR 076 95 CI 020
to 286) 368 (44) versus 464 (63)) (Analysis 16) In the
Keiding 1997 trial one patient in the UDCA group was retrans-
planted due to chronic rejection and four patients in the placebo
group were retransplanted either due to chronic rejection (three
cases) or acute rejection (one case) In the Fleckenstein 1998 trial
two patients in the UDCA group were retransplanted due to acute
rejection (one case) and chronic rejection (one case) respectively
Number of patients with acute cellular rejection
Seven trials reported the number of patients who had acute cellu-
lar rejection after liver transplantation Bile acids did not signifi-
cantly reduce the number of patients who experienced acute cel-
lular rejection (RR 089 95 CI 074 to 106) 93174(535)
versus 99165 (600)) There was no significant heterogeneity
(I2 = 0)
Six trials (Sama 1991 Koneru 1993 Pageaux 1995 Barnes 1997
10Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Keiding 1997 Fleckenstein 1998) compared UDCA with placebo
or no intervention and demonstrated that UDCA did not signifi-
cantly reduce the number of patients with acute cellular rejection
after liver transplantation (RR 089 95 CI 074 to 108 85
158 (538) versus 89148 (601)) Neither did the Angelico
1999 trial demonstrate significant reduction of the number of pa-
tients with acute cellular rejection with TUDCA (RR 085 95
CI 045 to 160) 816 (500) versus 1017 (588) (Analysis
17)
Subgroup analyses
Two trials (Koneru 1993 Keiding 1997) in which the patients
started bile acids intake less than three days after liver transplan-
tation did not demonstrate any significant reduction of the risk
of acute cellular rejection by bile acids (RR 084 95 CI 063 to
111) 3870 (543) versus 4164 (641) The other five tri-
als (Sama 1991 Pageaux 1995 Barnes 1997 Fleckenstein 1998
Angelico 1999) in which the patients were started on bile acid
intake three days or more after liver transplantation did not find
a significant reduction of the risk of acute cellular rejection by bile
acids (RR 092 95 CI 072 to 117) 55104 (529) versus 58
101 (574) (Analysis 18) There was no significant difference
between the two estimates
Bile acids did not significantly reduce the risk of acute cellular
rejection in the five trials (Koneru 1993 Pageaux 1995 Barnes
1997 Keiding 1997 Fleckenstein 1998) in which the patients
received treatment with bile acids less than six months (RR 087
95 CI 071 to 107) 72138 (522) versus 76128 (594)
Neither did bile acids in the two other trials (Sama 1991 Angelico
1999) in which the patients received bile acids for more than six
months (RR 094 95 CI 065 to 136) 2136 (583) versus
2337 (622) (Analysis 19) There were no significant difference
between the two estimates
Number of patients with chronic rejection
Three trials comparing UDCA versus placebo (Barnes 1997
Keiding 1997 Fleckenstein 1998) reported the number of patients
with chronic rejection after liver transplantation UDCA signifi-
cantly reduced the number of patients with chronic rejection in
the fixed-effect model analysis (RR 028 95 CI 008 to 095)
396 (31) versus 1088 (114) (Analysis 110) but not in the
random-effects model analysis (RR 030 95 CI 008 to 113) 3
96 (31) versus 1088 (114) There was no statistically signifi-
cant heterogeneity (I2 0) We performed trial sequential analysis
for the available data from three trials (Figure 3) with heterogene-
ity corrected required information size based on proportion of this
outcome of 12 in the control group a relative risk reduction of
50 in the intervention group at a type I error of 5 and a type
II error of 10 We obtained a required information size of 957
patients UDCA was not able to reach or break the trial sequential
monitoring boundary and only 183 out of 957 (19) patients
were randomised regarding this outcome
11Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Figure 3 Trial sequential analysis for the number of patients with chronic rejection at maximum follow-up
We calculated the heterogeneity-corrected required information size (HCRIS) based on a proportion of 12 of
the patients in the placebo group with chronic rejection at maximum follow-up a 50 risk ratio reduction in
the bile acid group an alpha of 5 a beta of 10 and a heterogeneity of 0 Only 184 patients have been
randomised reporting this outcome which is only 19 of the HCRIS of 957 patients The cumulative Z-score
crosses the conventional boundaries for P 005 but not the monitoring boundaries
Number of patients with steroid-resistant rejection
Four trials (Pageaux 1995 Barnes 1997 Keiding 1997
Fleckenstein 1998) reported the number of patients with steroid-
resistant rejection These trials demonstrated that UDCA did not
significantly reduce the number of patients with steroid-resistant
rejection when compared with placebo (22122 (18) versus 26
112 (232) (RR 077 95 CI 047 to 127) (Analysis 111)
There was no significant heterogeneity (I2 0)
Liver biochemistry
The Fleckenstein 1998 trial reported serum bilirubin levels after
a three-month-treatment period in 30 liver-transplanted patients
There was no statistically significant difference in serum bilirubin
levels between the UDCA group and the placebo group (MD 260
mgdl 95 CI -096 to 616 mgdl) (Analysis 112)
No data were available for other liver biochemical variables
Cost-effectiveness
One trial (Barnes 1997) with 52 liver-transplanted patients re-
ported the days of hospitalisation after liver transplantation
UDCA significantly decreased the number of days of hospitali-
sation when compared with placebo (MD -850 days 95 CI -
1667 to -033 days) (Analysis 113) We were not able to extract
other medical cost from the trials
Adverse events
Among all the included and excluded trials only four reported on
adverse events however adverse events only occurred in two of
the included trials (Barnes 1997 Keiding 1997) There were no
significant differences regarding adverse events (RR 088 95 CI
030 to 260) 6112 (54) versus 6105 (57) (Analysis 114)
In the Barnes 1997 trial diarrhoea was reported by two patients
(one in the UDCA group and one in the placebo group) In the
Keiding 1997 trial five UDCA patients and five placebo patients
stopped intake of the trial medicine because of diarrhoea or dif-
ficulties in swallowing the capsules The remaining included trial
by Angelico 1999 stated that no adverse events occurred during
the study period The excluded trial by Assy 2007 was the only
one reporting on a case of mild diarrhoea in one patient in the
12Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
intervention group No other excluded studies reported on adverse
events (see Table 1)
Quality of life
None of the included studies assessed quality of life as an outcome
Other subgroup analyses
We planned to perform subgroup analyses regarding the risk of
bias of trials the dosage of bile acid and any co-intervention
However none of the trials were considered to be of low risk of
bias they all used a similar dosage of bile acid and patients in all
trials received similar immunosuppressive treatment as co-inter-
ventions (steroids azathioprine and cyclosporine or tacrolimus)
after liver transplantation Therefore we were not able to perform
the planned subgroup analyses
Funnel plot asymmetry
We did not draw a funnel plot analysis due to the limited number
of trials included in the present review
D I S C U S S I O N
In the update of this review we included no new trials assessing
the use of bile acids for liver-transplanted patients The analyses
of the seven previously included trials showed that bile acids did
not significantly affect mortality acute cellular rejection steroid-
resistant rejection retransplantation or serum bilirubin Bile acids
might significantly decrease the length of hospital stay and the
number of patients with chronic rejection included in these tri-
als but more supportive evidence is needed The number of pa-
tients with chronic rejection was not significantly influenced by
bile acids when a random-effects model was used and length of
stay was assessed in one single trial Furthermore none of the trials
were considered to be of low risk of bias and few patients were en-
rolled Therefore our positive findings may be due to bias (Schulz
1995 Moher 1998 Kjaergard 2001 Wood 2008) or random er-
rors (Wetterslev 2008 Brok 2009 Thorlund 2009) On the other
hand we are not able to exclude type II errors (that is finding
no significant differences when in fact they exist) due to the low
number of participants Therefore this topic could be of potential
interest in future large randomised trials with adequate control of
bias
All-cause mortality at one year after liver transplantation is re-
ported to be about 20 (Thuluvath 2003) which we also ob-
served for the patients included in the present review According to
our subgroup analyses neither UDCA nor TUDCA significantly
decreased all-cause mortality We also performed a subgroup anal-
ysis regarding treatment duration but we were not able to find any
difference between short (less than six months) and long treatment
duration (six months or more) Thus bile acids do not seem to
have statistically significant effects in reducing all-cause mortal-
ity after liver transplantation We performed both worst-best-case
scenario and best-worst-case scenario analyses In the worst-best-
case scenario bile acids did not differ significantly from placebo or
no intervention regarding all-cause mortality However bile acids
significantly decreased all-cause mortality in the best-worst-case
scenario analysis However such an analysis is very extreme and
may not be realistic We have also found that UDCA may be able
to decrease the risk of chronic rejection in liver-transplanted pa-
tients but trial sequential analysis could not confirm this result
Due to a limited number of patients (Ioannidis 2001) we are not
able to exclude the possibility that it may be relevant to perform
placebo-controlled trials with low risk of bias on the use of bile
acids for liver-transplanted patients
We looked into the causes of deaths that were reported by the trials
and only one trial reported one death related to rejection At the
same time the number of retransplantations was 3 among 68 liver-
transplanted patients who received treatment with UDCA and 4
among 64 liver-transplanted patients who received treatment with
placebo We noticed that all patients in the included trials received
co-interventions of standard triple-drug regimens (steroids aza-
thioprine and cyclosporine or tacrolimus) which were able to
control the possible acute or chronic rejection and prevent deaths
due to allograft rejection (FK506 1994)
The assumption that UDCA might reduce the incidence of acute
graft rejection came from the findings that UDCA could regulate
major histocompatibility complex antigen expression in bile ducts
and liver endothelia and inhibit lymphocyte activity (Calmus
1990 Terasaki 1991 Perez 2009) However in the present review
bile acids did not significantly reduce the risk of acute cellular re-
jection in liver-transplanted patients Considering that acute cellu-
lar rejection is commonly found within a few days after liver trans-
plantation (Vierling 1992) some might argue that the adminis-
tration of bile acids was started too late to prevent acute cellular
rejection We performed subgroup analyses regarding the time bile
acids were started and no statistically significant difference was
found Furthermore bile acids were not able to decrease the risk
of steroid-resistant rejection Therefore the lack of effects of bile
acids does not seem to be due to a delayed start to bile acid ad-
ministration after liver transplantation However it is a possibility
that one should start bile acids intake before liver transplantation
A retrospective study found that rejection rates differed signifi-
cantly between patients with primary biliary cirrhosis treated with
or without UDCA before liver transplantation (Heathcote 1999)
One could argue whether UDCA-induced delay in transplantation
has an adverse effect on post-transplantation outcome Since we
did not find any prospective randomised clinical trials addressing
this issue further research might be needed Furthermore some
studies may provide an explanation why UDCA was not able to
prevent acute cellular rejection These studies found that UDCA
did not appear to change the expression of major histocompatibil-
ity complex class II antigens but rather major histocompatibility
complex class I antigens (Calmus 1990) The initial mechanism
of acute rejection is thought to be recognition of MHC class II
13Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
antigens by CD4+ T cells (Vierling 1992) Moreover the inhibi-
tion of the production of interleukin-2 by peripheral blood lym-
phocytes with UDCA (Heuman 1993) might be negated by the
immunosuppressive treatment after liver transplantation (van den
Berg 1998) so that UDCA is unable to demonstrate effects on
graft rejection In a recent study by Assy 2007 a significant re-
duction in the mean dose of immunosuppressive medications was
achieved in stable liver graft recipients treated with UDCA indi-
cating a possible influence of UDCA on rejection mechanisms
In accordance with previous systematic reviews (Chen 2003a
Chen 2007 Gong 2008) bile acids were not associated with the
occurrence of serious adverse events or any major occurrence of
adverse events
In summary our results do not support or refute the use of bile
acids (UDCA and TUDCA) additional to standard immunosup-
pressive treatment in liver-transplanted patients
A U T H O R S rsquo C O N C L U S I O N SImplications for practice
There seems to be no evidence to support or refute the use of bile
acids for liver-transplanted patients receiving standard immuno-
suppressive treatment
Implications for research
We need more randomised placebo-controlled clinical trials with
enough statistical power and low risk of bias to explore the poten-
tial effects of bile acids on chronic rejection and mortality in liver-
transplanted patients Such trials should also consider evaluation
of quality of life and length of hospitalisation Such trials may
consider starting bile acid and placebo interventions before liver
transplantation we were not able to identify any randomised trials
addressing this regimen Such trials ought to be reported accord-
ing to the CONSORT statement (wwwconsort-statementorg)
However before embarking on such trials the effects of bile acids
in other patient groups should be scrutinised as they may have
small or negative effects
A C K N O W L E D G E M E N T S
We thank all the patients and investigators who were involved in
the clinical trials mentioned in this review We thank Wendong
Chen for his work and contribution on the previous version of this
review We thank the staff of The Cochrane Hepato-Biliary Group
Editorial Team especially Dimitrinka Nikolova and Sarah Louise
Klingenberg for excellent collaboration and assistance during the
update of this review
Peer Reviewers Carlo Merkel Italy M Tomikawa Japan
Contact Editor Bodil Als-Nielsen Denmark
R E F E R E N C E S
References to studies included in this review
Angelico 1999 published data only
Angelico M Tisone G Baiocchi L Palmieri G Pisani F Negrini S
et alOne-year pilot study on tauroursodeoxycholic acid as an
adjuvant treatment after liver transplantation Italian Journal of
Gastroenterology and Hepatology 199931(6)462ndash8 [MEDLINE
10575563]
Barnes 1997 published data onlylowast Barnes D Talenti D Cammell G Goormastic M Farquhar L
Henderson M et alA randomized clinical trial of ursodeoxycholic
acid as adjuvant treatment to prevent liver transplant rejection
Hepatology 199726(4)853ndash7 [MEDLINE 9328304]
Barnes D Talenti D Goormastic M Farquhar L Cammell G
Henderson M et alUrsodeoxycholic acid (UDCA) reduces hepatic
allograft rejection after orthotopic liver transplantation (OLT) - a
prospective randomized placebo-controlled double-blind trial
Hepatology 199522149A
Fleckenstein 1998 published data only
Fleckenstein JF Paredes M Thuluvath PJ A prospective
randomized double-blind trial evaluating the efficacy of
ursodeoxycholic acid in prevention of liver transplant rejection
Liver Transplantation and Surgery 19984(4)276ndash9 [MEDLINE
9649640]
Keiding 1997 published data only
Keiding S Hockerstedt K Bjoro K Bondesen S Hjortrup A
Isoniemi H et alThe Nordic multicenter double-blind randomized
controlled trial of prophylactic ursodeoxycholic acid in liver
transplant patients Transplantation 199763(11)1591ndash4
[MEDLINE 9197351]
Koneru 1993 published data only
Koneru B Tint GS Wilson DJ Leevy CB Salen F Randomised
prospective trial of ursodeoxycholic acid in liver transplant
recipients Hepatology 199318336A
Pageaux 1995 published data only
Pageaux GP Blanc P Perrigault PF Navarro F Fabre JM Souche B
et alFailure of ursodeoxycholic acid to prevent acute cellular
rejection after liver transplantation Journal of Hepatology 199523
(2)119ndash22 [MEDLINE 7499781]
Sama 1991 published data only
Sama C Mazziotti A Grigioni W Morselli AM Chianura A
Stefanini GF et alUrsodeoxycholic acid administration does not
14Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
prevent rejection after OLT Journal of Hepatology 199113(Suppl
2)68
References to studies excluded from this review
Assy 2007 published data only
Assy N Adams PC Myers P Simon V Minuk GY Wall W et
alRandomized controlled trial of total immunosuppression
withdrawal in liver transplant recipients role of ursodeoxycholic
acid Transplantation 200783(12)1571ndash6 [MEDLINE
17589339]
Clavien 1996 published data only
Clavien PA Sharara AI Camargo CA Jr Harland RC Fitz JG
Evidence that ursodeoxycholic acid prevents steroid-resistant
rejection in adult liver transplantation Clinical Transplantation
199610(6 Pt 2)658ndash62 [MEDLINE 8996761]
Friman 1992 published data only
Friman S Persson H Schersten T Svanvik J Karlberg I Adjuvant
treatment with ursodeoxycholic acid reduces acute rejection after
liver transplantation Transplantation Proceedings 199224(1)
389ndash90 [MEDLINE 1539328]
Heathcote 1999 published data onlylowast Heathcote EJ Stone J Cauch-Dudek K Poupon R Chazouilleres
O Lindor KD et alEffect of pretransplantation ursodeoxycholic
acid therapy on the outcome of liver transplantation in patients
with primary biliary cirrhosis Liver Transplantation and Surgery
19995(4)269ndash74 [MEDLINE 10388499]
Henriksson 1991 published data only
Henriksson BA Persson H Friman S Wangberg B Svanvik J
Karlberg I Adjuvant ursodeoxycholic acid prevents acute rejection
in liver transplant recipients Transplantation Proceedings 199123
(3)1971 [MEDLINE 2063453]
Persson 1990 published data only
Persson H Friman S Schersten T Svanvik J Karlberg I
Ursodeoxycholic acid for prevention of acute rejection in liver
transplant recipients Lancet 1990336(8706)52ndash3 [MEDLINE
1973232]
Rafael 1995 published data only
Rafael E Duraj F Rudstrom H Wilczek H Ericzon B Effect of
ursodeoxycholic acid treatment for cholestasis in liver transplant
recipients Transplantation Proceedings 199527(6)3501ndash2
[MEDLINE 8540069]
Sama 1998 published data only
Sama C Morselli-Labate AM Grazi GL Mastroianni A Danesi G
Pianta P et alUrsodeoxycholic acid in liver transplantation effect
on cholestasis and rejection Gastroenterology 1998114(4 Suppl)
A1332
Additional references
Adams 1990
Adams DH Neuberger JM Patterns of graft rejection following
liver transplantation Journal of Hepatology 199010(1)113ndash9
[MEDLINE 2407770]
Al-Quaiz 1994
Al-Quaiz M OrsquoGrady J Tredger J Williams R Variable effect of
ursodeoxycholic acid on cyclosporin absorption after orthotopic
liver transplantation Transplant International 19947(3)190ndash4
[MEDLINE 8060468]
Armstrong 1982
Armstrong MJ Carey MC The hydrophobic-hydrophilic balance
of bile salt Inverse correlation between reverse phase high
performance liquid chromatographic mobilities and micellar
cholesterol-solubilizing capacities Journal of Lipid Research 1982
23(1)70ndash80 [MEDLINE 7057113]
Ascher 1988
Ascher NL Stock PG Baumgardner GL Payne WD Najarian JS
Infection and rejection of primary hepatic transplant in 93
consecutive patients treated with triple immunosuppressive therapy
Surgery Gynecology amp Obstetrics 1988167(6)474ndash84
[MEDLINE 3055368]
Brok 2008
Brok J Thorlund K Gluud C Wetterslev J Trial sequential
analysis reveals insufficient information size and potentially false
positive results in many meta-analyses Journal of Clinical
Epidemiology 200861(8)763ndash9 [MEDLINE 18411040]
Brok 2009
Brok J Thorlund K Wetterslev J Gluud C Apparently conclusive
meta-analysis may be inconclusive - Trial sequential analysis
adjustment of random error risk due to repetitive testing of
accumulating data in apparently conclusive neonatal meta-analysis
International Journal of Epidemiology 200938(1)298ndash303
[MEDLINE 18824466]
Calmus 1990
Calmus Y Gane P Rouger P Poupon R Hepatic expression of class
I and class II major histocompatibility complex molecules in
primary biliary cirrhosis effect of ursodeoxycholic acid Hepatology
199011(1)12ndash5 [MEDLINE 2403961]
Calmus 1992
Calmus Y Arvieux C Gane P Boucher E Nordlinger B Rouger P
et alCholestasis induces major histocompatibility complex class I
expression in hepatocytes Gastroenterology 1992102(4 Pt 1)
1371ndash7 [MEDLINE 1551542]
Chen 2003a
Chen W Gluud C Bile acids for primary sclerosing cholangitis
Cochrane Database of Systematic Reviews 2003 Issue 2 [DOI
10100214651858CD003626]
Chen 2007
Chen W Liu J Gluud C Bile acids for viral hepatitis Cochrane
Database of Systematic Reviews 2007 Issue 4 [DOI 101002
14651858CD003181pub2]
Cheng 2002
Cheng K Ashby D Smyth R Ursodeoxycholic acid for cystic
fibrosis-related liver disease Cochrane Database of Systematic
Reviews 2002 Issue 2 [DOI 10100214651858CD000222]
Corbani 2008
Corbani A Burroughs AK Intrahepatic cholestasis after liver
transplantation Clinics in Liver Disease 200812(1)111ndash29
[MEDLINE 18242500]
DeMets 1987
DeMets DL Methods for combining randomised clinical trials
strengths and limitations Statistics in Medicine 19876(3)341ndash50
[MEDLINE 3616287]
15Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
DerSimonian 1986
DerSimonian R Laird N Meta-analysis in clinical trials Controlled
Clinical Trials 19867(3)177ndash88 [MEDLINE 3802833]
Egger 1997
Egger M Davey Smith G Schneider M Minder C Bias in meta-
analysis detected by a simple graphical test BMJ (Clinical Research
Ed) 1997315(7109)629ndash34 [MEDLINE 9310563]
Ericzon 1990
Ericzon BG Eusufzai S Kubota K Einarsson K Angelin B
Characteristics of biliary lipid metabolism after liver
transplantation Hepatology 199012(5)1222ndash8 [MEDLINE
2227822]
FK506 1994
The US Multicenter FK506 Liver Study Group A comparison of
tacrolimus (FK506) and cyclosporine for immunosuppression in
liver transplantation New England Journal of Medicine 1994331
(17)1110ndash5 [MEDLINE 7523946]
Friman 1994
Friman S Svanvik J A possible role of ursodeoxycholic acid in liver
transplantation Scandinavian Journal of Gastroenterology 1994204
62ndash4 [MEDLINE 7824880]
Fuchs 1999
Fuchs M Stange EF Metabolism of bile acids In Johannes
Bircher Jean-Pierre Benhamou Neil McIntyre Mario Rizzetto
Juan Rodes editor(s) Oxford Textbook of Clinical Hepatology 2
Vol 1 Oxford Oxford University Press 1999223ndash56
Fusai 2006
Fusai G Dhaliwal P Rolando N Sabin CA Patch D Davidson BR
et alIncidence and risk factors for the development of prolonged
and severe intrahepatic cholestasis after liver transplantation Liver
Transplantation 200612(11)1626ndash33 [DOI 101002lt20870]
Gluud 2001
Gluud C Alcoholic hepatitis no glucocorticosteroids In
Leuschner U James OFW Dancygier H editor(s) Steatohepatitis
(NASH and ASH) Falk Symposium 121 Lancaster Kluwer
Academic Publisher 2001322ndash42
Gluud 2010
Gluud C Nikolova D Klingenberg SL Alexakis N Als-Nielsen B
Colli A et alCochrane Hepato-Biliary Group About The
Cochrane Collaboration (Cochrane Review Groups (CRGs))
2010 Issue 1 Art No LIVER
Gong 2008
Gong Y Huang ZB Christiansen E Gluud C Ursodeoxycholic
acid for primary biliary cirrhosis Cochrane Database of Systematic
Reviews 2008 Issue 3 [DOI 101002
14651858CD000551pub2]
Haddad 2006
Haddad EM McAlister VC Renouf E Malthaner R Kjaer MS
Gluud LL Cyclosporin versus tacrolimus for liver transplanted
patients Cochrane Database of Systematic Reviews 2006 Issue 4
[DOI 10100214651858CD005161pub2]
Heuman 1993
Heuman DM Hepatoprotective properties of ursodeoxycholic acid
Gastroenterology 1993104(6)1865ndash9 [MEDLINE 8500748]
Higgins 2008
Higgins PTJ Green S editors Cochrane Handbook for Systematic
Reviews of Interventions West Sussex England Wiley-Blackwell
2008
Hirschfield 2009
Hirschfield GM Gibbs P Griffiths WJH Adult liver
transplantation what non-specialists need to know BMJ (Clinical
Research Ed) 2009338(b1670)1321ndash7 [DOI 101136
bmjb1670]
Hussain 2002
Hussain HK Nghiem HV Imaging of hepatic transplantation
Clinics in Liver Disease 20026(1)247ndash70 [MEDLINE
11933592]
ICH-GCP 1997
International Conference on Harmonisation Expert Working
Group Code of Federal Regulations amp International Conference on
Harmonization Guidelines Media Parexel Barnett 1997
Ioannidis 2001
Ioannidis JPA Lau J Evolution of treatment effects over time
Empirical insight from recursive cumulative meta analyses
Proceedings of the National Academy of Sciences 200198(3)831ndash6
IWP 1995
International Working Party Terminology for hepatic allograft
rejection Hepatology 199522(2)648ndash54 [MEDLINE 7635435]
Kjaergard 2001
Kjaergard LL Villumsen J Gluud C Reported methodological
quality and discrepancies between large and small randomised trials
in meta-analyses Annals of Internal Medicine 2001135(11)982ndash9
[MEDLINE 11730399]
Klintmalm 1989
Klintmalm GB Nery JR Husberg BS Gonwa TA Tillery GW
Rejection in liver transplantation Hepatology 198910(6)978ndash85
[MEDLINE 2583691]
Knechtle 2009
Knechtle SJ Kwun J Unique aspects of rejection and tolerance in
liver transplantation Seminars in Liver Disease 200929(1)91ndash101
[MEDLINE 19235662]
Krams 1993
Krams SM Ascher NL Martinez OM New immunologic insights
into mechanisms of allograft rejection Gastroenterology Clinics of
North America 199318(2)374ndash7 [MEDLINE 8509176]
Lan 1983
Lan KKG DeMets DL Discrete sequential boundaries for clinical
trials Biometrika 198370659ndash63
Merion 1989
Merion RM Gorski DH Burtch GD Turcotte JG Colletti LM
Campbell DA Jr Bile refeeding after liver transplantation and
avoidance of intravenous cyclosporine Surgery 1989106(4)
604ndash9 [MEDLINE 2799635]
Moher 1998
Moher D Pham B Jones A Cook DJ Jadad AR Moher M et
alDoes quality of reports of randomised trials affect estimates of
intervention efficacy reported in meta-analyses Lancet 1998352
(9128)609ndash13 [MEDLINE 9746022]
16Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Neuberger 1999
Neuberger J Incidence timing and risk factors for acute and
chronic rejection Liver Transplantation and Surgery 19995(4 Suppl
1)S30ndashS36 [MEDLINE 10431015]
Okolicsanyi 1986
Okolicsanyi L Lirussi F Strazzabosco M Jemmolo RM Orlando R
Nassuato G et alThe effect of drugs on bile flow and composition
An overview Drugs 198631(5)430ndash48 [MEDLINE 2872047]
Palmer 1972
Palmer RH Bile acids liver injury and liver disease Archives of
Internal Medicine 1972130(4)606ndash17 [MEDLINE 4627840]
Perez 2009
Perez MJ Briz O Bile-acid-induced cell injury and protection
World Journal of Gastroenterology 200915(14)1677ndash89
[MEDLINE 19360911]
Pogue 1997
Pogue JM Yusuf S Cumulating evidence from randomized trials
Utilizing sequential monitoring boundaries for cumulative meta-
analysis Controlled Clinical Trials 199718(6)580ndash93
[MEDLINE 9408720]
Pogue 1998
Pogue J Yusuf S Overcoming the limitations of current meta-
analysis of randomised controlled trials Lancet 1998351(9095)
45ndash52 [MEDLINE 9433436]
RevMan 2008
The Nordic Cochrane Centre The Cochrane Collaboration
Review Manager (RevMan) 50 Copenhagen The Nordic
Cochrane Centre The Cochrane Collaboration 2008
Royle 2003
Royle P Milne R Literature searching for randomized controlled
trials used in Cochrane reviews rapid versus exhaustive searches
International Journal of Technology Assessment in Health Care 2003
19(4)591ndash603
Schulz 1995
Schulz KF Chalmers I Hayer R Altman D Empirical evidence of
bias JAMA 1995273(5)408ndash12 [MEDLINE 7823387]
Sharara 1995
Sharara AI Camargo CA Clavien PA Ursodeoxycholic acid
prevents steroid resistant rejection in liver transplant recipients
Gastroenterology 1995108A1168
Sholmerich 1984
Sholmerich J Becher MS Schmidt KH Schubert R Kremer B
Felhaus S et alInfluence of hydroxylation and conjugation of bile
salts on their membrane damaging properties Hepatology 19844
(4)661ndash7 [MEDLINE 6745854]
Soderdahl 1998
Soderdahl G Nowak G Duraj F Wang FH Einarsson C Ericzon
BG Ursodeoxycholic acid increased bile flow and affects bile
composition in the early postoperative phase following liver
transplantation Transplantation International 199811(Suppl 1)
S231ndashS238 [MEDLINE 9664985]
Terasaki 1991
Terasaki S Nakanuma Y Ogino H Unoura M Kobayashi K
Hepatocellular and biliary expression of HLA antigens in primary
biliary cirrhosis before and after ursodeoxycholic acid therapy
American Journal of Gastroenterology 199186(9)1194ndash9
[MEDLINE 1882800]
Thalheimer 2002
Thalheimer U Capra F Liver transplantation making the best out
of what we have Digestive Diseases and Sciences 200247(5)
945ndash53 [MEDLINE 12018919]
Thorlund 2009
Thorlund K Devereaux PJ Wetterslev J Guyatt G Ioannidis JP
Thabane L et alCan trial sequential monitoring boundaries reduce
spurious inferences from meta-analyses International Journal of
Epidemiology 200938(1)276ndash86 [MEDLINE 18824467]
Thuluvath 2003
Thuluvath PJ Yoo HY Thompson RE A model to predict survival
at one month one year and five years after liver transplantation
based on pretransplant clinical characteristics Liver Transplantation
20039(5)527ndash32 [MEDLINE 12740799]
van den Berg 1998
van den Berg AP Twilhaar WN Mesander G van Son WJ van der
Bij W Klompmaker IJ et alQuantitation of immunosuppression
by flow cytometric measurement of the capacity of T cells for
interleukin-2 production Transplantation 199865(8)1066ndash71
[MEDLINE 9583867]
Vierling 1992
Vierling J Immunologic mechanisms of hepatic allograft rejection
Seminars in Liver Disease 199212(1)16ndash27 [MEDLINE
1570548]
Wetterslev 2008
Wetterslev J Thorlund K Brok J Gluud C Trial sequential
analysis may establish when firm evidence is reached in cumulative
meta-analysis Journal of Clinical Epidemiology 200861(1)64ndash75
[MEDLINE 18083463]
Wiesner 1992
Wiesner RH Acute cellular rejection following liver
transplantation incidence risk factors and outcome in the
NIDDK Liver Transplant Database (LTD) study Gastroenterology
1992102A910
Wood 2008
Wood L Egger M Gluud LL Schulz KF Juni P Altman DG et
alEmpirical evidence of bias in treatment effect estimates in
controlled trials with different interventions and outcomes meta-
epidemiological study BMJ (Clinical Research Ed) 2008336
(7644)601ndash5 [MEDLINE 18316340]
Yoshikawa 1998
Yoshikawa M Matsui Y Kawamoto H Toyohara M Matsumura
K Yamao J et alIntragastric administration of ursodeoxycholic
acid suppresses immunoglobulin secretion by lymphocytes from
liver but not from peripheral blood spleen or Peyerrsquos patches in
mice International Journal of Immunopharmacology 199820(1-3)
29ndash38 [MEDLINE 9717080]
References to other published versions of this review
17Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Chen 2003b
Chen W Gluud C Bile acids for liver transplanted patients
Cochrane Database of Systematic Reviews 2005 Issue 3 [DOI
10100214651858CD005442]lowast Indicates the major publication for the study
18Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
C H A R A C T E R I S T I C S O F S T U D I E S
Characteristics of included studies [ordered by study ID]
Angelico 1999
Methods Study design open-label randomised one-year pilot study
Participants Country Italy
Publication language English
Inclusion criteria
- patients who underwent liver transplantation from April 1994 to December 1994
Exclusion criteria
- not mentioned
Participants
Two patients in TUDCA group and two patients in control group were excluded from
the basic information of participants by the study due to withdrawal
- TUDCA group (n = 14)
Mean age (years +- SD)
467 +- 84
Ratio of sex (malefemale) 122
Origins of liver diseases
hepatitis C cirrhosis (9) hepatitis B cirrhosis (2) hepatitis B and C cirrhosis (1) cryp-
togenic cirrhosis (2) alcoholic cirrhosis (0) Wilson cirrhosis (0)
- Control group (n = 15)
Mean age (years +- SD)
474 +- 74
Ratio of sex (malefemale) 123
Origins of liver diseases
hepatitis C cirrhosis (7) hepatitis B cirrhosis (2) hepatitis B and C cirrhosis (2) cryp-
togenic cirrhosis (2) alcoholic cirrhosis (1) Wilson cirrhosis (1)
Interventions TUDCA group
- Dose 500 mgday in two divided doses
- Route orally
- Duration the treatment was started on day 5 after transplantation and continued for
one year
Control group
- no treatment
Co-interventions all patients received standard triple-drug regimens (steroids azathio-
prine and cyclosporine or tacrolimus)
Outcomes All cause mortality
Number of patients with rejection after liver transplantation
Notes Letter was sent to the authors in September 2009 A reply with additional information
was received shortly after
Risk of bias
19Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Angelico 1999 (Continued)
Item Authorsrsquo judgement Description
Adequate sequence generation Yes Computer generated table
Allocation concealment Unclear No information provided
Blinding No Not performed
Incomplete outcome data addressed
All outcomes
Yes Withdrawal two patients from the
TUDCA group and two patients from the
placebo group Three of them died due to
transplant non-function in the first postop-
erative week and one patient was regrafted
due to thrombosis of hepatic artery
Free of selective reporting Unclear Post-transplant cholestasis and liver bio-
chemistry specified as outcomes Differ-
ence reported as not significant but no ac-
tual data given
Sample size calculation No Not reported
Intention-to-treat analysis No Not stated and not used
Baseline imbalance Unclear Not enough information provided
Early stopping of trial Unclear Not enough information provided
Barnes 1997
Methods Study design randomised placebo-controlled double-blind trial
Participants Country United States
Publication language English
Inclusion criteria
- patients aged 18 years or older who underwent liver transplantation at the Cleveland
Clinic Foundation from April 1992 through June of 1994
Exclusion criteria
- patients who were found to have cancer at surgically resected margins of the biliary
tree
- patents who underwent retransplantation
Participants
- UDCA group (n = 28)
Mean age (years +- SD)
505 +- 116
Ratio of sex (malefemale) 1810
Child class A 7
20Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Barnes 1997 (Continued)
B 13
and C 8
Origins of liver diseases Laennecrsquos cirrhosis 4
PBC 3
cryptogenic cirrhosis 6
hepatitis Ccirrhosis 4
hepatitis Bcirrhosis 3
autoimmune hepatitis with cirrhosis 3
PSC 2
other 3
- Placebo group (n = 24)
Mean age (years +- SD)
507 +- 93
Ratio of sex (malefemale) 159
Child class A 6
B 14
and C 4
Origins of liver diseases Laennecrsquos cirrhosis 9
PBC 5
cryptogenic cirrhosis 1
hepatitis Ccirrhosis 1
hepatitis Bcirrhosis 1
autoimmune hepatitis with cirrhosis 1
PSC 2
other 4
Interventions UDCA group
- Dose 10-15 mgkg body weightday in divided doses
- Route orally
- Duration immediately after intestinal transit recovery usually between postoperative
days three and five and continue for three months
Placebo group
- identical-appearing capsules administered in the same quantity and manner
Co-interventions all patients received standard triple-drug regimens (steroids azathio-
prine and cyclosporine or tacrolimus)
Outcomes All cause mortality
Number of patients with acute cellular rejection
Number of patients with chronic rejection
Number of patients with steroid-resistant rejection
Number of days of hospitalisation
Adverse events
Notes Letter was sent to the authors in September 2009 A reply with additional information
was received shortly after
Risk of bias
Item Authorsrsquo judgement Description
21Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Barnes 1997 (Continued)
Adequate sequence generation Yes Computer generated table
Allocation concealment Unclear No information provided
Blinding Yes Quote ldquorandomised to receive either
UDCA or an identical placebo capsulerdquo
Incomplete outcome data addressed
All outcomes
Yes Mean follow-up time 18 months Ten pa-
tients withdrawn from study 6 in UDCA
group and 4 in placebo group Reasons
for withdrawal were reported Four patients
died in the placebo group
Free of selective reporting Yes All expected outcomes reported
Sample size calculation Unclear The trial reported the method of sample
size calculation but the actual number of
patients needed was not reported
Intention-to-treat analysis Yes Stated and used
Baseline imbalance Unclear Not enough information provided
Early stopping of trial Unclear The number of patients needed to gain the
actual power was not reported Whether
the trial was terminated early is not clear
Fleckenstein 1998
Methods Study design prospective randomised double-blind trial
Participants Country United States
Publication language English
Inclusion criteria
- patients who underwent liver transplantation at the Johns Hopkins Hospital
Exclusion criteria
- patients who were under 18 years old undergoing repeat transplantation had primary
graft nonfunction or refused consent
Participants
- UDCA group (n = 14)
Mean age (years +- SD)
443 +- 127
Ratio of sex (malefemale) 68
Origins of liver diseases hepatitis C 6
alcohol 2
autoimmune 1
PBC 2
22Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Fleckenstein 1998 (Continued)
PSC 1
autoimmune cholangiopathy 1
hepatitis B 1
- Placebo group (n = 16)
Mean age (years +- SD)
496 +- 109
Ratio of sex (malefemale) 124
Origins of liver diseases hepatitis C 3
alcohol 3
autoimmune 3
PBC 1
PSC 2
cryptogenic 2
hepatitis B 1
alpha1-antitrypsin deficiency 1
Interventions UDCA group
- Dose 15 mgkg body weightday in divided doses
- Route orally
- Duration immediately after intestinal transit recovery usually between postoperative
days three and five and continue for three months
Placebo group
- Identical-appearing capsules administered in the same quantity and manner
Co-interventions all patients received standard triple-drug regimens (steroids azathio-
prine and cyclosporine or tacrolimus)
Outcomes All cause mortality
Number with retransplantation
Number of patients with acute cellular rejection
Number of patients with chronic rejection
Serum bilirubin levels at the end of treatment
Notes Follow-up time nine months
Letter was sent to the authors in September 2009 No reply was received
Risk of bias
Item Authorsrsquo judgement Description
Adequate sequence generation Unclear No information provided
Allocation concealment Unclear No information provided
Blinding Yes Method of blinding not described but
probably adequate
Incomplete outcome data addressed
All outcomes
Yes Withdrawal one patient from the UDCA
group and two patients from the placebo
group because of capsule size
23Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Fleckenstein 1998 (Continued)
Free of selective reporting Unclear Outcomes were not completely described
Sample size calculation No Not reported
Intention-to-treat analysis Yes Quote ldquoThree patients withdrew after in-
clusionThey were included in the statis-
tical analysisrdquo
Baseline imbalance Unclear Not enough information provided
Early stopping of trial Unclear Not enough information provided
Keiding 1997
Methods Study design prospective randomised placebo-controlled multicenter study
Participants Country Denmark Finland Norway and Sweden
Publication language English
Inclusion criteria
- patients who underwent liver transplantation in Denmark Finland Norway and Swe-
den from September 1 1992 to May 31 1994
Exclusion criteria
- patients with malignant diseases
Participants
The age of the children ranged from 0 to 13 years (median 15) and the age of adults
ranged from 14 to 59 years old (median 44) MaleFemale ratio was 96 for children and
4344 for adults
- UDCA group (n = 54)
Origins of liver diseases
paracetamol intoxication 1 hepatitis B 1 autoimmune hepatitis 0 biliary atresia 2
metabolic diseases 7 neonatal hepatitis 2 PBC 13 post hepatitis cirrhosis 8 PSC 3
cryptogenic cirrhosis 7 alcoholic cirrhosis 2 other reasons 8
- Placebo group (n = 48)
Origins of liver diseases paracetamol intoxication 1 hepatitis B 0 autoimmune hepatitis
1 biliary atresia 3 metabolic diseases 11 neonatal hepatitis 0 PBC 7 post hepatitis
cirrhosis 5 PSC 7 cryptogenic cirrhosis 2 alcoholic cirrhosis 6 other reasons 5
Interventions UDCA group
- Dose 15 mgkg body weightday in two or three divided doses
- Route orally
- Duration immediately after intestinal transit recovery usually between postoperative
days three and five and continue for three months
Placebo group
- Identical-appearing capsules administered in the same quantity and manner
Co-interventions all patients received standard triple-drug regimens (steroids azathio-
prine and cyclosporine or tacrolimus)
24Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Keiding 1997 (Continued)
Outcomes All cause mortality
Number of deaths related to rejection
Number of patients with acute cellular rejection
Number of patients with chronic rejection
Number of patients with steroid-resistant rejection
Adverse events
Notes Letter was sent to the authors in September 2009 No reply was received
Risk of bias
Item Authorsrsquo judgement Description
Adequate sequence generation Unclear Patients were randomised at a ratio of 11
Allocation concealment Yes Quote ldquo The allocation was performed in
blocks of 10 patients using the sealed serial
envelope methodrdquo
Blinding Yes Quote ldquoThe UDCA and the placebo cap-
sules had identical appearance and tasterdquo
Incomplete outcome data addressed
All outcomes
Yes Follow-up time 12 months Five UDCA
patients and five placebo patients withdrew
from study Reasons were reported
Free of selective reporting Unclear Insufficient information
Sample size calculation Yes Performed and allowed for a difference in
the incidence of at least one episode of
acute rejection of 50 between the treat-
ment and placebo groups with 90 statisti-
cal power and a significance level of P value
less than 005 The calculated sample size
was 80 patients
Intention-to-treat analysis Yes Stated and used
Baseline imbalance Yes The study seems to be free of baseline im-
balance
Early stopping of trial Yes Study attained the pre-specified sample
size
25Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Koneru 1993
Methods Study design randomised controlled trial
Participants Country United States
Publication language English
Inclusion criteria
- patients who underwent liver transplantation
Exclusion criteria
- not mentioned
Participants
- UDCA group (n = 16)
Mean age (years +- SD)
no information
Ratio of sex (malefemale) no information
Origins of liver diseases
no information
- Control group (n = 16)
Mean age (years +- SD)
no information
Ratio of sex (malefemale) no information
Origins of liver diseases
no information
Interventions UDCA group
- Dose 900 mgday
- Route orally
- Duration immediately after intestinal transit recovery usually between postoperative
days three and five and continue for three months
Control group
- no treatment
Co-interventions all patients received standard triple-drug regimens (steroids azathio-
prine and cyclosporine)
Outcomes Number of patients with retransplantation due to rejection
Number of patients with rejection episodes
Notes Abstract
Letter was sent to the authors in September 2009 No reply was received
Risk of bias
Item Authorsrsquo judgement Description
Adequate sequence generation Unclear No information provided
Allocation concealment Unclear No information provided
Blinding No Not performed
26Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Koneru 1993 (Continued)
Incomplete outcome data addressed
All outcomes
Unclear The study gives the impression that there
were no withdrawals but this was not ex-
plicitly stated
Free of selective reporting Unclear Insufficient information provided
Sample size calculation No Not performed
Intention-to-treat analysis Unclear No information provided
Baseline imbalance Unclear Not enough information provided
Early stopping of trial Unclear Not enough information provided
Pageaux 1995
Methods Study design double-blind randomised study
Participants Country France
Publication language English
Inclusion criteria
- patients who underwent liver transplantation
Exclusion criteria
- not mentioned
Participants
- UDCA group (n=26)
Mean age (years +- SD)
47 +- 10
Ratio of sex (malefemale) 179
Origins of liver diseases alcoholic cirrhosis 14
post-hepatic B cirrhosis 2
post-hepatitis C cirrhosis 4
PBC 2
liver cancer 2
fulminant hepatitis 1
miscellaneous 1
- Placebo group (n = 24)
Mean age (years +- SD)
51+- 9
Ratio of sex (malefemale) 159
Origins of liver diseases alcoholic cirrhosis 10
post-hepatic B cirrhosis 0
post-hepatic C cirrhosis 6
PBC 3
liver cancer 4
fulminant hepatitis 0
miscellaneous 1
27Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Pageaux 1995 (Continued)
Interventions UDCA group
- Dose 600 mgday in three divided doses
- Route orally
- Duration immediately after intestinal transit recovery usually between postoperative
days three and five and continue for two months
Placebo group
- identical-appearing capsules administered in the same quantity and manner
Co-interventions all patients received standard triple-drug regimens (steroids azathio-
prine and cyclosporine or tacrolimus)
Outcomes Number of patients with acute cellular rejection
Number of patients with steroid-resistant rejection
Notes Letter was sent to the authors in September 2009 No reply was received
Risk of bias
Item Authorsrsquo judgement Description
Adequate sequence generation Unclear No information provided
Allocation concealment Unclear No information provided
Blinding Unclear Method of blinding not described
Incomplete outcome data addressed
All outcomes
Yes Five patients died from non-immunologi-
cal causes before the end of the first month
and were excluded from the study Reasons
were reported
Free of selective reporting Unclear Not enough information provided
Sample size calculation No Not performed
Intention-to-treat analysis No Not stated and not used
Baseline imbalance Unclear Not enough information provided
Early stopping of trial Unclear Not enough information provided
Sama 1991
Methods Study design randomised controlled trial
Participants Country Italy
Publication language English
Inclusion criteria
28Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Sama 1991 (Continued)
- patients who underwent liver transplantation
Exclusion criteria
- not mentioned
Participants
- UDCA group (n = 20)
Mean age (years +- SD)
no information
Ratio of sex (malefemale) no information
Origins of liver diseases
no information
- Control group (n = 20)
Mean age (years +- SD)
no information
Ratio of sex (malefemale) no information
Origins of liver diseases
no information
Interventions UDCA group
- Dose 600 mgday in two divided doses
- Route orally
- Duration immediately after intestinal transit recovery usually between postoperative
day five and day seven and continue for six months
Control group
- no treatment
Co-interventions all patients received standard immunosuppressive treatment (steroids
and cyclosporine)
Outcomes All cause mortality
Number of patients with acute cellular rejection
Notes Abstract
Letter was sent to the authors in September 2009 No reply was received
Risk of bias
Item Authorsrsquo judgement Description
Adequate sequence generation Unclear A randomisation list was performed before
patients were admitted to the trial (infor-
mation from principal author)
Allocation concealment Unclear No information provided
Blinding Unclear The principle author provided information
that the study was made according to a
single-blind randomised protocol The pri-
mary outcome was the occurrence of biopsy
proven rejection episodes The pathologists
were blind but the patients were not
29Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Sama 1991 (Continued)
Incomplete outcome data addressed
All outcomes
Unclear Five patients from the UDCA group and
six patients from the placebo group were
excluded Reasons for exclusion were not
fully stated
Free of selective reporting No Data about survival of patients were not
adequately reported
Sample size calculation No Not performed
Intention-to-treat analysis No Not stated and not used
Baseline imbalance Unclear Basic characteristics of patients not re-
ported
Early stopping of trial Unclear Not enough information provided
UDCA = ursodeoxycholic acid
TUDCA = tauroursodeoxycholic acid
PBC = primary biliary cirrhosis
PSC = primary sclerosing cholangitis
OKT3 = anti-CD3 monoclonal antibody
Characteristics of excluded studies [ordered by study ID]
Assy 2007 A randomised controlled trial that included only recipients of liver transplantation with stable graft function and
no episodes of rejection for at least 2 years that were then offered total immunosuppression withdrawal Fourteen
patients received UDCA (15 mgkg body weightday) and 12 received placebo Rejection occurred in 43 and
75 of patients respectively (no significant difference) None developed chronic rejection After follow-up two
patients were free of immunosuppression 80 were steroid free and 50 were able to reduce their dose of
cyclosporine
Clavien 1996 Case series Fifty consecutive liver-transplanted patients were treated with a standard cyclosporine immunosup-
pressive regimen Twenty three of the 43 survivors developed an episode of rejection and UDCA (10 mgkg
weightday) was initiated Only one patient had a second episode of rejection
Friman 1992 Observational study Thirty-three liver-transplanted patients received 10 mg UDCAkg body weightday for
median of 10 months (range four to 21 months) Eight historical liver-transplanted patients served as control
group The rejection incidence was significantly lower in the patients who received the treatment with UDCA
Biochemistry one month after transplantation demonstrated significantly lower average values of aminotrans-
ferases and alkaline phosphatases in patients treated with UDCA than in the control group
30Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
Heathcote 1999 Observational study From 1987 to 1996 37 UDCA treated and 53 placebo treated patients with primary biliary
cirrhosis were referred for transplantation Posttransplantation survival rates at one month were 939 in the
UDCA group and 884 in the placebo group and one year survival rates were 903 and 784 respectively
(no significant differences) However rejection (type not defined - a secondary outcome measure) occurred
significantly less often in the UDCA group (429) than in placebo group (688)
Henriksson 1991 Observational study All patients in this study were given sequential quadruple immunosuppression with anti-
lymphocyte globulin azathioprine steroids and cyclosporine All patients with primary graft function (n = 11)
were treated with 10 mg UDCAkg body weightday starting during the first postoperative week Patients who
received liver transplantation in the first 6 months of 1989 (n = 8) served as controls In the control group one
patient died after 9 months with chronic graft dysfunction and six patients had rejection episodes during the
first postoperative month All patients in the UDCA group were alive without rejection episodes
Persson 1990 Observational study All 11 adult patients transplanted between August 1989 and January 1990 with primary
graft function were treated with 10 mg UDCA kg body weightday Eight patients transplanted during the first
half of 1989 served as control UDCA was started during the first postoperative week and the treatment was
continued for six months All patients in the UDCA treated group survived with satisfactory graft function In
the control group six patients had at least one rejection episode needing treatment during the first postoperative
month
Rafael 1995 Observational study Seventeen patients who underwent liver transplantation between February 1990 and April
1993 and developed biliary complications after transplantation were retrospectively analysed regarding treatment
with UDCA UDCA was given in a dose of 500 to 1000 mgday Ten patients were treated for at least one year while
seven patients were treated for 14 to 250 days UDCA significantly improved gammaglutamyl transpeptidase in
liver graft recipients with biliary complications There was also a trend towards improvement in serum bilirubin
and alanine transaminase values
Sama 1998 Observational study Thirty-four patients who underwent liver transplantation between January 1995 and June
1996 were included in the study Seventeen were treated with UDCA 10 mgkg body weightday during 6
months while 17 served as controls on the basis of having undergone liver transplantation closest to UDCA
patients A significant decrease in serum bilirubin levels was observed in UDCA patients There was a significantly
higher incidence of recurrent hepatitis in the control group
UDCA ursodeoxycholic acid
31Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
D A T A A N D A N A L Y S E S
Comparison 1 Bile acids for liver-transplanted patients
Outcome or subgroup titleNo of
studies
No of
participants Statistical method Effect size
1 All-cause mortality at maximum
follow-up
5 257 Risk Ratio (M-H Fixed 95 CI) 085 [053 136]
11 UDCA versus placebo or
no treatment
4 224 Risk Ratio (M-H Fixed 95 CI) 080 [049 130]
12 TUDCA versus no
treatment
1 33 Risk Ratio (M-H Fixed 95 CI) 159 [030 833]
2 All-cause mortality worst-best
case and best-worst case
scenarios
5 Risk Ratio (M-H Fixed 95 CI) Subtotals only
21 Worst-best case scenario 5 257 Risk Ratio (M-H Fixed 95 CI) 130 [086 196]
22 Best-worst case scenario 5 257 Risk Ratio (M-H Fixed 95 CI) 058 [038 090]
3 Subgroup analyses all-cause
mortality at maximum
follow-up according to time of
start of bile acids
5 257 Risk Ratio (M-H Fixed 95 CI) 085 [053 136]
31 Less than three days after
transplantation
1 102 Risk Ratio (M-H Fixed 95 CI) 124 [061 254]
32 Three days or more after
transplantation
4 155 Risk Ratio (M-H Fixed 95 CI) 063 [033 120]
4 Subgroup analyses all cause
mortality at maximum
follow-up according to
treatment duration
5 257 Risk Ratio (M-H Fixed 95 CI) 085 [053 136]
41 Less than six months 3 184 Risk Ratio (M-H Fixed 95 CI) 078 [045 138]
42 Six months or more 2 73 Risk Ratio (M-H Fixed 95 CI) 102 [043 240]
5 Number of deaths related
to rejection at maximum
follow-up
1 102 Risk Ratio (M-H Fixed 95 CI) 030 [001 712]
51 UDCA versus placebo 1 102 Risk Ratio (M-H Fixed 95 CI) 030 [001 712]
6 Number of retransplantations at
maximum follow-up
2 132 Risk Ratio (M-H Fixed 95 CI) 076 [020 286]
7 Number of patients with acute
cellular rejection at maximum
follow-up
7 339 Risk Ratio (M-H Fixed 95 CI) 089 [074 106]
71 UDCA versus placebo or
no treatment
6 306 Risk Ratio (M-H Fixed 95 CI) 089 [074 108]
72 TUDCA versus no
treatment
1 33 Risk Ratio (M-H Fixed 95 CI) 085 [045 160]
8 Subgroup analysis number of
patients with acute cellular
rejection according to time of
start of bile acid
7 339 Risk Ratio (M-H Fixed 95 CI) 089 [074 106]
32Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
81 Less than three days after
transplantation
2 134 Risk Ratio (M-H Fixed 95 CI) 084 [063 111]
82 Three days or more after
liver transplantation
5 205 Risk Ratio (M-H Fixed 95 CI) 092 [072 117]
9 Subgroup analysis number
of patients with acute
cellular rejection according to
treatment duration
7 339 Risk Ratio (M-H Fixed 95 CI) 089 [074 106]
91 Less than six months 5 266 Risk Ratio (M-H Fixed 95 CI) 087 [071 107]
92 Six months or more 2 73 Risk Ratio (M-H Fixed 95 CI) 094 [065 136]
10 Number of patients with
chronic rejection at maximum
follow-up
3 184 Risk Ratio (M-H Fixed 95 CI) 028 [008 095]
11 Number of patients with
steroid-resistant rejection at
maximum follow-up
4 234 Risk Ratio (M-H Fixed 95 CI) 077 [047 127]
12 Serum bilirubin (mgdl) at the
end of treatment
1 30 Mean Difference (IV Fixed 95 CI) 26 [-096 616]
13 Number of days of
hospitalisation after liver
transplantation
1 52 Mean Difference (IV Fixed 95 CI) -85 [-1667 -033]
14 Adverse events 3 187 Risk Ratio (M-H Fixed 95 CI) 088 [030 260]
Analysis 11 Comparison 1 Bile acids for liver-transplanted patients Outcome 1 All-cause mortality at
maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 1 All-cause mortality at maximum follow-up
Study or subgroup Favours bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 UDCA versus placebo or no treatment
Barnes 1997 228 724 253 024 [ 006 107 ]
Fleckenstein 1998 214 416 125 057 [ 012 266 ]
Keiding 1997 1454 1048 355 124 [ 061 254 ]
Sama 1991 520 620 201 083 [ 030 229 ]
Subtotal (95 CI) 116 108 935 080 [ 049 130 ]
Total events 23 (Favours bile acids) 27 (Control)
Heterogeneity Chi2 = 416 df = 3 (P = 025) I2 =28
Test for overall effect Z = 091 (P = 036)
01 02 05 1 2 5 10
Favours bile acids Favours control
(Continued )
33Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Favours bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
2 TUDCA versus no treatment
Angelico 1999 316 217 65 159 [ 030 833 ]
Subtotal (95 CI) 16 17 65 159 [ 030 833 ]
Total events 3 (Favours bile acids) 2 (Control)
Heterogeneity not applicable
Test for overall effect Z = 055 (P = 058)
Total (95 CI) 132 125 1000 085 [ 053 136 ]
Total events 26 (Favours bile acids) 29 (Control)
Heterogeneity Chi2 = 466 df = 4 (P = 032) I2 =14
Test for overall effect Z = 069 (P = 049)
01 02 05 1 2 5 10
Favours bile acids Favours control
Analysis 12 Comparison 1 Bile acids for liver-transplanted patients Outcome 2 All-cause mortality worst-
best case and best-worst case scenarios
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 2 All-cause mortality worst-best case and best-worst case scenarios
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 Worst-best case scenario
Angelico 1999 516 217 65 266 [ 060 1180 ]
Barnes 1997 828 724 253 098 [ 042 230 ]
Fleckenstein 1998 314 416 125 086 [ 023 319 ]
Keiding 1997 1954 1048 355 169 [ 087 327 ]
Sama 1991 520 620 201 083 [ 030 229 ]
Subtotal (95 CI) 132 125 1000 130 [ 086 196 ]
Total events 40 (Bile acids) 29 (Control)
Heterogeneity Chi2 = 303 df = 4 (P = 055) I2 =00
Test for overall effect Z = 123 (P = 022)
2 Best-worst case scenario
005 02 1 5 20
Favours bile acids Favours control
(Continued )
34Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Angelico 1999 316 417 90 080 [ 021 302 ]
Barnes 1997 228 1124 274 016 [ 004 063 ]
Fleckenstein 1998 214 616 130 038 [ 009 159 ]
Keiding 1997 1454 1548 368 083 [ 045 154 ]
Sama 1991 520 620 139 083 [ 030 229 ]
Subtotal (95 CI) 132 125 1000 058 [ 038 090 ]
Total events 26 (Bile acids) 42 (Control)
Heterogeneity Chi2 = 567 df = 4 (P = 023) I2 =29
Test for overall effect Z = 247 (P = 0014)
005 02 1 5 20
Favours bile acids Favours control
Analysis 13 Comparison 1 Bile acids for liver-transplanted patients Outcome 3 Subgroup analyses all-
cause mortality at maximum follow-up according to time of start of bile acids
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 3 Subgroup analyses all-cause mortality at maximum follow-up according to time of start of bile acids
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 Less than three days after transplantation
Keiding 1997 1454 1048 355 124 [ 061 254 ]
Subtotal (95 CI) 54 48 355 124 [ 061 254 ]
Total events 14 (Bile acids) 10 (Control)
Heterogeneity not applicable
Test for overall effect Z = 060 (P = 055)
2 Three days or more after transplantation
Angelico 1999 316 217 65 159 [ 030 833 ]
Barnes 1997 228 724 253 024 [ 006 107 ]
Fleckenstein 1998 214 416 125 057 [ 012 266 ]
Sama 1991 520 620 201 083 [ 030 229 ]
005 02 1 5 20
Favours bile acids Favours control
(Continued )
35Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Subtotal (95 CI) 78 77 645 063 [ 033 120 ]
Total events 12 (Bile acids) 19 (Control)
Heterogeneity Chi2 = 310 df = 3 (P = 038) I2 =3
Test for overall effect Z = 141 (P = 016)
Total (95 CI) 132 125 1000 085 [ 053 136 ]
Total events 26 (Bile acids) 29 (Control)
Heterogeneity Chi2 = 466 df = 4 (P = 032) I2 =14
Test for overall effect Z = 069 (P = 049)
005 02 1 5 20
Favours bile acids Favours control
Analysis 14 Comparison 1 Bile acids for liver-transplanted patients Outcome 4 Subgroup analyses all
cause mortality at maximum follow-up according to treatment duration
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 4 Subgroup analyses all cause mortality at maximum follow-up according to treatment duration
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 Less than six months
Barnes 1997 228 724 253 024 [ 006 107 ]
Fleckenstein 1998 214 416 125 057 [ 012 266 ]
Keiding 1997 1454 1048 355 124 [ 061 254 ]
Subtotal (95 CI) 96 88 734 078 [ 045 138 ]
Total events 18 (Bile acids) 21 (Control)
Heterogeneity Chi2 = 417 df = 2 (P = 012) I2 =52
Test for overall effect Z = 084 (P = 040)
2 Six months or more
Angelico 1999 316 217 65 159 [ 030 833 ]
Sama 1991 520 620 201 083 [ 030 229 ]
Subtotal (95 CI) 36 37 266 102 [ 043 240 ]
Total events 8 (Bile acids) 8 (Control)
Heterogeneity Chi2 = 043 df = 1 (P = 051) I2 =00
005 02 1 5 20
Favours bile acids Favours control
(Continued )
36Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Test for overall effect Z = 004 (P = 097)
Total (95 CI) 132 125 1000 085 [ 053 136 ]
Total events 26 (Bile acids) 29 (Control)
Heterogeneity Chi2 = 466 df = 4 (P = 032) I2 =14
Test for overall effect Z = 069 (P = 049)
005 02 1 5 20
Favours bile acids Favours control
Analysis 15 Comparison 1 Bile acids for liver-transplanted patients Outcome 5 Number of deaths related
to rejection at maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 5 Number of deaths related to rejection at maximum follow-up
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 UDCA versus placebo
Keiding 1997 054 148 1000 030 [ 001 712 ]
Total (95 CI) 54 48 1000 030 [ 001 712 ]
Total events 0 (Bile acids) 1 (Control)
Heterogeneity not applicable
Test for overall effect Z = 075 (P = 045)
0001 001 01 1 10 100 1000
Favours bile acids Favours control
37Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 16 Comparison 1 Bile acids for liver-transplanted patients Outcome 6 Number of
retransplantations at maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 6 Number of retransplantations at maximum follow-up
Study or subgroup Bile acids Placebo Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Fleckenstein 1998 214 016 100 567 [ 029 10891 ]
Keiding 1997 154 448 900 022 [ 003 192 ]
Total (95 CI) 68 64 1000 076 [ 020 286 ]
Total events 3 (Bile acids) 4 (Placebo)
Heterogeneity Chi2 = 303 df = 1 (P = 008) I2 =67
Test for overall effect Z = 040 (P = 069)
0001 001 01 1 10 100 1000
Favours bile acids Favours placebo
Analysis 17 Comparison 1 Bile acids for liver-transplanted patients Outcome 7 Number of patients with
acute cellular rejection at maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 7 Number of patients with acute cellular rejection at maximum follow-up
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 UDCA versus placebo or no treatment
Barnes 1997 1728 1724 180 086 [ 058 127 ]
Fleckenstein 1998 814 916 83 102 [ 054 190 ]
Keiding 1997 3554 3248 333 097 [ 073 129 ]
Koneru 1993 316 916 89 033 [ 011 101 ]
Pageaux 1995 926 924 92 092 [ 044 193 ]
Sama 1991 1320 1320 128 100 [ 063 158 ]
Subtotal (95 CI) 158 148 905 089 [ 074 108 ]
01 02 05 1 2 5 10
Favours bile acids Favours control
(Continued )
38Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Total events 85 (Bile acids) 89 (Control)
Heterogeneity Chi2 = 387 df = 5 (P = 057) I2 =00
Test for overall effect Z = 120 (P = 023)
2 TUDCA versus no treatment
Angelico 1999 816 1017 95 085 [ 045 160 ]
Subtotal (95 CI) 16 17 95 085 [ 045 160 ]
Total events 8 (Bile acids) 10 (Control)
Heterogeneity not applicable
Test for overall effect Z = 050 (P = 061)
Total (95 CI) 174 165 1000 089 [ 074 106 ]
Total events 93 (Bile acids) 99 (Control)
Heterogeneity Chi2 = 392 df = 6 (P = 069) I2 =00
Test for overall effect Z = 130 (P = 019)
01 02 05 1 2 5 10
Favours bile acids Favours control
Analysis 18 Comparison 1 Bile acids for liver-transplanted patients Outcome 8 Subgroup analysis
number of patients with acute cellular rejection according to time of start of bile acid
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 8 Subgroup analysis number of patients with acute cellular rejection according to time of start of bile acid
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 Less than three days after transplantation
Keiding 1997 3554 3248 333 097 [ 073 129 ]
Koneru 1993 316 916 89 033 [ 011 101 ]
Subtotal (95 CI) 70 64 422 084 [ 063 111 ]
Total events 38 (Bile acids) 41 (Control)
Heterogeneity Chi2 = 374 df = 1 (P = 005) I2 =73
Test for overall effect Z = 124 (P = 022)
2 Three days or more after liver transplantation
Angelico 1999 816 1017 95 085 [ 045 160 ]
01 02 05 1 2 5 10
Favours bile acids Favours control
(Continued )
39Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Barnes 1997 1728 1724 180 086 [ 058 127 ]
Fleckenstein 1998 814 916 83 102 [ 054 190 ]
Pageaux 1995 926 924 92 092 [ 044 193 ]
Sama 1991 1320 1320 128 100 [ 063 158 ]
Subtotal (95 CI) 104 101 578 092 [ 072 117 ]
Total events 55 (Bile acids) 58 (Control)
Heterogeneity Chi2 = 041 df = 4 (P = 098) I2 =00
Test for overall effect Z = 067 (P = 050)
Total (95 CI) 174 165 1000 089 [ 074 106 ]
Total events 93 (Bile acids) 99 (Control)
Heterogeneity Chi2 = 392 df = 6 (P = 069) I2 =00
Test for overall effect Z = 130 (P = 019)
01 02 05 1 2 5 10
Favours bile acids Favours control
40Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 19 Comparison 1 Bile acids for liver-transplanted patients Outcome 9 Subgroup analysis
number of patients with acute cellular rejection according to treatment duration
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 9 Subgroup analysis number of patients with acute cellular rejection according to treatment duration
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 Less than six months
Barnes 1997 1728 1724 180 086 [ 058 127 ]
Fleckenstein 1998 814 916 83 102 [ 054 190 ]
Keiding 1997 3554 3248 333 097 [ 073 129 ]
Koneru 1993 316 916 89 033 [ 011 101 ]
Pageaux 1995 926 924 92 092 [ 044 193 ]
Subtotal (95 CI) 138 128 777 087 [ 071 107 ]
Total events 72 (Bile acids) 76 (Control)
Heterogeneity Chi2 = 374 df = 4 (P = 044) I2 =00
Test for overall effect Z = 129 (P = 020)
2 Six months or more
Angelico 1999 816 1017 95 085 [ 045 160 ]
Sama 1991 1320 1320 128 100 [ 063 158 ]
Subtotal (95 CI) 36 37 223 094 [ 065 136 ]
Total events 21 (Bile acids) 23 (Control)
Heterogeneity Chi2 = 017 df = 1 (P = 068) I2 =00
Test for overall effect Z = 035 (P = 073)
Total (95 CI) 174 165 1000 089 [ 074 106 ]
Total events 93 (Bile acids) 99 (Control)
Heterogeneity Chi2 = 392 df = 6 (P = 069) I2 =00
Test for overall effect Z = 130 (P = 019)
01 02 05 1 2 5 10
Favours bile acids Favours control
41Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 110 Comparison 1 Bile acids for liver-transplanted patients Outcome 10 Number of patients
with chronic rejection at maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 10 Number of patients with chronic rejection at maximum follow-up
Study or subgroup Bile acids Placebo Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Barnes 1997 128 624 611 014 [ 002 110 ]
Fleckenstein 1998 114 116 88 114 [ 008 1663 ]
Keiding 1997 154 348 300 030 [ 003 275 ]
Total (95 CI) 96 88 1000 028 [ 008 095 ]
Total events 3 (Bile acids) 10 (Placebo)
Heterogeneity Chi2 = 148 df = 2 (P = 048) I2 =00
Test for overall effect Z = 204 (P = 0041)
0001 001 01 1 10 100 1000
Favours bile acids Favours placebo
Analysis 111 Comparison 1 Bile acids for liver-transplanted patients Outcome 11 Number of patients
with steroid-resistant rejection at maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 11 Number of patients with steroid-resistant rejection at maximum follow-up
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Barnes 1997 328 724 277 037 [ 011 127 ]
Fleckenstein 1998 314 316 103 114 [ 027 478 ]
Keiding 1997 1454 1548 583 083 [ 045 154 ]
Pageaux 1995 226 124 38 185 [ 018 1908 ]
Total (95 CI) 122 112 1000 077 [ 047 127 ]
Total events 22 (Bile acids) 26 (Control)
Heterogeneity Chi2 = 226 df = 3 (P = 052) I2 =00
Test for overall effect Z = 102 (P = 031)
001 01 1 10 100
Favours bile acids Favours placebo
42Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 112 Comparison 1 Bile acids for liver-transplanted patients Outcome 12 Serum bilirubin (mgdl)
at the end of treatment
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 12 Serum bilirubin (mgdl) at the end of treatment
Study or subgroup Bile acids Placebo Mean Difference Weight Mean Difference
N Mean(SD) N Mean(SD) IVFixed95 CI IVFixed95 CI
Fleckenstein 1998 14 319 (68) 16 059 (022) 1000 260 [ -096 616 ]
Total (95 CI) 14 16 1000 260 [ -096 616 ]
Heterogeneity not applicable
Test for overall effect Z = 143 (P = 015)
-10 -5 0 5 10
Favours bile acids Favours placebo
Analysis 113 Comparison 1 Bile acids for liver-transplanted patients Outcome 13 Number of days of
hospitalisation after liver transplantation
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 13 Number of days of hospitalisation after liver transplantation
Study or subgroup Bile acids Placebo Mean Difference Weight Mean Difference
N Mean(SD) N Mean(SD) IVFixed95 CI IVFixed95 CI
Barnes 1997 28 25 (17) 24 335 (13) 1000 -850 [ -1667 -033 ]
Total (95 CI) 28 24 1000 -850 [ -1667 -033 ]
Heterogeneity not applicable
Test for overall effect Z = 204 (P = 0041)
-100 -50 0 50 100
Favours bile acids Favours placebo
43Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 114 Comparison 1 Bile acids for liver-transplanted patients Outcome 14 Adverse events
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 14 Adverse events
Study or subgroup Bile acids Placebo Risk Ratio Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Angelico 1999 016 017 00 [ 00 00 ]
Barnes 1997 128 124 086 [ 006 1298 ]
Keiding 1997 554 548 089 [ 027 288 ]
Total (95 CI) 98 89 088 [ 030 260 ]
Total events 6 (Bile acids) 6 (Placebo)
Heterogeneity Chi2 = 000 df = 1 (P = 098) I2 =00
Test for overall effect Z = 022 (P = 082)
001 01 1 10 100
Favours bile acids Favours placebo
A P P E N D I C E S
Appendix 1 Search strategies
Data Base Date of Search Search Strategy
The Cochrane Hepato-Biliary Group Con-
trolled Trials Register
September 2009 1 rsquoliver transplantationrsquo and rsquochenodeoxy-
cholicrsquo
2 rsquoliver transplantationrsquo and rsquocholicrsquo
3 rsquoliver transplantationrsquo and rsquodeoxycholicrsquo
4 rsquoliver transplantationrsquo and rsquoglycochen-
odeoxycholicrsquo
5 rsquoliver transplantationrsquo and rsquoglycocholicrsquo
6 rsquoliver transplantationrsquo and rsquoglycodeoxy-
cholicrsquo
7 rsquoliver transplantationrsquo and rsquoglycolitho-
cholicrsquo
8 rsquoliver transplantationrsquo and rsquohyodeoxy-
cholicrsquo
9 rsquoliver transplantationrsquo and rsquolithocholicrsquo
10 rsquoliver transplantationrsquo and rsquotaurochen-
odeoxycholicrsquo
44Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
11 rsquoliver transplantationrsquo and rsquotauro-
cholicrsquo
12 rsquoliver transplantationrsquo and rsquotaurodehy-
drocholicrsquo
13 rsquoliver transplantationrsquo and rsquotau-
rodeoxycholicrsquo
14 rsquoliver transplantationrsquo and rsquotauroglyco-
cholicrsquo
15 rsquoliver transplantationrsquo and rsquotaurolitho-
cholicrsquo
16 rsquoliver transplantationrsquo and rsquotaurosel-
cholicrsquo
17 rsquoliver transplantationrsquo and rsquotaurourso-
cholicrsquo
18 rsquoliver transplantationrsquo and rsquotaurour-
sodeoxycholicrsquo
19 rsquoliver transplantationrsquo and rsquoursocholicrsquo
20 rsquoliver transplantationrsquo and rsquoursodeoxy-
cholicrsquo
The Cochrane Central Register of Con-
trolled Trials in The Cochrane Library
Issue 3 2009 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
6 3 or 4
7 5 and 6
MEDLINE September 2009 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
45Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
6 3 or 4
7 5 and 6
8 RANDOMIZED-CONTROLLED-
TRIAL ME
9 RANDOM
10 8 or 9
11 7 and 10
EMBASE September 2009 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
6 3 or 4
7 5 and 6
8 RANDOMIZED-CONTROLLED-
TRIAL ME
9 RANDOM
10 8 or 9
11 7 and 10
46Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
Science Citation Index Expanded September 2009 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
6 3 or 4
7 5 and 6
8 RANDOMIZED-CONTROLLED-
TRIAL ME
9 RANDOM
10 8 or 9
11 7 and 10
The Chinese Biomedical Database Searched from January 1980 to April 2002 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
47Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
6 3 or 4
7 5 and 6
8 RANDOMIZED-CONTROLLED-
TRIAL ME
9 RANDOM
10 8 or 9
11 7 and 10
W H A T rsquo S N E W
Last assessed as up-to-date 8 February 2010
18 September 2009 New citation required but conclusions have not
changed
This review is an updated version of a review that was
published for the first time in Issue 3 2005 of TheCochrane Library by Chen 2003b
18 September 2009 New search has been performed No new studies fulfilled the inclusion criteria
H I S T O R Y
Protocol first published Issue 3 2003
Review first published Issue 3 2005
C O N T R I B U T I O N S O F A U T H O R S
GP and VG independently performed searches of relevant databases GP validated the search selected trials for inclusion contacted
the authors of the trials performed data extraction and data analysis and drafted the systematic review VG revised the review update
CG and DS revised the review update solved discrepancies of data extraction validated data analyses and provided consultation
D E C L A R A T I O N S O F I N T E R E S T
None known
48Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
S O U R C E S O F S U P P O R T
Internal sources
bull Copenhagen Trial Unit Denmark
External sources
bull Danish Medical Research Councilrsquos Grant on Getting Research into Practice (GRIP) Denmark
D I F F E R E N C E S B E T W E E N P R O T O C O L A N D R E V I E W
We assessed the risk of bias in the included studies for another four domains that were added to the review protocol (incomplete
outcome data selective outcome reporting baseline imbalance and early stopping of trial) In general the text of the risk of bias
domains were updated following Higgins 2008 Trials were considered at low risk of bias when judged as adequate in all domains
Quasi-randomised studies observational and case-control studies were included for the report of adverse events
We performed trial sequential analysis for outcomes demonstrating a statistically significant result
I N D E X T E R M S
Medical Subject Headings (MeSH)
lowastLiver Transplantation Cholagogues and Choleretics [lowasttherapeutic use] Graft Rejection [lowastprevention amp control] Randomized Con-
trolled Trials as Topic Taurochenodeoxycholic Acid [lowasttherapeutic use] Ursodeoxycholic Acid [lowasttherapeutic use]
MeSH check words
Humans
49Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
and rsquotransplantationrsquo in combination with the bile acids mentioned
above (Royle 2003) The search strategies with the time span of
the searches are given in Appendix 1 We contacted the Chinese
Cochrane Centre regarding the search of The Chinese BiomedicalDatabase and received a reply that they are unable to help us with
this search Therefore the latter database could not be included
in the search strategy of this update
Further trials were identified by reading the reference lists of the
identified studies We wrote to the principal authors of the reports
of the identified randomised clinical trials in September 2009 and
enquired about additional trials which they might know of The
first team of authors had also written to pharmaceutical companies
involved in the production of bile acids to obtain information on
published or unpublished randomised clinical trials in 2002 but
no information had been received at that time
Data collection and analysis
The update of this review was conducted according to the proto-
col previously published in The Cochrane Library (Chen 2003b)
and following the recommendations given by the Cochrane Hand-book for Systematic Reviews of Interventions (Higgins 2008) and the
Cochrane Hepato-Biliary Group Module (Gluud 2010)
Trial identification
Identified trials were listed and the two review authors evaluated
whether the trials fulfilled the inclusion criteria Excluded trials
were listed with the reasons for exclusion
Data extraction
GP and VG extracted the data independently and disagreements
were resolved by discussion or by CG We extracted the following
characteristics from each trial primary author number of patients
randomised patient inclusion and exclusion criteria methodolog-
ical quality follow-up (number and reasons for withdrawal) sam-
ple size calculation intention-to-treat analysis intervention reg-
imens mean age proportion of males and females aetiology of
liver disease origin of allograft matching criteria between donor
and recipient time to follow-up number of outcomes and num-
ber and type of adverse events in both the intervention and the
control groups Additional information was sought by correspon-
dence with the principal investigator or co-investigators of the trial
in cases where the relevant data were not published
Assessment of risk of bias
Risk of bias was defined as the confidence that the study design and
reporting restricted bias in the intervention comparison (Schulz
1995 Moher 1998 Kjaergard 2001 Wood 2008) Due to the risk
of overestimation of intervention effects in randomised trials with
unclear or inadequate components we assessed the risk of bias by
separate domains
Allocation sequence generation
bull Adequate if the allocation sequence was generated by a
computer or random number table Drawing of lots tossing of a
coin shuffling of cards or throwing dice was considered as
adequate if a person who was not otherwise involved in the
recruitment of participants performed the procedure
bull Unclear if the trial was described as randomised but the
method used for the allocation sequence generation was not
described
bull Inadequate if a system involving dates names or
admittance numbers were used for the allocation of patients
Such quasi-randomised studies were excluded
Allocation concealment
bull Adequate if the allocation of patients involved a central
independent unit on-site locked computer identically appearing
numbered drug bottles or containers prepared by an
independent pharmacist or investigator or serially numbered
sealed and opaque envelopes
bull Unclear if the trial was described as randomised but the
method used to conceal the allocation was not described
bull Inadequate if the allocation sequence was known to the
investigators who assigned participants or if the study was quasi-
randomised The latter studies were excluded
Blinding
bull Adequate the trial was described as blinded the parties that
were blinded and the method of blinding was described so that
knowledge of allocation was adequately prevented during the
trial
bull Unclear the trial was described as double blind but the
method of blinding was not described so that knowledge of
allocation was possible during the trial
bull Not performed the trial was not blinded so that the
allocation was known during the trial
Incomplete outcome data
bull Adequate if the numbers and reasons for dropouts and
withdrawals in all intervention groups were described or if it was
specified that there were no dropouts or withdrawals
bull Unclear if the report gave the impression that there had
been no dropouts or withdrawals but this was not specifically
stated
bull Inadequate if the number or reasons for dropouts and
withdrawals were not described
Selective outcome reporting
bull Adequate if study protocol is available and all pre-specified
outcomes are reported in the manuscript or if the study protocol
is not available but it is clear that the report includes all expected
outcomes
bull Unclear if there are no sufficient information to permit
judgement
bull Inadequate if not all of the pre-specified outcomes were
reported andor were reported incompletely or one or more
reported outcomes were not pre-specified
Baseline imbalance
5Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
bull Adequate if there is no baseline imbalance in the main
characteristics
bull Unclear if there is no sufficient information to assess
baseline characteristics
bull Inadequate if there was a baseline imbalance due to chance
or due to imbalanced exclusion after randomisation
Early stopping
bull Adequate if sample size calculation was reported and the
trial was not stopped or the trial was stopped early by formal
stopping rules at a point where the likelihood of observing an
extreme intervention effect due to chance was low
bull Unclear if sample size calculation was not reported and it is
not clear whether the trial was stopped early or not
bull Inadequate if the trial was stopped early due to informal
stopping rules or the trial was stopped early by a formal stopping
rule at a point where the likelihood of observing an extreme
intervention effect due to chance was high
Furthermore we registered whether the randomised clinical trials
had used an intention-to-treat analysis (Gluud 2001) and had
calculated a sample size estimate
Statistical methods
We performed the analyses in RevMan 5 (RevMan 2008) Anal-
yses included all patients irrespective of compliance or follow-up
according to the intention-to-treat principle and using the last
reported observed response (rsquocarry forwardrsquo) Regarding death
both a worst-best-case scenario analysis considering all dropped-
out patients in the bile acid group as dead and the dropped-out
patients in the control group as alive and a best-worst-case sce-
nario analysis considering all dropped-out patients in the bile acid
group as alive and the dropped-out patients in the control group as
dead were performed Both a random-effects model (DerSimonian
1986) and a fixed-effect model (DeMets 1987) were used The re-
sults of the fixed-effect model were reported if there were no differ-
ences between the results produced by the two models otherwise
we reported the results produced by both models We presented
binary outcome measures as relative risks (RR) with 95 confi-
dence intervals (CI) and continuous outcome measures as mean
differences (MD) with 95 CI
The risk of type I errors increases in single trials with interim anal-
yses To avoid type I errors group sequential monitoring bound-
aries (Lan 1983) can be performed when deciding to terminate the
trial earlier than planned This requires analyses at different time
intervals to record when the P-value has become sufficiently small
that is when the cumulative Z-curve will cross the monitoring
boundaries Sequential monitoring boundaries the so called rsquotrial
sequential monitoring boundariesrsquo can also be applied to meta-
analyses In a trial sequential analysis (TSA) every trial that is
added in a cumulative meta-analysis is regarded as an interim meta-
analysis and the information it adds on helps on deciding if more
trials need to be included
The interpretation of the TSA is as follows if the cumulative Z-
curve has crossed the boundary a sufficient level of evidence is
reached and no further trials may be needed If the Z-curve has
not crossed the boundary then the evidence is insufficient in order
to reach a conclusion To construct the trial sequential monitor-
ing boundaries information size is needed It is calculated as the
minimum number of participants needed in a well-powered single
trial (Pogue 1997 Pogue 1998 Brok 2008 Wetterslev 2008) We
applied TSA since it prevents an increase of the risk of type I error
due to sparse and multiple updating in a cumulative meta-analysis
and provides us with important information in order to estimate
the level of evidence of the experimental intervention Addition-
ally TSA provides us with important information regarding the
need for additional trials and the required information size We
applied trial sequential monitoring boundaries according to an in-
formation size suggested by the trials with low risk of bias and a
50 relative risk reduction (RRR)
Subgroup analyses
We planned to perform the following subgroup analyses on the
main outcome measures (all-cause mortality and number of pa-
tients with acute rejection)
1 Risk of bias of the trials comparing the intervention effect for
trials with low risk of bias components to the intervention effect
in trials with unclear or high risk of bias components
2 Dose and duration of treatment with bile acids comparing the
intervention effect in trials administrating bile acid at or above the
median dose multiplied by duration to the intervention effect of
trials administrating bile acid at less than the median dose multi-
plied by duration
3 Time between transplantation and the start of bile acids com-
paring the intervention effect of trials having less than three days
between transplantation and starting bile acid intake to the inter-
vention effect of trials with a duration of three days or more be-
tween transplantation and the start of bile acid intake (Neuberger
1999)
4 Co-interventions comparing the intervention effect of trials
with co-interventions to the intervention effect of trials without
co-interventions
Funnel plot analysis
We planned to explore bias by funnel plot analysis (Egger 1997)
R E S U L T S
Description of studies
See Characteristics of included studies Characteristics of excluded
studies
The performed electronic searches resulted in a total of 378 ref-
erences We excluded 362 duplicates or irrelevant references by
reading abstracts We excluded eight of the 16 further assessed ref-
erences because they were observational studies case series or ran-
6Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
domised clinical trials with a different reason for exclusion They
are listed under rsquoCharacteristic of excluded studiesrsquo with reasons
for exclusion Seven references already included in the previous
version of this review and one new reference referring to an al-
ready included trial (Barnes 1997) were included in this review
We were not able to identify more trials by reading the reference
lists of the identified studies contacting the principle authors of
the identified trials or approaching pharmaceutical companies for
unpublished trials
Seven publications included in the review (five full publications
and two abstracts) were randomised clinical trials that reported
the random allocation of liver-transplanted patients into groups
receiving bile acid placebo or no treatment We listed these trials
in the table of Characteristics of included studies All seven trials
were published in English Three randomised clinical trials were
from the United States (Koneru 1993 Barnes 1997 Fleckenstein
1998) two from Italy (Sama 1991 Angelico 1999) one from
France (Pageaux 1995) and one from Denmark (Keiding 1997)
Patients
In the included trials all patients received blood group-compatible
grafts The median size of the seven trials was 40 patients (range
29 to 102 patients) In total 335 patients were randomised
Five trials were published as full publications (Pageaux 1995
Barnes 1997 Keiding 1997 Fleckenstein 1998 Angelico 1999)
which allowed us to extract detailed information on 263 of the
patients The mean age of the patients ranged from 44 to 51 years
One trial (Keiding 1997) also enrolled children ranging in age
from 0 to 13 years (median 15 years) The male to female ratio in
these five trials was 159104 The diseases that led to liver trans-
plantation were alcoholic cirrhosis in 51 patients (194) cirrho-
sis caused by chronic hepatitis C in 40 patients (152) primary
biliary cirrhosis in 36 patients (137) cryptogenic cirrhosis in
22 patients (84) metabolic diseases in 19 patients (72) pri-
mary sclerosing cholangitis in 17 patients (65) non-specified
post-hepatitis cirrhosis in 17 patients (65) cirrhosis caused by
chronic hepatitis B in 13 patients (49) 9 with autoimmune
hepatitis and cirrhosis (34) six with liver cancer (23) five
with biliary atresia (19) and 28 with other diseases (106)
Only one trial reported the severity of liver function according to
the Child-Pugh class (Barnes 1997)
Bile acids and collateral interventions
Six trials (Sama 1991 Koneru 1993 Pageaux 1995 Barnes
1997 Keiding 1997 Fleckenstein 1998) compared UDCA versus
placebo or no intervention One trial (Angelico 1999) compared
TUDCA versus no intervention Bile acid treatment began one
day after transplantation in the Keiding 1997 trial three days after
transplantation in the Koneru 1993 trial three or five days in the
Fleckenstein 1998 and Pageaux 1995 trials five days after trans-
plantation in the Barnes 1997 and Angelico 1999 trials and five
or seven days after transplantation in the Sama 1991 trial
Patients received UCDA (10 to 15 mgkg body weightday) for
two months in the Pageaux 1995 trial for three months in the
Koneru 1993 Barnes 1997 Keiding 1997 and Fleckenstein 1998
trials and for six months in the Sama 1991 trial In the Barnes
1997 trial patients were followed up for 18 months Patients in the
Fleckenstein 1998 trial and the Keiding 1997 trial were followed
up for nine months There was no post-treatment follow-up in
three trials (Sama 1991 Koneru 1993 Pageaux 1995) Patients
received TUDCA (500 mgday) for one year and no follow-up
was conducted in the Angelico 1999 trial
In addition to the bile acids or control intervention all patients
in the seven trials received standard triple-drug regimens (steroids
azathioprine and cyclosporine or tacrolimus) The patients who
had steroid-resistant rejection received treatment with immuno-
suppressive antibodies (OKT3)
Outcome measures
The outcome measures reported by most trials were all-cause mor-
tality and acute cellular rejection Three trials reported on death
related to rejection (Barnes 1997 Keiding 1997 Angelico 1999)
two trials reported the number of patients who received retrans-
plantation due to rejection (Keiding 1997 Fleckenstein 1998)
three trials reported the number of patients with chronic rejection
(Barnes 1997 Keiding 1997 Fleckenstein 1998) and four trials
reported the number of patients with steroid-resistant rejection
(Pageaux 1995 Barnes 1997 Keiding 1997 Fleckenstein 1998)
Four trials had adverse events as outcome measures (Barnes 1997
Keiding 1997 Fleckenstein 1998 Angelico 1999) Serum biliru-
bin level was only reported by the Fleckenstein 1998 trial No tri-
als provided data on other liver biochemical parameters quality
of life or cost-effectiveness
Risk of bias in included studies
Two trials reported adequate allocation sequence generation by
using computer-generated random tables (Barnes 1997 Angelico
1999) One trial (Keiding 1997) reported adequate allocation con-
cealment by using sealed serially numbered envelopes Three tri-
als (Barnes 1997 Keiding 1997 Fleckenstein 1998) reported ad-
equate blinding by using placebo with an identical appearance
and taste Five trials (Pageaux 1995 Barnes 1997 Keiding 1997
Fleckenstein 1998 Angelico 1999) reported adequate description
of incomplete outcome data by the number of withdrawals the
reasons for withdrawal or no patients dropped out The trial by
Keiding 1997 is the only one free of selective reporting since all
the pre-specified outcomes were fairly reported Two trials (Barnes
1997 Keiding 1997) performed sample-size calculations Only
the trial by Keiding 1997 seemed to be free of baseline imbalance
and it is the only trial achieving the calculated sample size and
therefore probably the only that was not terminated early Other
trials did not perform sample size calculation or the authors did
not report whether the calculated sample size was achieved The
lack of this information made it unclear for us to judge whether
7Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
a trial was terminated early that is before an adequate number
of patients was included in the trial Three trials (Barnes 1997
Keiding 1997 Fleckenstein 1998) stated that intention-to-treat
analyses were used (Figure 1 Figure 2)
Figure 1 Methodological quality graph review authorsrsquo judgements about each methodological quality
item presented as percentages across all included studies
8Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Figure 2 Methodological quality summary review authorsrsquo judgements about each methodological quality
item for each included study
9Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Following the assessment of risk of bias domains none of the seven
trials were considered to have low risk of bias that is having all
the nine domains for risk of bias assessed as adequate
Effects of interventions
We were able to include seven randomised clinical trials in this
review Six trials with 306 liver-transplanted patients compared
ursodeoxycholic acid (UDCA) with placebo or no intervention
and one trial with 29 liver-transplanted patients compared tauro-
UDCA (TUDCA) with no intervention
All-cause mortality
Five trials including 257 liver-transplanted patients reported on
all-cause mortality at the end of treatment or at maximum follow-
up Bile acids did not significantly reduce all-cause mortality (RR
085 95 CI 053 to 136) there were 26 deaths among 132
patients treated with bile acids (197) versus 29 deaths among
125 patients in the control groups (232) (Analysis 11) There
was no statistically significant heterogeneity (I2 = 141)
Four trials (Sama 1991 Barnes 1997 Keiding 1997 Fleckenstein
1998) showed that UDCA did not significantly reduce all-cause
mortality (RR 080 95 CI 049 to 130) 23 deaths among 116
patients treated with UCDA (198) versus 27 deaths among
108 patients in the control groups (250) The Angelico 1999
trial demonstrated that TUDCA was not able to reduce all-cause
mortality (RR 159 95 CI 030 to 833) there were 3 deaths
among 16 patients (188) versus 2 deaths among 17 patients
(118)
The Fleckenstein 1998 trial and the Sama 1991 trial did not report
the causes of deaths In the three other trials the deaths were
considered to be caused by infections (n = 11) hepatic failure (n =
7) abdominal bleeding (n = 3) renal failure (n = 2) multiple organ
failure (n = 2) hepatitis B virus fibrosis (n = 2) acute rejection
(n = 1) hepatic artery thrombosis (n = 1) encephalitis (n = 1)
lymphoproliferative disorder (n = 1) cerebral haemorrhage (n =
1) or other reasons (n = 6)
Worst-best case and best-worst case scenario analyses
In the worst-best case scenario analysis bile acids did not signif-
icantly reduce all-cause mortality when compared with placebo
or no intervention (RR 130 95 CI 086 to 196) 40 deaths
among 132 patients on bile acids (303) versus 29 deaths among
125 patients in the control groups (232) However all-cause
mortality was significantly reduced by bile acids in the best-worst
case scenario analysis (RR 058 95 CI 038 to 090) 26 deaths
among 132 patients (197) versus 42 deaths among 125 patients
in the control groups (336) (Analysis 12)
Subgroup analyses
We performed subgroup analyses regarding the time that bile acid
intake was started The Keiding 1997 trial started bile acid intake
less than three days after liver transplantation and demonstrated
no significant effect of UDCA on all-cause mortality (RR 124
95 CI 061 to 254) 14 deaths out of 54 patients (259)
versus 10 out of 48 control patients (208) The same effect
was noticed in the four other trials (Sama 1991 Barnes 1997
Fleckenstein 1998 Angelico 1999) which started bile acids three
days or more after liver transplantation (RR 063 95 CI 033
to 120) 12 deaths among 78 patients (154) versus 9 deaths
among 77 control patients (247) (Analysis 13) There were no
statistically significant differences between the two estimates
We also performed subgroup analyses regarding the duration of
bile acid treatment Bile acids were administrated for less than six
months in three trials (Barnes 1997 Keiding 1997 Fleckenstein
1998) and were not able to significantly decrease all-cause mor-
tality (RR 078 95 CI 045 to 138) 18 deaths in a group of
96 treated patients (188) versus 21 deaths among 88 control
patients (239) In the other two trials (Sama 1991 Angelico
1999) patients were treated with bile acids for six months or more
The treatment did not show statistically significant decrease in all-
cause mortality (RR 102 95 CI 043 to 24) 8 deaths in a
group of 36 treated patients (222) versus 8 deaths in a group
of 37 control patients (216) (Analysis 14) There were no sta-
tistically significant differences between the two estimates
Mortality related to allograft rejection
We did not find statistically significant reduction in mortality re-
lated to allograft rejection at maximum follow-up in the three tri-
als reporting cause of death (Barnes 1997 Keiding 1997 Angelico
1999) (RR 030 95 CI 001 to 712) 098 (0) versus 189
(11)) (Analysis 15) The only death due to acute rejection was
found in the placebo group of the Keiding 1997 trial
Number of liver retransplantations
Two trials (Fleckenstein 1998 Keiding 1997) including 132 liver-
transplanted patients reported the number of liver retransplan-
tations UDCA did not significantly reduce the risk of liver re-
transplantation at maximum follow-up (RR 076 95 CI 020
to 286) 368 (44) versus 464 (63)) (Analysis 16) In the
Keiding 1997 trial one patient in the UDCA group was retrans-
planted due to chronic rejection and four patients in the placebo
group were retransplanted either due to chronic rejection (three
cases) or acute rejection (one case) In the Fleckenstein 1998 trial
two patients in the UDCA group were retransplanted due to acute
rejection (one case) and chronic rejection (one case) respectively
Number of patients with acute cellular rejection
Seven trials reported the number of patients who had acute cellu-
lar rejection after liver transplantation Bile acids did not signifi-
cantly reduce the number of patients who experienced acute cel-
lular rejection (RR 089 95 CI 074 to 106) 93174(535)
versus 99165 (600)) There was no significant heterogeneity
(I2 = 0)
Six trials (Sama 1991 Koneru 1993 Pageaux 1995 Barnes 1997
10Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Keiding 1997 Fleckenstein 1998) compared UDCA with placebo
or no intervention and demonstrated that UDCA did not signifi-
cantly reduce the number of patients with acute cellular rejection
after liver transplantation (RR 089 95 CI 074 to 108 85
158 (538) versus 89148 (601)) Neither did the Angelico
1999 trial demonstrate significant reduction of the number of pa-
tients with acute cellular rejection with TUDCA (RR 085 95
CI 045 to 160) 816 (500) versus 1017 (588) (Analysis
17)
Subgroup analyses
Two trials (Koneru 1993 Keiding 1997) in which the patients
started bile acids intake less than three days after liver transplan-
tation did not demonstrate any significant reduction of the risk
of acute cellular rejection by bile acids (RR 084 95 CI 063 to
111) 3870 (543) versus 4164 (641) The other five tri-
als (Sama 1991 Pageaux 1995 Barnes 1997 Fleckenstein 1998
Angelico 1999) in which the patients were started on bile acid
intake three days or more after liver transplantation did not find
a significant reduction of the risk of acute cellular rejection by bile
acids (RR 092 95 CI 072 to 117) 55104 (529) versus 58
101 (574) (Analysis 18) There was no significant difference
between the two estimates
Bile acids did not significantly reduce the risk of acute cellular
rejection in the five trials (Koneru 1993 Pageaux 1995 Barnes
1997 Keiding 1997 Fleckenstein 1998) in which the patients
received treatment with bile acids less than six months (RR 087
95 CI 071 to 107) 72138 (522) versus 76128 (594)
Neither did bile acids in the two other trials (Sama 1991 Angelico
1999) in which the patients received bile acids for more than six
months (RR 094 95 CI 065 to 136) 2136 (583) versus
2337 (622) (Analysis 19) There were no significant difference
between the two estimates
Number of patients with chronic rejection
Three trials comparing UDCA versus placebo (Barnes 1997
Keiding 1997 Fleckenstein 1998) reported the number of patients
with chronic rejection after liver transplantation UDCA signifi-
cantly reduced the number of patients with chronic rejection in
the fixed-effect model analysis (RR 028 95 CI 008 to 095)
396 (31) versus 1088 (114) (Analysis 110) but not in the
random-effects model analysis (RR 030 95 CI 008 to 113) 3
96 (31) versus 1088 (114) There was no statistically signifi-
cant heterogeneity (I2 0) We performed trial sequential analysis
for the available data from three trials (Figure 3) with heterogene-
ity corrected required information size based on proportion of this
outcome of 12 in the control group a relative risk reduction of
50 in the intervention group at a type I error of 5 and a type
II error of 10 We obtained a required information size of 957
patients UDCA was not able to reach or break the trial sequential
monitoring boundary and only 183 out of 957 (19) patients
were randomised regarding this outcome
11Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Figure 3 Trial sequential analysis for the number of patients with chronic rejection at maximum follow-up
We calculated the heterogeneity-corrected required information size (HCRIS) based on a proportion of 12 of
the patients in the placebo group with chronic rejection at maximum follow-up a 50 risk ratio reduction in
the bile acid group an alpha of 5 a beta of 10 and a heterogeneity of 0 Only 184 patients have been
randomised reporting this outcome which is only 19 of the HCRIS of 957 patients The cumulative Z-score
crosses the conventional boundaries for P 005 but not the monitoring boundaries
Number of patients with steroid-resistant rejection
Four trials (Pageaux 1995 Barnes 1997 Keiding 1997
Fleckenstein 1998) reported the number of patients with steroid-
resistant rejection These trials demonstrated that UDCA did not
significantly reduce the number of patients with steroid-resistant
rejection when compared with placebo (22122 (18) versus 26
112 (232) (RR 077 95 CI 047 to 127) (Analysis 111)
There was no significant heterogeneity (I2 0)
Liver biochemistry
The Fleckenstein 1998 trial reported serum bilirubin levels after
a three-month-treatment period in 30 liver-transplanted patients
There was no statistically significant difference in serum bilirubin
levels between the UDCA group and the placebo group (MD 260
mgdl 95 CI -096 to 616 mgdl) (Analysis 112)
No data were available for other liver biochemical variables
Cost-effectiveness
One trial (Barnes 1997) with 52 liver-transplanted patients re-
ported the days of hospitalisation after liver transplantation
UDCA significantly decreased the number of days of hospitali-
sation when compared with placebo (MD -850 days 95 CI -
1667 to -033 days) (Analysis 113) We were not able to extract
other medical cost from the trials
Adverse events
Among all the included and excluded trials only four reported on
adverse events however adverse events only occurred in two of
the included trials (Barnes 1997 Keiding 1997) There were no
significant differences regarding adverse events (RR 088 95 CI
030 to 260) 6112 (54) versus 6105 (57) (Analysis 114)
In the Barnes 1997 trial diarrhoea was reported by two patients
(one in the UDCA group and one in the placebo group) In the
Keiding 1997 trial five UDCA patients and five placebo patients
stopped intake of the trial medicine because of diarrhoea or dif-
ficulties in swallowing the capsules The remaining included trial
by Angelico 1999 stated that no adverse events occurred during
the study period The excluded trial by Assy 2007 was the only
one reporting on a case of mild diarrhoea in one patient in the
12Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
intervention group No other excluded studies reported on adverse
events (see Table 1)
Quality of life
None of the included studies assessed quality of life as an outcome
Other subgroup analyses
We planned to perform subgroup analyses regarding the risk of
bias of trials the dosage of bile acid and any co-intervention
However none of the trials were considered to be of low risk of
bias they all used a similar dosage of bile acid and patients in all
trials received similar immunosuppressive treatment as co-inter-
ventions (steroids azathioprine and cyclosporine or tacrolimus)
after liver transplantation Therefore we were not able to perform
the planned subgroup analyses
Funnel plot asymmetry
We did not draw a funnel plot analysis due to the limited number
of trials included in the present review
D I S C U S S I O N
In the update of this review we included no new trials assessing
the use of bile acids for liver-transplanted patients The analyses
of the seven previously included trials showed that bile acids did
not significantly affect mortality acute cellular rejection steroid-
resistant rejection retransplantation or serum bilirubin Bile acids
might significantly decrease the length of hospital stay and the
number of patients with chronic rejection included in these tri-
als but more supportive evidence is needed The number of pa-
tients with chronic rejection was not significantly influenced by
bile acids when a random-effects model was used and length of
stay was assessed in one single trial Furthermore none of the trials
were considered to be of low risk of bias and few patients were en-
rolled Therefore our positive findings may be due to bias (Schulz
1995 Moher 1998 Kjaergard 2001 Wood 2008) or random er-
rors (Wetterslev 2008 Brok 2009 Thorlund 2009) On the other
hand we are not able to exclude type II errors (that is finding
no significant differences when in fact they exist) due to the low
number of participants Therefore this topic could be of potential
interest in future large randomised trials with adequate control of
bias
All-cause mortality at one year after liver transplantation is re-
ported to be about 20 (Thuluvath 2003) which we also ob-
served for the patients included in the present review According to
our subgroup analyses neither UDCA nor TUDCA significantly
decreased all-cause mortality We also performed a subgroup anal-
ysis regarding treatment duration but we were not able to find any
difference between short (less than six months) and long treatment
duration (six months or more) Thus bile acids do not seem to
have statistically significant effects in reducing all-cause mortal-
ity after liver transplantation We performed both worst-best-case
scenario and best-worst-case scenario analyses In the worst-best-
case scenario bile acids did not differ significantly from placebo or
no intervention regarding all-cause mortality However bile acids
significantly decreased all-cause mortality in the best-worst-case
scenario analysis However such an analysis is very extreme and
may not be realistic We have also found that UDCA may be able
to decrease the risk of chronic rejection in liver-transplanted pa-
tients but trial sequential analysis could not confirm this result
Due to a limited number of patients (Ioannidis 2001) we are not
able to exclude the possibility that it may be relevant to perform
placebo-controlled trials with low risk of bias on the use of bile
acids for liver-transplanted patients
We looked into the causes of deaths that were reported by the trials
and only one trial reported one death related to rejection At the
same time the number of retransplantations was 3 among 68 liver-
transplanted patients who received treatment with UDCA and 4
among 64 liver-transplanted patients who received treatment with
placebo We noticed that all patients in the included trials received
co-interventions of standard triple-drug regimens (steroids aza-
thioprine and cyclosporine or tacrolimus) which were able to
control the possible acute or chronic rejection and prevent deaths
due to allograft rejection (FK506 1994)
The assumption that UDCA might reduce the incidence of acute
graft rejection came from the findings that UDCA could regulate
major histocompatibility complex antigen expression in bile ducts
and liver endothelia and inhibit lymphocyte activity (Calmus
1990 Terasaki 1991 Perez 2009) However in the present review
bile acids did not significantly reduce the risk of acute cellular re-
jection in liver-transplanted patients Considering that acute cellu-
lar rejection is commonly found within a few days after liver trans-
plantation (Vierling 1992) some might argue that the adminis-
tration of bile acids was started too late to prevent acute cellular
rejection We performed subgroup analyses regarding the time bile
acids were started and no statistically significant difference was
found Furthermore bile acids were not able to decrease the risk
of steroid-resistant rejection Therefore the lack of effects of bile
acids does not seem to be due to a delayed start to bile acid ad-
ministration after liver transplantation However it is a possibility
that one should start bile acids intake before liver transplantation
A retrospective study found that rejection rates differed signifi-
cantly between patients with primary biliary cirrhosis treated with
or without UDCA before liver transplantation (Heathcote 1999)
One could argue whether UDCA-induced delay in transplantation
has an adverse effect on post-transplantation outcome Since we
did not find any prospective randomised clinical trials addressing
this issue further research might be needed Furthermore some
studies may provide an explanation why UDCA was not able to
prevent acute cellular rejection These studies found that UDCA
did not appear to change the expression of major histocompatibil-
ity complex class II antigens but rather major histocompatibility
complex class I antigens (Calmus 1990) The initial mechanism
of acute rejection is thought to be recognition of MHC class II
13Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
antigens by CD4+ T cells (Vierling 1992) Moreover the inhibi-
tion of the production of interleukin-2 by peripheral blood lym-
phocytes with UDCA (Heuman 1993) might be negated by the
immunosuppressive treatment after liver transplantation (van den
Berg 1998) so that UDCA is unable to demonstrate effects on
graft rejection In a recent study by Assy 2007 a significant re-
duction in the mean dose of immunosuppressive medications was
achieved in stable liver graft recipients treated with UDCA indi-
cating a possible influence of UDCA on rejection mechanisms
In accordance with previous systematic reviews (Chen 2003a
Chen 2007 Gong 2008) bile acids were not associated with the
occurrence of serious adverse events or any major occurrence of
adverse events
In summary our results do not support or refute the use of bile
acids (UDCA and TUDCA) additional to standard immunosup-
pressive treatment in liver-transplanted patients
A U T H O R S rsquo C O N C L U S I O N SImplications for practice
There seems to be no evidence to support or refute the use of bile
acids for liver-transplanted patients receiving standard immuno-
suppressive treatment
Implications for research
We need more randomised placebo-controlled clinical trials with
enough statistical power and low risk of bias to explore the poten-
tial effects of bile acids on chronic rejection and mortality in liver-
transplanted patients Such trials should also consider evaluation
of quality of life and length of hospitalisation Such trials may
consider starting bile acid and placebo interventions before liver
transplantation we were not able to identify any randomised trials
addressing this regimen Such trials ought to be reported accord-
ing to the CONSORT statement (wwwconsort-statementorg)
However before embarking on such trials the effects of bile acids
in other patient groups should be scrutinised as they may have
small or negative effects
A C K N O W L E D G E M E N T S
We thank all the patients and investigators who were involved in
the clinical trials mentioned in this review We thank Wendong
Chen for his work and contribution on the previous version of this
review We thank the staff of The Cochrane Hepato-Biliary Group
Editorial Team especially Dimitrinka Nikolova and Sarah Louise
Klingenberg for excellent collaboration and assistance during the
update of this review
Peer Reviewers Carlo Merkel Italy M Tomikawa Japan
Contact Editor Bodil Als-Nielsen Denmark
R E F E R E N C E S
References to studies included in this review
Angelico 1999 published data only
Angelico M Tisone G Baiocchi L Palmieri G Pisani F Negrini S
et alOne-year pilot study on tauroursodeoxycholic acid as an
adjuvant treatment after liver transplantation Italian Journal of
Gastroenterology and Hepatology 199931(6)462ndash8 [MEDLINE
10575563]
Barnes 1997 published data onlylowast Barnes D Talenti D Cammell G Goormastic M Farquhar L
Henderson M et alA randomized clinical trial of ursodeoxycholic
acid as adjuvant treatment to prevent liver transplant rejection
Hepatology 199726(4)853ndash7 [MEDLINE 9328304]
Barnes D Talenti D Goormastic M Farquhar L Cammell G
Henderson M et alUrsodeoxycholic acid (UDCA) reduces hepatic
allograft rejection after orthotopic liver transplantation (OLT) - a
prospective randomized placebo-controlled double-blind trial
Hepatology 199522149A
Fleckenstein 1998 published data only
Fleckenstein JF Paredes M Thuluvath PJ A prospective
randomized double-blind trial evaluating the efficacy of
ursodeoxycholic acid in prevention of liver transplant rejection
Liver Transplantation and Surgery 19984(4)276ndash9 [MEDLINE
9649640]
Keiding 1997 published data only
Keiding S Hockerstedt K Bjoro K Bondesen S Hjortrup A
Isoniemi H et alThe Nordic multicenter double-blind randomized
controlled trial of prophylactic ursodeoxycholic acid in liver
transplant patients Transplantation 199763(11)1591ndash4
[MEDLINE 9197351]
Koneru 1993 published data only
Koneru B Tint GS Wilson DJ Leevy CB Salen F Randomised
prospective trial of ursodeoxycholic acid in liver transplant
recipients Hepatology 199318336A
Pageaux 1995 published data only
Pageaux GP Blanc P Perrigault PF Navarro F Fabre JM Souche B
et alFailure of ursodeoxycholic acid to prevent acute cellular
rejection after liver transplantation Journal of Hepatology 199523
(2)119ndash22 [MEDLINE 7499781]
Sama 1991 published data only
Sama C Mazziotti A Grigioni W Morselli AM Chianura A
Stefanini GF et alUrsodeoxycholic acid administration does not
14Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
prevent rejection after OLT Journal of Hepatology 199113(Suppl
2)68
References to studies excluded from this review
Assy 2007 published data only
Assy N Adams PC Myers P Simon V Minuk GY Wall W et
alRandomized controlled trial of total immunosuppression
withdrawal in liver transplant recipients role of ursodeoxycholic
acid Transplantation 200783(12)1571ndash6 [MEDLINE
17589339]
Clavien 1996 published data only
Clavien PA Sharara AI Camargo CA Jr Harland RC Fitz JG
Evidence that ursodeoxycholic acid prevents steroid-resistant
rejection in adult liver transplantation Clinical Transplantation
199610(6 Pt 2)658ndash62 [MEDLINE 8996761]
Friman 1992 published data only
Friman S Persson H Schersten T Svanvik J Karlberg I Adjuvant
treatment with ursodeoxycholic acid reduces acute rejection after
liver transplantation Transplantation Proceedings 199224(1)
389ndash90 [MEDLINE 1539328]
Heathcote 1999 published data onlylowast Heathcote EJ Stone J Cauch-Dudek K Poupon R Chazouilleres
O Lindor KD et alEffect of pretransplantation ursodeoxycholic
acid therapy on the outcome of liver transplantation in patients
with primary biliary cirrhosis Liver Transplantation and Surgery
19995(4)269ndash74 [MEDLINE 10388499]
Henriksson 1991 published data only
Henriksson BA Persson H Friman S Wangberg B Svanvik J
Karlberg I Adjuvant ursodeoxycholic acid prevents acute rejection
in liver transplant recipients Transplantation Proceedings 199123
(3)1971 [MEDLINE 2063453]
Persson 1990 published data only
Persson H Friman S Schersten T Svanvik J Karlberg I
Ursodeoxycholic acid for prevention of acute rejection in liver
transplant recipients Lancet 1990336(8706)52ndash3 [MEDLINE
1973232]
Rafael 1995 published data only
Rafael E Duraj F Rudstrom H Wilczek H Ericzon B Effect of
ursodeoxycholic acid treatment for cholestasis in liver transplant
recipients Transplantation Proceedings 199527(6)3501ndash2
[MEDLINE 8540069]
Sama 1998 published data only
Sama C Morselli-Labate AM Grazi GL Mastroianni A Danesi G
Pianta P et alUrsodeoxycholic acid in liver transplantation effect
on cholestasis and rejection Gastroenterology 1998114(4 Suppl)
A1332
Additional references
Adams 1990
Adams DH Neuberger JM Patterns of graft rejection following
liver transplantation Journal of Hepatology 199010(1)113ndash9
[MEDLINE 2407770]
Al-Quaiz 1994
Al-Quaiz M OrsquoGrady J Tredger J Williams R Variable effect of
ursodeoxycholic acid on cyclosporin absorption after orthotopic
liver transplantation Transplant International 19947(3)190ndash4
[MEDLINE 8060468]
Armstrong 1982
Armstrong MJ Carey MC The hydrophobic-hydrophilic balance
of bile salt Inverse correlation between reverse phase high
performance liquid chromatographic mobilities and micellar
cholesterol-solubilizing capacities Journal of Lipid Research 1982
23(1)70ndash80 [MEDLINE 7057113]
Ascher 1988
Ascher NL Stock PG Baumgardner GL Payne WD Najarian JS
Infection and rejection of primary hepatic transplant in 93
consecutive patients treated with triple immunosuppressive therapy
Surgery Gynecology amp Obstetrics 1988167(6)474ndash84
[MEDLINE 3055368]
Brok 2008
Brok J Thorlund K Gluud C Wetterslev J Trial sequential
analysis reveals insufficient information size and potentially false
positive results in many meta-analyses Journal of Clinical
Epidemiology 200861(8)763ndash9 [MEDLINE 18411040]
Brok 2009
Brok J Thorlund K Wetterslev J Gluud C Apparently conclusive
meta-analysis may be inconclusive - Trial sequential analysis
adjustment of random error risk due to repetitive testing of
accumulating data in apparently conclusive neonatal meta-analysis
International Journal of Epidemiology 200938(1)298ndash303
[MEDLINE 18824466]
Calmus 1990
Calmus Y Gane P Rouger P Poupon R Hepatic expression of class
I and class II major histocompatibility complex molecules in
primary biliary cirrhosis effect of ursodeoxycholic acid Hepatology
199011(1)12ndash5 [MEDLINE 2403961]
Calmus 1992
Calmus Y Arvieux C Gane P Boucher E Nordlinger B Rouger P
et alCholestasis induces major histocompatibility complex class I
expression in hepatocytes Gastroenterology 1992102(4 Pt 1)
1371ndash7 [MEDLINE 1551542]
Chen 2003a
Chen W Gluud C Bile acids for primary sclerosing cholangitis
Cochrane Database of Systematic Reviews 2003 Issue 2 [DOI
10100214651858CD003626]
Chen 2007
Chen W Liu J Gluud C Bile acids for viral hepatitis Cochrane
Database of Systematic Reviews 2007 Issue 4 [DOI 101002
14651858CD003181pub2]
Cheng 2002
Cheng K Ashby D Smyth R Ursodeoxycholic acid for cystic
fibrosis-related liver disease Cochrane Database of Systematic
Reviews 2002 Issue 2 [DOI 10100214651858CD000222]
Corbani 2008
Corbani A Burroughs AK Intrahepatic cholestasis after liver
transplantation Clinics in Liver Disease 200812(1)111ndash29
[MEDLINE 18242500]
DeMets 1987
DeMets DL Methods for combining randomised clinical trials
strengths and limitations Statistics in Medicine 19876(3)341ndash50
[MEDLINE 3616287]
15Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
DerSimonian 1986
DerSimonian R Laird N Meta-analysis in clinical trials Controlled
Clinical Trials 19867(3)177ndash88 [MEDLINE 3802833]
Egger 1997
Egger M Davey Smith G Schneider M Minder C Bias in meta-
analysis detected by a simple graphical test BMJ (Clinical Research
Ed) 1997315(7109)629ndash34 [MEDLINE 9310563]
Ericzon 1990
Ericzon BG Eusufzai S Kubota K Einarsson K Angelin B
Characteristics of biliary lipid metabolism after liver
transplantation Hepatology 199012(5)1222ndash8 [MEDLINE
2227822]
FK506 1994
The US Multicenter FK506 Liver Study Group A comparison of
tacrolimus (FK506) and cyclosporine for immunosuppression in
liver transplantation New England Journal of Medicine 1994331
(17)1110ndash5 [MEDLINE 7523946]
Friman 1994
Friman S Svanvik J A possible role of ursodeoxycholic acid in liver
transplantation Scandinavian Journal of Gastroenterology 1994204
62ndash4 [MEDLINE 7824880]
Fuchs 1999
Fuchs M Stange EF Metabolism of bile acids In Johannes
Bircher Jean-Pierre Benhamou Neil McIntyre Mario Rizzetto
Juan Rodes editor(s) Oxford Textbook of Clinical Hepatology 2
Vol 1 Oxford Oxford University Press 1999223ndash56
Fusai 2006
Fusai G Dhaliwal P Rolando N Sabin CA Patch D Davidson BR
et alIncidence and risk factors for the development of prolonged
and severe intrahepatic cholestasis after liver transplantation Liver
Transplantation 200612(11)1626ndash33 [DOI 101002lt20870]
Gluud 2001
Gluud C Alcoholic hepatitis no glucocorticosteroids In
Leuschner U James OFW Dancygier H editor(s) Steatohepatitis
(NASH and ASH) Falk Symposium 121 Lancaster Kluwer
Academic Publisher 2001322ndash42
Gluud 2010
Gluud C Nikolova D Klingenberg SL Alexakis N Als-Nielsen B
Colli A et alCochrane Hepato-Biliary Group About The
Cochrane Collaboration (Cochrane Review Groups (CRGs))
2010 Issue 1 Art No LIVER
Gong 2008
Gong Y Huang ZB Christiansen E Gluud C Ursodeoxycholic
acid for primary biliary cirrhosis Cochrane Database of Systematic
Reviews 2008 Issue 3 [DOI 101002
14651858CD000551pub2]
Haddad 2006
Haddad EM McAlister VC Renouf E Malthaner R Kjaer MS
Gluud LL Cyclosporin versus tacrolimus for liver transplanted
patients Cochrane Database of Systematic Reviews 2006 Issue 4
[DOI 10100214651858CD005161pub2]
Heuman 1993
Heuman DM Hepatoprotective properties of ursodeoxycholic acid
Gastroenterology 1993104(6)1865ndash9 [MEDLINE 8500748]
Higgins 2008
Higgins PTJ Green S editors Cochrane Handbook for Systematic
Reviews of Interventions West Sussex England Wiley-Blackwell
2008
Hirschfield 2009
Hirschfield GM Gibbs P Griffiths WJH Adult liver
transplantation what non-specialists need to know BMJ (Clinical
Research Ed) 2009338(b1670)1321ndash7 [DOI 101136
bmjb1670]
Hussain 2002
Hussain HK Nghiem HV Imaging of hepatic transplantation
Clinics in Liver Disease 20026(1)247ndash70 [MEDLINE
11933592]
ICH-GCP 1997
International Conference on Harmonisation Expert Working
Group Code of Federal Regulations amp International Conference on
Harmonization Guidelines Media Parexel Barnett 1997
Ioannidis 2001
Ioannidis JPA Lau J Evolution of treatment effects over time
Empirical insight from recursive cumulative meta analyses
Proceedings of the National Academy of Sciences 200198(3)831ndash6
IWP 1995
International Working Party Terminology for hepatic allograft
rejection Hepatology 199522(2)648ndash54 [MEDLINE 7635435]
Kjaergard 2001
Kjaergard LL Villumsen J Gluud C Reported methodological
quality and discrepancies between large and small randomised trials
in meta-analyses Annals of Internal Medicine 2001135(11)982ndash9
[MEDLINE 11730399]
Klintmalm 1989
Klintmalm GB Nery JR Husberg BS Gonwa TA Tillery GW
Rejection in liver transplantation Hepatology 198910(6)978ndash85
[MEDLINE 2583691]
Knechtle 2009
Knechtle SJ Kwun J Unique aspects of rejection and tolerance in
liver transplantation Seminars in Liver Disease 200929(1)91ndash101
[MEDLINE 19235662]
Krams 1993
Krams SM Ascher NL Martinez OM New immunologic insights
into mechanisms of allograft rejection Gastroenterology Clinics of
North America 199318(2)374ndash7 [MEDLINE 8509176]
Lan 1983
Lan KKG DeMets DL Discrete sequential boundaries for clinical
trials Biometrika 198370659ndash63
Merion 1989
Merion RM Gorski DH Burtch GD Turcotte JG Colletti LM
Campbell DA Jr Bile refeeding after liver transplantation and
avoidance of intravenous cyclosporine Surgery 1989106(4)
604ndash9 [MEDLINE 2799635]
Moher 1998
Moher D Pham B Jones A Cook DJ Jadad AR Moher M et
alDoes quality of reports of randomised trials affect estimates of
intervention efficacy reported in meta-analyses Lancet 1998352
(9128)609ndash13 [MEDLINE 9746022]
16Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Neuberger 1999
Neuberger J Incidence timing and risk factors for acute and
chronic rejection Liver Transplantation and Surgery 19995(4 Suppl
1)S30ndashS36 [MEDLINE 10431015]
Okolicsanyi 1986
Okolicsanyi L Lirussi F Strazzabosco M Jemmolo RM Orlando R
Nassuato G et alThe effect of drugs on bile flow and composition
An overview Drugs 198631(5)430ndash48 [MEDLINE 2872047]
Palmer 1972
Palmer RH Bile acids liver injury and liver disease Archives of
Internal Medicine 1972130(4)606ndash17 [MEDLINE 4627840]
Perez 2009
Perez MJ Briz O Bile-acid-induced cell injury and protection
World Journal of Gastroenterology 200915(14)1677ndash89
[MEDLINE 19360911]
Pogue 1997
Pogue JM Yusuf S Cumulating evidence from randomized trials
Utilizing sequential monitoring boundaries for cumulative meta-
analysis Controlled Clinical Trials 199718(6)580ndash93
[MEDLINE 9408720]
Pogue 1998
Pogue J Yusuf S Overcoming the limitations of current meta-
analysis of randomised controlled trials Lancet 1998351(9095)
45ndash52 [MEDLINE 9433436]
RevMan 2008
The Nordic Cochrane Centre The Cochrane Collaboration
Review Manager (RevMan) 50 Copenhagen The Nordic
Cochrane Centre The Cochrane Collaboration 2008
Royle 2003
Royle P Milne R Literature searching for randomized controlled
trials used in Cochrane reviews rapid versus exhaustive searches
International Journal of Technology Assessment in Health Care 2003
19(4)591ndash603
Schulz 1995
Schulz KF Chalmers I Hayer R Altman D Empirical evidence of
bias JAMA 1995273(5)408ndash12 [MEDLINE 7823387]
Sharara 1995
Sharara AI Camargo CA Clavien PA Ursodeoxycholic acid
prevents steroid resistant rejection in liver transplant recipients
Gastroenterology 1995108A1168
Sholmerich 1984
Sholmerich J Becher MS Schmidt KH Schubert R Kremer B
Felhaus S et alInfluence of hydroxylation and conjugation of bile
salts on their membrane damaging properties Hepatology 19844
(4)661ndash7 [MEDLINE 6745854]
Soderdahl 1998
Soderdahl G Nowak G Duraj F Wang FH Einarsson C Ericzon
BG Ursodeoxycholic acid increased bile flow and affects bile
composition in the early postoperative phase following liver
transplantation Transplantation International 199811(Suppl 1)
S231ndashS238 [MEDLINE 9664985]
Terasaki 1991
Terasaki S Nakanuma Y Ogino H Unoura M Kobayashi K
Hepatocellular and biliary expression of HLA antigens in primary
biliary cirrhosis before and after ursodeoxycholic acid therapy
American Journal of Gastroenterology 199186(9)1194ndash9
[MEDLINE 1882800]
Thalheimer 2002
Thalheimer U Capra F Liver transplantation making the best out
of what we have Digestive Diseases and Sciences 200247(5)
945ndash53 [MEDLINE 12018919]
Thorlund 2009
Thorlund K Devereaux PJ Wetterslev J Guyatt G Ioannidis JP
Thabane L et alCan trial sequential monitoring boundaries reduce
spurious inferences from meta-analyses International Journal of
Epidemiology 200938(1)276ndash86 [MEDLINE 18824467]
Thuluvath 2003
Thuluvath PJ Yoo HY Thompson RE A model to predict survival
at one month one year and five years after liver transplantation
based on pretransplant clinical characteristics Liver Transplantation
20039(5)527ndash32 [MEDLINE 12740799]
van den Berg 1998
van den Berg AP Twilhaar WN Mesander G van Son WJ van der
Bij W Klompmaker IJ et alQuantitation of immunosuppression
by flow cytometric measurement of the capacity of T cells for
interleukin-2 production Transplantation 199865(8)1066ndash71
[MEDLINE 9583867]
Vierling 1992
Vierling J Immunologic mechanisms of hepatic allograft rejection
Seminars in Liver Disease 199212(1)16ndash27 [MEDLINE
1570548]
Wetterslev 2008
Wetterslev J Thorlund K Brok J Gluud C Trial sequential
analysis may establish when firm evidence is reached in cumulative
meta-analysis Journal of Clinical Epidemiology 200861(1)64ndash75
[MEDLINE 18083463]
Wiesner 1992
Wiesner RH Acute cellular rejection following liver
transplantation incidence risk factors and outcome in the
NIDDK Liver Transplant Database (LTD) study Gastroenterology
1992102A910
Wood 2008
Wood L Egger M Gluud LL Schulz KF Juni P Altman DG et
alEmpirical evidence of bias in treatment effect estimates in
controlled trials with different interventions and outcomes meta-
epidemiological study BMJ (Clinical Research Ed) 2008336
(7644)601ndash5 [MEDLINE 18316340]
Yoshikawa 1998
Yoshikawa M Matsui Y Kawamoto H Toyohara M Matsumura
K Yamao J et alIntragastric administration of ursodeoxycholic
acid suppresses immunoglobulin secretion by lymphocytes from
liver but not from peripheral blood spleen or Peyerrsquos patches in
mice International Journal of Immunopharmacology 199820(1-3)
29ndash38 [MEDLINE 9717080]
References to other published versions of this review
17Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Chen 2003b
Chen W Gluud C Bile acids for liver transplanted patients
Cochrane Database of Systematic Reviews 2005 Issue 3 [DOI
10100214651858CD005442]lowast Indicates the major publication for the study
18Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
C H A R A C T E R I S T I C S O F S T U D I E S
Characteristics of included studies [ordered by study ID]
Angelico 1999
Methods Study design open-label randomised one-year pilot study
Participants Country Italy
Publication language English
Inclusion criteria
- patients who underwent liver transplantation from April 1994 to December 1994
Exclusion criteria
- not mentioned
Participants
Two patients in TUDCA group and two patients in control group were excluded from
the basic information of participants by the study due to withdrawal
- TUDCA group (n = 14)
Mean age (years +- SD)
467 +- 84
Ratio of sex (malefemale) 122
Origins of liver diseases
hepatitis C cirrhosis (9) hepatitis B cirrhosis (2) hepatitis B and C cirrhosis (1) cryp-
togenic cirrhosis (2) alcoholic cirrhosis (0) Wilson cirrhosis (0)
- Control group (n = 15)
Mean age (years +- SD)
474 +- 74
Ratio of sex (malefemale) 123
Origins of liver diseases
hepatitis C cirrhosis (7) hepatitis B cirrhosis (2) hepatitis B and C cirrhosis (2) cryp-
togenic cirrhosis (2) alcoholic cirrhosis (1) Wilson cirrhosis (1)
Interventions TUDCA group
- Dose 500 mgday in two divided doses
- Route orally
- Duration the treatment was started on day 5 after transplantation and continued for
one year
Control group
- no treatment
Co-interventions all patients received standard triple-drug regimens (steroids azathio-
prine and cyclosporine or tacrolimus)
Outcomes All cause mortality
Number of patients with rejection after liver transplantation
Notes Letter was sent to the authors in September 2009 A reply with additional information
was received shortly after
Risk of bias
19Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Angelico 1999 (Continued)
Item Authorsrsquo judgement Description
Adequate sequence generation Yes Computer generated table
Allocation concealment Unclear No information provided
Blinding No Not performed
Incomplete outcome data addressed
All outcomes
Yes Withdrawal two patients from the
TUDCA group and two patients from the
placebo group Three of them died due to
transplant non-function in the first postop-
erative week and one patient was regrafted
due to thrombosis of hepatic artery
Free of selective reporting Unclear Post-transplant cholestasis and liver bio-
chemistry specified as outcomes Differ-
ence reported as not significant but no ac-
tual data given
Sample size calculation No Not reported
Intention-to-treat analysis No Not stated and not used
Baseline imbalance Unclear Not enough information provided
Early stopping of trial Unclear Not enough information provided
Barnes 1997
Methods Study design randomised placebo-controlled double-blind trial
Participants Country United States
Publication language English
Inclusion criteria
- patients aged 18 years or older who underwent liver transplantation at the Cleveland
Clinic Foundation from April 1992 through June of 1994
Exclusion criteria
- patients who were found to have cancer at surgically resected margins of the biliary
tree
- patents who underwent retransplantation
Participants
- UDCA group (n = 28)
Mean age (years +- SD)
505 +- 116
Ratio of sex (malefemale) 1810
Child class A 7
20Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Barnes 1997 (Continued)
B 13
and C 8
Origins of liver diseases Laennecrsquos cirrhosis 4
PBC 3
cryptogenic cirrhosis 6
hepatitis Ccirrhosis 4
hepatitis Bcirrhosis 3
autoimmune hepatitis with cirrhosis 3
PSC 2
other 3
- Placebo group (n = 24)
Mean age (years +- SD)
507 +- 93
Ratio of sex (malefemale) 159
Child class A 6
B 14
and C 4
Origins of liver diseases Laennecrsquos cirrhosis 9
PBC 5
cryptogenic cirrhosis 1
hepatitis Ccirrhosis 1
hepatitis Bcirrhosis 1
autoimmune hepatitis with cirrhosis 1
PSC 2
other 4
Interventions UDCA group
- Dose 10-15 mgkg body weightday in divided doses
- Route orally
- Duration immediately after intestinal transit recovery usually between postoperative
days three and five and continue for three months
Placebo group
- identical-appearing capsules administered in the same quantity and manner
Co-interventions all patients received standard triple-drug regimens (steroids azathio-
prine and cyclosporine or tacrolimus)
Outcomes All cause mortality
Number of patients with acute cellular rejection
Number of patients with chronic rejection
Number of patients with steroid-resistant rejection
Number of days of hospitalisation
Adverse events
Notes Letter was sent to the authors in September 2009 A reply with additional information
was received shortly after
Risk of bias
Item Authorsrsquo judgement Description
21Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Barnes 1997 (Continued)
Adequate sequence generation Yes Computer generated table
Allocation concealment Unclear No information provided
Blinding Yes Quote ldquorandomised to receive either
UDCA or an identical placebo capsulerdquo
Incomplete outcome data addressed
All outcomes
Yes Mean follow-up time 18 months Ten pa-
tients withdrawn from study 6 in UDCA
group and 4 in placebo group Reasons
for withdrawal were reported Four patients
died in the placebo group
Free of selective reporting Yes All expected outcomes reported
Sample size calculation Unclear The trial reported the method of sample
size calculation but the actual number of
patients needed was not reported
Intention-to-treat analysis Yes Stated and used
Baseline imbalance Unclear Not enough information provided
Early stopping of trial Unclear The number of patients needed to gain the
actual power was not reported Whether
the trial was terminated early is not clear
Fleckenstein 1998
Methods Study design prospective randomised double-blind trial
Participants Country United States
Publication language English
Inclusion criteria
- patients who underwent liver transplantation at the Johns Hopkins Hospital
Exclusion criteria
- patients who were under 18 years old undergoing repeat transplantation had primary
graft nonfunction or refused consent
Participants
- UDCA group (n = 14)
Mean age (years +- SD)
443 +- 127
Ratio of sex (malefemale) 68
Origins of liver diseases hepatitis C 6
alcohol 2
autoimmune 1
PBC 2
22Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Fleckenstein 1998 (Continued)
PSC 1
autoimmune cholangiopathy 1
hepatitis B 1
- Placebo group (n = 16)
Mean age (years +- SD)
496 +- 109
Ratio of sex (malefemale) 124
Origins of liver diseases hepatitis C 3
alcohol 3
autoimmune 3
PBC 1
PSC 2
cryptogenic 2
hepatitis B 1
alpha1-antitrypsin deficiency 1
Interventions UDCA group
- Dose 15 mgkg body weightday in divided doses
- Route orally
- Duration immediately after intestinal transit recovery usually between postoperative
days three and five and continue for three months
Placebo group
- Identical-appearing capsules administered in the same quantity and manner
Co-interventions all patients received standard triple-drug regimens (steroids azathio-
prine and cyclosporine or tacrolimus)
Outcomes All cause mortality
Number with retransplantation
Number of patients with acute cellular rejection
Number of patients with chronic rejection
Serum bilirubin levels at the end of treatment
Notes Follow-up time nine months
Letter was sent to the authors in September 2009 No reply was received
Risk of bias
Item Authorsrsquo judgement Description
Adequate sequence generation Unclear No information provided
Allocation concealment Unclear No information provided
Blinding Yes Method of blinding not described but
probably adequate
Incomplete outcome data addressed
All outcomes
Yes Withdrawal one patient from the UDCA
group and two patients from the placebo
group because of capsule size
23Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Fleckenstein 1998 (Continued)
Free of selective reporting Unclear Outcomes were not completely described
Sample size calculation No Not reported
Intention-to-treat analysis Yes Quote ldquoThree patients withdrew after in-
clusionThey were included in the statis-
tical analysisrdquo
Baseline imbalance Unclear Not enough information provided
Early stopping of trial Unclear Not enough information provided
Keiding 1997
Methods Study design prospective randomised placebo-controlled multicenter study
Participants Country Denmark Finland Norway and Sweden
Publication language English
Inclusion criteria
- patients who underwent liver transplantation in Denmark Finland Norway and Swe-
den from September 1 1992 to May 31 1994
Exclusion criteria
- patients with malignant diseases
Participants
The age of the children ranged from 0 to 13 years (median 15) and the age of adults
ranged from 14 to 59 years old (median 44) MaleFemale ratio was 96 for children and
4344 for adults
- UDCA group (n = 54)
Origins of liver diseases
paracetamol intoxication 1 hepatitis B 1 autoimmune hepatitis 0 biliary atresia 2
metabolic diseases 7 neonatal hepatitis 2 PBC 13 post hepatitis cirrhosis 8 PSC 3
cryptogenic cirrhosis 7 alcoholic cirrhosis 2 other reasons 8
- Placebo group (n = 48)
Origins of liver diseases paracetamol intoxication 1 hepatitis B 0 autoimmune hepatitis
1 biliary atresia 3 metabolic diseases 11 neonatal hepatitis 0 PBC 7 post hepatitis
cirrhosis 5 PSC 7 cryptogenic cirrhosis 2 alcoholic cirrhosis 6 other reasons 5
Interventions UDCA group
- Dose 15 mgkg body weightday in two or three divided doses
- Route orally
- Duration immediately after intestinal transit recovery usually between postoperative
days three and five and continue for three months
Placebo group
- Identical-appearing capsules administered in the same quantity and manner
Co-interventions all patients received standard triple-drug regimens (steroids azathio-
prine and cyclosporine or tacrolimus)
24Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Keiding 1997 (Continued)
Outcomes All cause mortality
Number of deaths related to rejection
Number of patients with acute cellular rejection
Number of patients with chronic rejection
Number of patients with steroid-resistant rejection
Adverse events
Notes Letter was sent to the authors in September 2009 No reply was received
Risk of bias
Item Authorsrsquo judgement Description
Adequate sequence generation Unclear Patients were randomised at a ratio of 11
Allocation concealment Yes Quote ldquo The allocation was performed in
blocks of 10 patients using the sealed serial
envelope methodrdquo
Blinding Yes Quote ldquoThe UDCA and the placebo cap-
sules had identical appearance and tasterdquo
Incomplete outcome data addressed
All outcomes
Yes Follow-up time 12 months Five UDCA
patients and five placebo patients withdrew
from study Reasons were reported
Free of selective reporting Unclear Insufficient information
Sample size calculation Yes Performed and allowed for a difference in
the incidence of at least one episode of
acute rejection of 50 between the treat-
ment and placebo groups with 90 statisti-
cal power and a significance level of P value
less than 005 The calculated sample size
was 80 patients
Intention-to-treat analysis Yes Stated and used
Baseline imbalance Yes The study seems to be free of baseline im-
balance
Early stopping of trial Yes Study attained the pre-specified sample
size
25Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Koneru 1993
Methods Study design randomised controlled trial
Participants Country United States
Publication language English
Inclusion criteria
- patients who underwent liver transplantation
Exclusion criteria
- not mentioned
Participants
- UDCA group (n = 16)
Mean age (years +- SD)
no information
Ratio of sex (malefemale) no information
Origins of liver diseases
no information
- Control group (n = 16)
Mean age (years +- SD)
no information
Ratio of sex (malefemale) no information
Origins of liver diseases
no information
Interventions UDCA group
- Dose 900 mgday
- Route orally
- Duration immediately after intestinal transit recovery usually between postoperative
days three and five and continue for three months
Control group
- no treatment
Co-interventions all patients received standard triple-drug regimens (steroids azathio-
prine and cyclosporine)
Outcomes Number of patients with retransplantation due to rejection
Number of patients with rejection episodes
Notes Abstract
Letter was sent to the authors in September 2009 No reply was received
Risk of bias
Item Authorsrsquo judgement Description
Adequate sequence generation Unclear No information provided
Allocation concealment Unclear No information provided
Blinding No Not performed
26Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Koneru 1993 (Continued)
Incomplete outcome data addressed
All outcomes
Unclear The study gives the impression that there
were no withdrawals but this was not ex-
plicitly stated
Free of selective reporting Unclear Insufficient information provided
Sample size calculation No Not performed
Intention-to-treat analysis Unclear No information provided
Baseline imbalance Unclear Not enough information provided
Early stopping of trial Unclear Not enough information provided
Pageaux 1995
Methods Study design double-blind randomised study
Participants Country France
Publication language English
Inclusion criteria
- patients who underwent liver transplantation
Exclusion criteria
- not mentioned
Participants
- UDCA group (n=26)
Mean age (years +- SD)
47 +- 10
Ratio of sex (malefemale) 179
Origins of liver diseases alcoholic cirrhosis 14
post-hepatic B cirrhosis 2
post-hepatitis C cirrhosis 4
PBC 2
liver cancer 2
fulminant hepatitis 1
miscellaneous 1
- Placebo group (n = 24)
Mean age (years +- SD)
51+- 9
Ratio of sex (malefemale) 159
Origins of liver diseases alcoholic cirrhosis 10
post-hepatic B cirrhosis 0
post-hepatic C cirrhosis 6
PBC 3
liver cancer 4
fulminant hepatitis 0
miscellaneous 1
27Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Pageaux 1995 (Continued)
Interventions UDCA group
- Dose 600 mgday in three divided doses
- Route orally
- Duration immediately after intestinal transit recovery usually between postoperative
days three and five and continue for two months
Placebo group
- identical-appearing capsules administered in the same quantity and manner
Co-interventions all patients received standard triple-drug regimens (steroids azathio-
prine and cyclosporine or tacrolimus)
Outcomes Number of patients with acute cellular rejection
Number of patients with steroid-resistant rejection
Notes Letter was sent to the authors in September 2009 No reply was received
Risk of bias
Item Authorsrsquo judgement Description
Adequate sequence generation Unclear No information provided
Allocation concealment Unclear No information provided
Blinding Unclear Method of blinding not described
Incomplete outcome data addressed
All outcomes
Yes Five patients died from non-immunologi-
cal causes before the end of the first month
and were excluded from the study Reasons
were reported
Free of selective reporting Unclear Not enough information provided
Sample size calculation No Not performed
Intention-to-treat analysis No Not stated and not used
Baseline imbalance Unclear Not enough information provided
Early stopping of trial Unclear Not enough information provided
Sama 1991
Methods Study design randomised controlled trial
Participants Country Italy
Publication language English
Inclusion criteria
28Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Sama 1991 (Continued)
- patients who underwent liver transplantation
Exclusion criteria
- not mentioned
Participants
- UDCA group (n = 20)
Mean age (years +- SD)
no information
Ratio of sex (malefemale) no information
Origins of liver diseases
no information
- Control group (n = 20)
Mean age (years +- SD)
no information
Ratio of sex (malefemale) no information
Origins of liver diseases
no information
Interventions UDCA group
- Dose 600 mgday in two divided doses
- Route orally
- Duration immediately after intestinal transit recovery usually between postoperative
day five and day seven and continue for six months
Control group
- no treatment
Co-interventions all patients received standard immunosuppressive treatment (steroids
and cyclosporine)
Outcomes All cause mortality
Number of patients with acute cellular rejection
Notes Abstract
Letter was sent to the authors in September 2009 No reply was received
Risk of bias
Item Authorsrsquo judgement Description
Adequate sequence generation Unclear A randomisation list was performed before
patients were admitted to the trial (infor-
mation from principal author)
Allocation concealment Unclear No information provided
Blinding Unclear The principle author provided information
that the study was made according to a
single-blind randomised protocol The pri-
mary outcome was the occurrence of biopsy
proven rejection episodes The pathologists
were blind but the patients were not
29Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Sama 1991 (Continued)
Incomplete outcome data addressed
All outcomes
Unclear Five patients from the UDCA group and
six patients from the placebo group were
excluded Reasons for exclusion were not
fully stated
Free of selective reporting No Data about survival of patients were not
adequately reported
Sample size calculation No Not performed
Intention-to-treat analysis No Not stated and not used
Baseline imbalance Unclear Basic characteristics of patients not re-
ported
Early stopping of trial Unclear Not enough information provided
UDCA = ursodeoxycholic acid
TUDCA = tauroursodeoxycholic acid
PBC = primary biliary cirrhosis
PSC = primary sclerosing cholangitis
OKT3 = anti-CD3 monoclonal antibody
Characteristics of excluded studies [ordered by study ID]
Assy 2007 A randomised controlled trial that included only recipients of liver transplantation with stable graft function and
no episodes of rejection for at least 2 years that were then offered total immunosuppression withdrawal Fourteen
patients received UDCA (15 mgkg body weightday) and 12 received placebo Rejection occurred in 43 and
75 of patients respectively (no significant difference) None developed chronic rejection After follow-up two
patients were free of immunosuppression 80 were steroid free and 50 were able to reduce their dose of
cyclosporine
Clavien 1996 Case series Fifty consecutive liver-transplanted patients were treated with a standard cyclosporine immunosup-
pressive regimen Twenty three of the 43 survivors developed an episode of rejection and UDCA (10 mgkg
weightday) was initiated Only one patient had a second episode of rejection
Friman 1992 Observational study Thirty-three liver-transplanted patients received 10 mg UDCAkg body weightday for
median of 10 months (range four to 21 months) Eight historical liver-transplanted patients served as control
group The rejection incidence was significantly lower in the patients who received the treatment with UDCA
Biochemistry one month after transplantation demonstrated significantly lower average values of aminotrans-
ferases and alkaline phosphatases in patients treated with UDCA than in the control group
30Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
Heathcote 1999 Observational study From 1987 to 1996 37 UDCA treated and 53 placebo treated patients with primary biliary
cirrhosis were referred for transplantation Posttransplantation survival rates at one month were 939 in the
UDCA group and 884 in the placebo group and one year survival rates were 903 and 784 respectively
(no significant differences) However rejection (type not defined - a secondary outcome measure) occurred
significantly less often in the UDCA group (429) than in placebo group (688)
Henriksson 1991 Observational study All patients in this study were given sequential quadruple immunosuppression with anti-
lymphocyte globulin azathioprine steroids and cyclosporine All patients with primary graft function (n = 11)
were treated with 10 mg UDCAkg body weightday starting during the first postoperative week Patients who
received liver transplantation in the first 6 months of 1989 (n = 8) served as controls In the control group one
patient died after 9 months with chronic graft dysfunction and six patients had rejection episodes during the
first postoperative month All patients in the UDCA group were alive without rejection episodes
Persson 1990 Observational study All 11 adult patients transplanted between August 1989 and January 1990 with primary
graft function were treated with 10 mg UDCA kg body weightday Eight patients transplanted during the first
half of 1989 served as control UDCA was started during the first postoperative week and the treatment was
continued for six months All patients in the UDCA treated group survived with satisfactory graft function In
the control group six patients had at least one rejection episode needing treatment during the first postoperative
month
Rafael 1995 Observational study Seventeen patients who underwent liver transplantation between February 1990 and April
1993 and developed biliary complications after transplantation were retrospectively analysed regarding treatment
with UDCA UDCA was given in a dose of 500 to 1000 mgday Ten patients were treated for at least one year while
seven patients were treated for 14 to 250 days UDCA significantly improved gammaglutamyl transpeptidase in
liver graft recipients with biliary complications There was also a trend towards improvement in serum bilirubin
and alanine transaminase values
Sama 1998 Observational study Thirty-four patients who underwent liver transplantation between January 1995 and June
1996 were included in the study Seventeen were treated with UDCA 10 mgkg body weightday during 6
months while 17 served as controls on the basis of having undergone liver transplantation closest to UDCA
patients A significant decrease in serum bilirubin levels was observed in UDCA patients There was a significantly
higher incidence of recurrent hepatitis in the control group
UDCA ursodeoxycholic acid
31Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
D A T A A N D A N A L Y S E S
Comparison 1 Bile acids for liver-transplanted patients
Outcome or subgroup titleNo of
studies
No of
participants Statistical method Effect size
1 All-cause mortality at maximum
follow-up
5 257 Risk Ratio (M-H Fixed 95 CI) 085 [053 136]
11 UDCA versus placebo or
no treatment
4 224 Risk Ratio (M-H Fixed 95 CI) 080 [049 130]
12 TUDCA versus no
treatment
1 33 Risk Ratio (M-H Fixed 95 CI) 159 [030 833]
2 All-cause mortality worst-best
case and best-worst case
scenarios
5 Risk Ratio (M-H Fixed 95 CI) Subtotals only
21 Worst-best case scenario 5 257 Risk Ratio (M-H Fixed 95 CI) 130 [086 196]
22 Best-worst case scenario 5 257 Risk Ratio (M-H Fixed 95 CI) 058 [038 090]
3 Subgroup analyses all-cause
mortality at maximum
follow-up according to time of
start of bile acids
5 257 Risk Ratio (M-H Fixed 95 CI) 085 [053 136]
31 Less than three days after
transplantation
1 102 Risk Ratio (M-H Fixed 95 CI) 124 [061 254]
32 Three days or more after
transplantation
4 155 Risk Ratio (M-H Fixed 95 CI) 063 [033 120]
4 Subgroup analyses all cause
mortality at maximum
follow-up according to
treatment duration
5 257 Risk Ratio (M-H Fixed 95 CI) 085 [053 136]
41 Less than six months 3 184 Risk Ratio (M-H Fixed 95 CI) 078 [045 138]
42 Six months or more 2 73 Risk Ratio (M-H Fixed 95 CI) 102 [043 240]
5 Number of deaths related
to rejection at maximum
follow-up
1 102 Risk Ratio (M-H Fixed 95 CI) 030 [001 712]
51 UDCA versus placebo 1 102 Risk Ratio (M-H Fixed 95 CI) 030 [001 712]
6 Number of retransplantations at
maximum follow-up
2 132 Risk Ratio (M-H Fixed 95 CI) 076 [020 286]
7 Number of patients with acute
cellular rejection at maximum
follow-up
7 339 Risk Ratio (M-H Fixed 95 CI) 089 [074 106]
71 UDCA versus placebo or
no treatment
6 306 Risk Ratio (M-H Fixed 95 CI) 089 [074 108]
72 TUDCA versus no
treatment
1 33 Risk Ratio (M-H Fixed 95 CI) 085 [045 160]
8 Subgroup analysis number of
patients with acute cellular
rejection according to time of
start of bile acid
7 339 Risk Ratio (M-H Fixed 95 CI) 089 [074 106]
32Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
81 Less than three days after
transplantation
2 134 Risk Ratio (M-H Fixed 95 CI) 084 [063 111]
82 Three days or more after
liver transplantation
5 205 Risk Ratio (M-H Fixed 95 CI) 092 [072 117]
9 Subgroup analysis number
of patients with acute
cellular rejection according to
treatment duration
7 339 Risk Ratio (M-H Fixed 95 CI) 089 [074 106]
91 Less than six months 5 266 Risk Ratio (M-H Fixed 95 CI) 087 [071 107]
92 Six months or more 2 73 Risk Ratio (M-H Fixed 95 CI) 094 [065 136]
10 Number of patients with
chronic rejection at maximum
follow-up
3 184 Risk Ratio (M-H Fixed 95 CI) 028 [008 095]
11 Number of patients with
steroid-resistant rejection at
maximum follow-up
4 234 Risk Ratio (M-H Fixed 95 CI) 077 [047 127]
12 Serum bilirubin (mgdl) at the
end of treatment
1 30 Mean Difference (IV Fixed 95 CI) 26 [-096 616]
13 Number of days of
hospitalisation after liver
transplantation
1 52 Mean Difference (IV Fixed 95 CI) -85 [-1667 -033]
14 Adverse events 3 187 Risk Ratio (M-H Fixed 95 CI) 088 [030 260]
Analysis 11 Comparison 1 Bile acids for liver-transplanted patients Outcome 1 All-cause mortality at
maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 1 All-cause mortality at maximum follow-up
Study or subgroup Favours bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 UDCA versus placebo or no treatment
Barnes 1997 228 724 253 024 [ 006 107 ]
Fleckenstein 1998 214 416 125 057 [ 012 266 ]
Keiding 1997 1454 1048 355 124 [ 061 254 ]
Sama 1991 520 620 201 083 [ 030 229 ]
Subtotal (95 CI) 116 108 935 080 [ 049 130 ]
Total events 23 (Favours bile acids) 27 (Control)
Heterogeneity Chi2 = 416 df = 3 (P = 025) I2 =28
Test for overall effect Z = 091 (P = 036)
01 02 05 1 2 5 10
Favours bile acids Favours control
(Continued )
33Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Favours bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
2 TUDCA versus no treatment
Angelico 1999 316 217 65 159 [ 030 833 ]
Subtotal (95 CI) 16 17 65 159 [ 030 833 ]
Total events 3 (Favours bile acids) 2 (Control)
Heterogeneity not applicable
Test for overall effect Z = 055 (P = 058)
Total (95 CI) 132 125 1000 085 [ 053 136 ]
Total events 26 (Favours bile acids) 29 (Control)
Heterogeneity Chi2 = 466 df = 4 (P = 032) I2 =14
Test for overall effect Z = 069 (P = 049)
01 02 05 1 2 5 10
Favours bile acids Favours control
Analysis 12 Comparison 1 Bile acids for liver-transplanted patients Outcome 2 All-cause mortality worst-
best case and best-worst case scenarios
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 2 All-cause mortality worst-best case and best-worst case scenarios
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 Worst-best case scenario
Angelico 1999 516 217 65 266 [ 060 1180 ]
Barnes 1997 828 724 253 098 [ 042 230 ]
Fleckenstein 1998 314 416 125 086 [ 023 319 ]
Keiding 1997 1954 1048 355 169 [ 087 327 ]
Sama 1991 520 620 201 083 [ 030 229 ]
Subtotal (95 CI) 132 125 1000 130 [ 086 196 ]
Total events 40 (Bile acids) 29 (Control)
Heterogeneity Chi2 = 303 df = 4 (P = 055) I2 =00
Test for overall effect Z = 123 (P = 022)
2 Best-worst case scenario
005 02 1 5 20
Favours bile acids Favours control
(Continued )
34Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Angelico 1999 316 417 90 080 [ 021 302 ]
Barnes 1997 228 1124 274 016 [ 004 063 ]
Fleckenstein 1998 214 616 130 038 [ 009 159 ]
Keiding 1997 1454 1548 368 083 [ 045 154 ]
Sama 1991 520 620 139 083 [ 030 229 ]
Subtotal (95 CI) 132 125 1000 058 [ 038 090 ]
Total events 26 (Bile acids) 42 (Control)
Heterogeneity Chi2 = 567 df = 4 (P = 023) I2 =29
Test for overall effect Z = 247 (P = 0014)
005 02 1 5 20
Favours bile acids Favours control
Analysis 13 Comparison 1 Bile acids for liver-transplanted patients Outcome 3 Subgroup analyses all-
cause mortality at maximum follow-up according to time of start of bile acids
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 3 Subgroup analyses all-cause mortality at maximum follow-up according to time of start of bile acids
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 Less than three days after transplantation
Keiding 1997 1454 1048 355 124 [ 061 254 ]
Subtotal (95 CI) 54 48 355 124 [ 061 254 ]
Total events 14 (Bile acids) 10 (Control)
Heterogeneity not applicable
Test for overall effect Z = 060 (P = 055)
2 Three days or more after transplantation
Angelico 1999 316 217 65 159 [ 030 833 ]
Barnes 1997 228 724 253 024 [ 006 107 ]
Fleckenstein 1998 214 416 125 057 [ 012 266 ]
Sama 1991 520 620 201 083 [ 030 229 ]
005 02 1 5 20
Favours bile acids Favours control
(Continued )
35Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Subtotal (95 CI) 78 77 645 063 [ 033 120 ]
Total events 12 (Bile acids) 19 (Control)
Heterogeneity Chi2 = 310 df = 3 (P = 038) I2 =3
Test for overall effect Z = 141 (P = 016)
Total (95 CI) 132 125 1000 085 [ 053 136 ]
Total events 26 (Bile acids) 29 (Control)
Heterogeneity Chi2 = 466 df = 4 (P = 032) I2 =14
Test for overall effect Z = 069 (P = 049)
005 02 1 5 20
Favours bile acids Favours control
Analysis 14 Comparison 1 Bile acids for liver-transplanted patients Outcome 4 Subgroup analyses all
cause mortality at maximum follow-up according to treatment duration
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 4 Subgroup analyses all cause mortality at maximum follow-up according to treatment duration
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 Less than six months
Barnes 1997 228 724 253 024 [ 006 107 ]
Fleckenstein 1998 214 416 125 057 [ 012 266 ]
Keiding 1997 1454 1048 355 124 [ 061 254 ]
Subtotal (95 CI) 96 88 734 078 [ 045 138 ]
Total events 18 (Bile acids) 21 (Control)
Heterogeneity Chi2 = 417 df = 2 (P = 012) I2 =52
Test for overall effect Z = 084 (P = 040)
2 Six months or more
Angelico 1999 316 217 65 159 [ 030 833 ]
Sama 1991 520 620 201 083 [ 030 229 ]
Subtotal (95 CI) 36 37 266 102 [ 043 240 ]
Total events 8 (Bile acids) 8 (Control)
Heterogeneity Chi2 = 043 df = 1 (P = 051) I2 =00
005 02 1 5 20
Favours bile acids Favours control
(Continued )
36Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Test for overall effect Z = 004 (P = 097)
Total (95 CI) 132 125 1000 085 [ 053 136 ]
Total events 26 (Bile acids) 29 (Control)
Heterogeneity Chi2 = 466 df = 4 (P = 032) I2 =14
Test for overall effect Z = 069 (P = 049)
005 02 1 5 20
Favours bile acids Favours control
Analysis 15 Comparison 1 Bile acids for liver-transplanted patients Outcome 5 Number of deaths related
to rejection at maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 5 Number of deaths related to rejection at maximum follow-up
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 UDCA versus placebo
Keiding 1997 054 148 1000 030 [ 001 712 ]
Total (95 CI) 54 48 1000 030 [ 001 712 ]
Total events 0 (Bile acids) 1 (Control)
Heterogeneity not applicable
Test for overall effect Z = 075 (P = 045)
0001 001 01 1 10 100 1000
Favours bile acids Favours control
37Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 16 Comparison 1 Bile acids for liver-transplanted patients Outcome 6 Number of
retransplantations at maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 6 Number of retransplantations at maximum follow-up
Study or subgroup Bile acids Placebo Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Fleckenstein 1998 214 016 100 567 [ 029 10891 ]
Keiding 1997 154 448 900 022 [ 003 192 ]
Total (95 CI) 68 64 1000 076 [ 020 286 ]
Total events 3 (Bile acids) 4 (Placebo)
Heterogeneity Chi2 = 303 df = 1 (P = 008) I2 =67
Test for overall effect Z = 040 (P = 069)
0001 001 01 1 10 100 1000
Favours bile acids Favours placebo
Analysis 17 Comparison 1 Bile acids for liver-transplanted patients Outcome 7 Number of patients with
acute cellular rejection at maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 7 Number of patients with acute cellular rejection at maximum follow-up
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 UDCA versus placebo or no treatment
Barnes 1997 1728 1724 180 086 [ 058 127 ]
Fleckenstein 1998 814 916 83 102 [ 054 190 ]
Keiding 1997 3554 3248 333 097 [ 073 129 ]
Koneru 1993 316 916 89 033 [ 011 101 ]
Pageaux 1995 926 924 92 092 [ 044 193 ]
Sama 1991 1320 1320 128 100 [ 063 158 ]
Subtotal (95 CI) 158 148 905 089 [ 074 108 ]
01 02 05 1 2 5 10
Favours bile acids Favours control
(Continued )
38Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Total events 85 (Bile acids) 89 (Control)
Heterogeneity Chi2 = 387 df = 5 (P = 057) I2 =00
Test for overall effect Z = 120 (P = 023)
2 TUDCA versus no treatment
Angelico 1999 816 1017 95 085 [ 045 160 ]
Subtotal (95 CI) 16 17 95 085 [ 045 160 ]
Total events 8 (Bile acids) 10 (Control)
Heterogeneity not applicable
Test for overall effect Z = 050 (P = 061)
Total (95 CI) 174 165 1000 089 [ 074 106 ]
Total events 93 (Bile acids) 99 (Control)
Heterogeneity Chi2 = 392 df = 6 (P = 069) I2 =00
Test for overall effect Z = 130 (P = 019)
01 02 05 1 2 5 10
Favours bile acids Favours control
Analysis 18 Comparison 1 Bile acids for liver-transplanted patients Outcome 8 Subgroup analysis
number of patients with acute cellular rejection according to time of start of bile acid
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 8 Subgroup analysis number of patients with acute cellular rejection according to time of start of bile acid
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 Less than three days after transplantation
Keiding 1997 3554 3248 333 097 [ 073 129 ]
Koneru 1993 316 916 89 033 [ 011 101 ]
Subtotal (95 CI) 70 64 422 084 [ 063 111 ]
Total events 38 (Bile acids) 41 (Control)
Heterogeneity Chi2 = 374 df = 1 (P = 005) I2 =73
Test for overall effect Z = 124 (P = 022)
2 Three days or more after liver transplantation
Angelico 1999 816 1017 95 085 [ 045 160 ]
01 02 05 1 2 5 10
Favours bile acids Favours control
(Continued )
39Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Barnes 1997 1728 1724 180 086 [ 058 127 ]
Fleckenstein 1998 814 916 83 102 [ 054 190 ]
Pageaux 1995 926 924 92 092 [ 044 193 ]
Sama 1991 1320 1320 128 100 [ 063 158 ]
Subtotal (95 CI) 104 101 578 092 [ 072 117 ]
Total events 55 (Bile acids) 58 (Control)
Heterogeneity Chi2 = 041 df = 4 (P = 098) I2 =00
Test for overall effect Z = 067 (P = 050)
Total (95 CI) 174 165 1000 089 [ 074 106 ]
Total events 93 (Bile acids) 99 (Control)
Heterogeneity Chi2 = 392 df = 6 (P = 069) I2 =00
Test for overall effect Z = 130 (P = 019)
01 02 05 1 2 5 10
Favours bile acids Favours control
40Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 19 Comparison 1 Bile acids for liver-transplanted patients Outcome 9 Subgroup analysis
number of patients with acute cellular rejection according to treatment duration
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 9 Subgroup analysis number of patients with acute cellular rejection according to treatment duration
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 Less than six months
Barnes 1997 1728 1724 180 086 [ 058 127 ]
Fleckenstein 1998 814 916 83 102 [ 054 190 ]
Keiding 1997 3554 3248 333 097 [ 073 129 ]
Koneru 1993 316 916 89 033 [ 011 101 ]
Pageaux 1995 926 924 92 092 [ 044 193 ]
Subtotal (95 CI) 138 128 777 087 [ 071 107 ]
Total events 72 (Bile acids) 76 (Control)
Heterogeneity Chi2 = 374 df = 4 (P = 044) I2 =00
Test for overall effect Z = 129 (P = 020)
2 Six months or more
Angelico 1999 816 1017 95 085 [ 045 160 ]
Sama 1991 1320 1320 128 100 [ 063 158 ]
Subtotal (95 CI) 36 37 223 094 [ 065 136 ]
Total events 21 (Bile acids) 23 (Control)
Heterogeneity Chi2 = 017 df = 1 (P = 068) I2 =00
Test for overall effect Z = 035 (P = 073)
Total (95 CI) 174 165 1000 089 [ 074 106 ]
Total events 93 (Bile acids) 99 (Control)
Heterogeneity Chi2 = 392 df = 6 (P = 069) I2 =00
Test for overall effect Z = 130 (P = 019)
01 02 05 1 2 5 10
Favours bile acids Favours control
41Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 110 Comparison 1 Bile acids for liver-transplanted patients Outcome 10 Number of patients
with chronic rejection at maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 10 Number of patients with chronic rejection at maximum follow-up
Study or subgroup Bile acids Placebo Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Barnes 1997 128 624 611 014 [ 002 110 ]
Fleckenstein 1998 114 116 88 114 [ 008 1663 ]
Keiding 1997 154 348 300 030 [ 003 275 ]
Total (95 CI) 96 88 1000 028 [ 008 095 ]
Total events 3 (Bile acids) 10 (Placebo)
Heterogeneity Chi2 = 148 df = 2 (P = 048) I2 =00
Test for overall effect Z = 204 (P = 0041)
0001 001 01 1 10 100 1000
Favours bile acids Favours placebo
Analysis 111 Comparison 1 Bile acids for liver-transplanted patients Outcome 11 Number of patients
with steroid-resistant rejection at maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 11 Number of patients with steroid-resistant rejection at maximum follow-up
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Barnes 1997 328 724 277 037 [ 011 127 ]
Fleckenstein 1998 314 316 103 114 [ 027 478 ]
Keiding 1997 1454 1548 583 083 [ 045 154 ]
Pageaux 1995 226 124 38 185 [ 018 1908 ]
Total (95 CI) 122 112 1000 077 [ 047 127 ]
Total events 22 (Bile acids) 26 (Control)
Heterogeneity Chi2 = 226 df = 3 (P = 052) I2 =00
Test for overall effect Z = 102 (P = 031)
001 01 1 10 100
Favours bile acids Favours placebo
42Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 112 Comparison 1 Bile acids for liver-transplanted patients Outcome 12 Serum bilirubin (mgdl)
at the end of treatment
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 12 Serum bilirubin (mgdl) at the end of treatment
Study or subgroup Bile acids Placebo Mean Difference Weight Mean Difference
N Mean(SD) N Mean(SD) IVFixed95 CI IVFixed95 CI
Fleckenstein 1998 14 319 (68) 16 059 (022) 1000 260 [ -096 616 ]
Total (95 CI) 14 16 1000 260 [ -096 616 ]
Heterogeneity not applicable
Test for overall effect Z = 143 (P = 015)
-10 -5 0 5 10
Favours bile acids Favours placebo
Analysis 113 Comparison 1 Bile acids for liver-transplanted patients Outcome 13 Number of days of
hospitalisation after liver transplantation
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 13 Number of days of hospitalisation after liver transplantation
Study or subgroup Bile acids Placebo Mean Difference Weight Mean Difference
N Mean(SD) N Mean(SD) IVFixed95 CI IVFixed95 CI
Barnes 1997 28 25 (17) 24 335 (13) 1000 -850 [ -1667 -033 ]
Total (95 CI) 28 24 1000 -850 [ -1667 -033 ]
Heterogeneity not applicable
Test for overall effect Z = 204 (P = 0041)
-100 -50 0 50 100
Favours bile acids Favours placebo
43Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 114 Comparison 1 Bile acids for liver-transplanted patients Outcome 14 Adverse events
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 14 Adverse events
Study or subgroup Bile acids Placebo Risk Ratio Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Angelico 1999 016 017 00 [ 00 00 ]
Barnes 1997 128 124 086 [ 006 1298 ]
Keiding 1997 554 548 089 [ 027 288 ]
Total (95 CI) 98 89 088 [ 030 260 ]
Total events 6 (Bile acids) 6 (Placebo)
Heterogeneity Chi2 = 000 df = 1 (P = 098) I2 =00
Test for overall effect Z = 022 (P = 082)
001 01 1 10 100
Favours bile acids Favours placebo
A P P E N D I C E S
Appendix 1 Search strategies
Data Base Date of Search Search Strategy
The Cochrane Hepato-Biliary Group Con-
trolled Trials Register
September 2009 1 rsquoliver transplantationrsquo and rsquochenodeoxy-
cholicrsquo
2 rsquoliver transplantationrsquo and rsquocholicrsquo
3 rsquoliver transplantationrsquo and rsquodeoxycholicrsquo
4 rsquoliver transplantationrsquo and rsquoglycochen-
odeoxycholicrsquo
5 rsquoliver transplantationrsquo and rsquoglycocholicrsquo
6 rsquoliver transplantationrsquo and rsquoglycodeoxy-
cholicrsquo
7 rsquoliver transplantationrsquo and rsquoglycolitho-
cholicrsquo
8 rsquoliver transplantationrsquo and rsquohyodeoxy-
cholicrsquo
9 rsquoliver transplantationrsquo and rsquolithocholicrsquo
10 rsquoliver transplantationrsquo and rsquotaurochen-
odeoxycholicrsquo
44Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
11 rsquoliver transplantationrsquo and rsquotauro-
cholicrsquo
12 rsquoliver transplantationrsquo and rsquotaurodehy-
drocholicrsquo
13 rsquoliver transplantationrsquo and rsquotau-
rodeoxycholicrsquo
14 rsquoliver transplantationrsquo and rsquotauroglyco-
cholicrsquo
15 rsquoliver transplantationrsquo and rsquotaurolitho-
cholicrsquo
16 rsquoliver transplantationrsquo and rsquotaurosel-
cholicrsquo
17 rsquoliver transplantationrsquo and rsquotaurourso-
cholicrsquo
18 rsquoliver transplantationrsquo and rsquotaurour-
sodeoxycholicrsquo
19 rsquoliver transplantationrsquo and rsquoursocholicrsquo
20 rsquoliver transplantationrsquo and rsquoursodeoxy-
cholicrsquo
The Cochrane Central Register of Con-
trolled Trials in The Cochrane Library
Issue 3 2009 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
6 3 or 4
7 5 and 6
MEDLINE September 2009 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
45Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
6 3 or 4
7 5 and 6
8 RANDOMIZED-CONTROLLED-
TRIAL ME
9 RANDOM
10 8 or 9
11 7 and 10
EMBASE September 2009 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
6 3 or 4
7 5 and 6
8 RANDOMIZED-CONTROLLED-
TRIAL ME
9 RANDOM
10 8 or 9
11 7 and 10
46Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
Science Citation Index Expanded September 2009 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
6 3 or 4
7 5 and 6
8 RANDOMIZED-CONTROLLED-
TRIAL ME
9 RANDOM
10 8 or 9
11 7 and 10
The Chinese Biomedical Database Searched from January 1980 to April 2002 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
47Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
6 3 or 4
7 5 and 6
8 RANDOMIZED-CONTROLLED-
TRIAL ME
9 RANDOM
10 8 or 9
11 7 and 10
W H A T rsquo S N E W
Last assessed as up-to-date 8 February 2010
18 September 2009 New citation required but conclusions have not
changed
This review is an updated version of a review that was
published for the first time in Issue 3 2005 of TheCochrane Library by Chen 2003b
18 September 2009 New search has been performed No new studies fulfilled the inclusion criteria
H I S T O R Y
Protocol first published Issue 3 2003
Review first published Issue 3 2005
C O N T R I B U T I O N S O F A U T H O R S
GP and VG independently performed searches of relevant databases GP validated the search selected trials for inclusion contacted
the authors of the trials performed data extraction and data analysis and drafted the systematic review VG revised the review update
CG and DS revised the review update solved discrepancies of data extraction validated data analyses and provided consultation
D E C L A R A T I O N S O F I N T E R E S T
None known
48Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
S O U R C E S O F S U P P O R T
Internal sources
bull Copenhagen Trial Unit Denmark
External sources
bull Danish Medical Research Councilrsquos Grant on Getting Research into Practice (GRIP) Denmark
D I F F E R E N C E S B E T W E E N P R O T O C O L A N D R E V I E W
We assessed the risk of bias in the included studies for another four domains that were added to the review protocol (incomplete
outcome data selective outcome reporting baseline imbalance and early stopping of trial) In general the text of the risk of bias
domains were updated following Higgins 2008 Trials were considered at low risk of bias when judged as adequate in all domains
Quasi-randomised studies observational and case-control studies were included for the report of adverse events
We performed trial sequential analysis for outcomes demonstrating a statistically significant result
I N D E X T E R M S
Medical Subject Headings (MeSH)
lowastLiver Transplantation Cholagogues and Choleretics [lowasttherapeutic use] Graft Rejection [lowastprevention amp control] Randomized Con-
trolled Trials as Topic Taurochenodeoxycholic Acid [lowasttherapeutic use] Ursodeoxycholic Acid [lowasttherapeutic use]
MeSH check words
Humans
49Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
bull Adequate if there is no baseline imbalance in the main
characteristics
bull Unclear if there is no sufficient information to assess
baseline characteristics
bull Inadequate if there was a baseline imbalance due to chance
or due to imbalanced exclusion after randomisation
Early stopping
bull Adequate if sample size calculation was reported and the
trial was not stopped or the trial was stopped early by formal
stopping rules at a point where the likelihood of observing an
extreme intervention effect due to chance was low
bull Unclear if sample size calculation was not reported and it is
not clear whether the trial was stopped early or not
bull Inadequate if the trial was stopped early due to informal
stopping rules or the trial was stopped early by a formal stopping
rule at a point where the likelihood of observing an extreme
intervention effect due to chance was high
Furthermore we registered whether the randomised clinical trials
had used an intention-to-treat analysis (Gluud 2001) and had
calculated a sample size estimate
Statistical methods
We performed the analyses in RevMan 5 (RevMan 2008) Anal-
yses included all patients irrespective of compliance or follow-up
according to the intention-to-treat principle and using the last
reported observed response (rsquocarry forwardrsquo) Regarding death
both a worst-best-case scenario analysis considering all dropped-
out patients in the bile acid group as dead and the dropped-out
patients in the control group as alive and a best-worst-case sce-
nario analysis considering all dropped-out patients in the bile acid
group as alive and the dropped-out patients in the control group as
dead were performed Both a random-effects model (DerSimonian
1986) and a fixed-effect model (DeMets 1987) were used The re-
sults of the fixed-effect model were reported if there were no differ-
ences between the results produced by the two models otherwise
we reported the results produced by both models We presented
binary outcome measures as relative risks (RR) with 95 confi-
dence intervals (CI) and continuous outcome measures as mean
differences (MD) with 95 CI
The risk of type I errors increases in single trials with interim anal-
yses To avoid type I errors group sequential monitoring bound-
aries (Lan 1983) can be performed when deciding to terminate the
trial earlier than planned This requires analyses at different time
intervals to record when the P-value has become sufficiently small
that is when the cumulative Z-curve will cross the monitoring
boundaries Sequential monitoring boundaries the so called rsquotrial
sequential monitoring boundariesrsquo can also be applied to meta-
analyses In a trial sequential analysis (TSA) every trial that is
added in a cumulative meta-analysis is regarded as an interim meta-
analysis and the information it adds on helps on deciding if more
trials need to be included
The interpretation of the TSA is as follows if the cumulative Z-
curve has crossed the boundary a sufficient level of evidence is
reached and no further trials may be needed If the Z-curve has
not crossed the boundary then the evidence is insufficient in order
to reach a conclusion To construct the trial sequential monitor-
ing boundaries information size is needed It is calculated as the
minimum number of participants needed in a well-powered single
trial (Pogue 1997 Pogue 1998 Brok 2008 Wetterslev 2008) We
applied TSA since it prevents an increase of the risk of type I error
due to sparse and multiple updating in a cumulative meta-analysis
and provides us with important information in order to estimate
the level of evidence of the experimental intervention Addition-
ally TSA provides us with important information regarding the
need for additional trials and the required information size We
applied trial sequential monitoring boundaries according to an in-
formation size suggested by the trials with low risk of bias and a
50 relative risk reduction (RRR)
Subgroup analyses
We planned to perform the following subgroup analyses on the
main outcome measures (all-cause mortality and number of pa-
tients with acute rejection)
1 Risk of bias of the trials comparing the intervention effect for
trials with low risk of bias components to the intervention effect
in trials with unclear or high risk of bias components
2 Dose and duration of treatment with bile acids comparing the
intervention effect in trials administrating bile acid at or above the
median dose multiplied by duration to the intervention effect of
trials administrating bile acid at less than the median dose multi-
plied by duration
3 Time between transplantation and the start of bile acids com-
paring the intervention effect of trials having less than three days
between transplantation and starting bile acid intake to the inter-
vention effect of trials with a duration of three days or more be-
tween transplantation and the start of bile acid intake (Neuberger
1999)
4 Co-interventions comparing the intervention effect of trials
with co-interventions to the intervention effect of trials without
co-interventions
Funnel plot analysis
We planned to explore bias by funnel plot analysis (Egger 1997)
R E S U L T S
Description of studies
See Characteristics of included studies Characteristics of excluded
studies
The performed electronic searches resulted in a total of 378 ref-
erences We excluded 362 duplicates or irrelevant references by
reading abstracts We excluded eight of the 16 further assessed ref-
erences because they were observational studies case series or ran-
6Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
domised clinical trials with a different reason for exclusion They
are listed under rsquoCharacteristic of excluded studiesrsquo with reasons
for exclusion Seven references already included in the previous
version of this review and one new reference referring to an al-
ready included trial (Barnes 1997) were included in this review
We were not able to identify more trials by reading the reference
lists of the identified studies contacting the principle authors of
the identified trials or approaching pharmaceutical companies for
unpublished trials
Seven publications included in the review (five full publications
and two abstracts) were randomised clinical trials that reported
the random allocation of liver-transplanted patients into groups
receiving bile acid placebo or no treatment We listed these trials
in the table of Characteristics of included studies All seven trials
were published in English Three randomised clinical trials were
from the United States (Koneru 1993 Barnes 1997 Fleckenstein
1998) two from Italy (Sama 1991 Angelico 1999) one from
France (Pageaux 1995) and one from Denmark (Keiding 1997)
Patients
In the included trials all patients received blood group-compatible
grafts The median size of the seven trials was 40 patients (range
29 to 102 patients) In total 335 patients were randomised
Five trials were published as full publications (Pageaux 1995
Barnes 1997 Keiding 1997 Fleckenstein 1998 Angelico 1999)
which allowed us to extract detailed information on 263 of the
patients The mean age of the patients ranged from 44 to 51 years
One trial (Keiding 1997) also enrolled children ranging in age
from 0 to 13 years (median 15 years) The male to female ratio in
these five trials was 159104 The diseases that led to liver trans-
plantation were alcoholic cirrhosis in 51 patients (194) cirrho-
sis caused by chronic hepatitis C in 40 patients (152) primary
biliary cirrhosis in 36 patients (137) cryptogenic cirrhosis in
22 patients (84) metabolic diseases in 19 patients (72) pri-
mary sclerosing cholangitis in 17 patients (65) non-specified
post-hepatitis cirrhosis in 17 patients (65) cirrhosis caused by
chronic hepatitis B in 13 patients (49) 9 with autoimmune
hepatitis and cirrhosis (34) six with liver cancer (23) five
with biliary atresia (19) and 28 with other diseases (106)
Only one trial reported the severity of liver function according to
the Child-Pugh class (Barnes 1997)
Bile acids and collateral interventions
Six trials (Sama 1991 Koneru 1993 Pageaux 1995 Barnes
1997 Keiding 1997 Fleckenstein 1998) compared UDCA versus
placebo or no intervention One trial (Angelico 1999) compared
TUDCA versus no intervention Bile acid treatment began one
day after transplantation in the Keiding 1997 trial three days after
transplantation in the Koneru 1993 trial three or five days in the
Fleckenstein 1998 and Pageaux 1995 trials five days after trans-
plantation in the Barnes 1997 and Angelico 1999 trials and five
or seven days after transplantation in the Sama 1991 trial
Patients received UCDA (10 to 15 mgkg body weightday) for
two months in the Pageaux 1995 trial for three months in the
Koneru 1993 Barnes 1997 Keiding 1997 and Fleckenstein 1998
trials and for six months in the Sama 1991 trial In the Barnes
1997 trial patients were followed up for 18 months Patients in the
Fleckenstein 1998 trial and the Keiding 1997 trial were followed
up for nine months There was no post-treatment follow-up in
three trials (Sama 1991 Koneru 1993 Pageaux 1995) Patients
received TUDCA (500 mgday) for one year and no follow-up
was conducted in the Angelico 1999 trial
In addition to the bile acids or control intervention all patients
in the seven trials received standard triple-drug regimens (steroids
azathioprine and cyclosporine or tacrolimus) The patients who
had steroid-resistant rejection received treatment with immuno-
suppressive antibodies (OKT3)
Outcome measures
The outcome measures reported by most trials were all-cause mor-
tality and acute cellular rejection Three trials reported on death
related to rejection (Barnes 1997 Keiding 1997 Angelico 1999)
two trials reported the number of patients who received retrans-
plantation due to rejection (Keiding 1997 Fleckenstein 1998)
three trials reported the number of patients with chronic rejection
(Barnes 1997 Keiding 1997 Fleckenstein 1998) and four trials
reported the number of patients with steroid-resistant rejection
(Pageaux 1995 Barnes 1997 Keiding 1997 Fleckenstein 1998)
Four trials had adverse events as outcome measures (Barnes 1997
Keiding 1997 Fleckenstein 1998 Angelico 1999) Serum biliru-
bin level was only reported by the Fleckenstein 1998 trial No tri-
als provided data on other liver biochemical parameters quality
of life or cost-effectiveness
Risk of bias in included studies
Two trials reported adequate allocation sequence generation by
using computer-generated random tables (Barnes 1997 Angelico
1999) One trial (Keiding 1997) reported adequate allocation con-
cealment by using sealed serially numbered envelopes Three tri-
als (Barnes 1997 Keiding 1997 Fleckenstein 1998) reported ad-
equate blinding by using placebo with an identical appearance
and taste Five trials (Pageaux 1995 Barnes 1997 Keiding 1997
Fleckenstein 1998 Angelico 1999) reported adequate description
of incomplete outcome data by the number of withdrawals the
reasons for withdrawal or no patients dropped out The trial by
Keiding 1997 is the only one free of selective reporting since all
the pre-specified outcomes were fairly reported Two trials (Barnes
1997 Keiding 1997) performed sample-size calculations Only
the trial by Keiding 1997 seemed to be free of baseline imbalance
and it is the only trial achieving the calculated sample size and
therefore probably the only that was not terminated early Other
trials did not perform sample size calculation or the authors did
not report whether the calculated sample size was achieved The
lack of this information made it unclear for us to judge whether
7Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
a trial was terminated early that is before an adequate number
of patients was included in the trial Three trials (Barnes 1997
Keiding 1997 Fleckenstein 1998) stated that intention-to-treat
analyses were used (Figure 1 Figure 2)
Figure 1 Methodological quality graph review authorsrsquo judgements about each methodological quality
item presented as percentages across all included studies
8Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Figure 2 Methodological quality summary review authorsrsquo judgements about each methodological quality
item for each included study
9Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Following the assessment of risk of bias domains none of the seven
trials were considered to have low risk of bias that is having all
the nine domains for risk of bias assessed as adequate
Effects of interventions
We were able to include seven randomised clinical trials in this
review Six trials with 306 liver-transplanted patients compared
ursodeoxycholic acid (UDCA) with placebo or no intervention
and one trial with 29 liver-transplanted patients compared tauro-
UDCA (TUDCA) with no intervention
All-cause mortality
Five trials including 257 liver-transplanted patients reported on
all-cause mortality at the end of treatment or at maximum follow-
up Bile acids did not significantly reduce all-cause mortality (RR
085 95 CI 053 to 136) there were 26 deaths among 132
patients treated with bile acids (197) versus 29 deaths among
125 patients in the control groups (232) (Analysis 11) There
was no statistically significant heterogeneity (I2 = 141)
Four trials (Sama 1991 Barnes 1997 Keiding 1997 Fleckenstein
1998) showed that UDCA did not significantly reduce all-cause
mortality (RR 080 95 CI 049 to 130) 23 deaths among 116
patients treated with UCDA (198) versus 27 deaths among
108 patients in the control groups (250) The Angelico 1999
trial demonstrated that TUDCA was not able to reduce all-cause
mortality (RR 159 95 CI 030 to 833) there were 3 deaths
among 16 patients (188) versus 2 deaths among 17 patients
(118)
The Fleckenstein 1998 trial and the Sama 1991 trial did not report
the causes of deaths In the three other trials the deaths were
considered to be caused by infections (n = 11) hepatic failure (n =
7) abdominal bleeding (n = 3) renal failure (n = 2) multiple organ
failure (n = 2) hepatitis B virus fibrosis (n = 2) acute rejection
(n = 1) hepatic artery thrombosis (n = 1) encephalitis (n = 1)
lymphoproliferative disorder (n = 1) cerebral haemorrhage (n =
1) or other reasons (n = 6)
Worst-best case and best-worst case scenario analyses
In the worst-best case scenario analysis bile acids did not signif-
icantly reduce all-cause mortality when compared with placebo
or no intervention (RR 130 95 CI 086 to 196) 40 deaths
among 132 patients on bile acids (303) versus 29 deaths among
125 patients in the control groups (232) However all-cause
mortality was significantly reduced by bile acids in the best-worst
case scenario analysis (RR 058 95 CI 038 to 090) 26 deaths
among 132 patients (197) versus 42 deaths among 125 patients
in the control groups (336) (Analysis 12)
Subgroup analyses
We performed subgroup analyses regarding the time that bile acid
intake was started The Keiding 1997 trial started bile acid intake
less than three days after liver transplantation and demonstrated
no significant effect of UDCA on all-cause mortality (RR 124
95 CI 061 to 254) 14 deaths out of 54 patients (259)
versus 10 out of 48 control patients (208) The same effect
was noticed in the four other trials (Sama 1991 Barnes 1997
Fleckenstein 1998 Angelico 1999) which started bile acids three
days or more after liver transplantation (RR 063 95 CI 033
to 120) 12 deaths among 78 patients (154) versus 9 deaths
among 77 control patients (247) (Analysis 13) There were no
statistically significant differences between the two estimates
We also performed subgroup analyses regarding the duration of
bile acid treatment Bile acids were administrated for less than six
months in three trials (Barnes 1997 Keiding 1997 Fleckenstein
1998) and were not able to significantly decrease all-cause mor-
tality (RR 078 95 CI 045 to 138) 18 deaths in a group of
96 treated patients (188) versus 21 deaths among 88 control
patients (239) In the other two trials (Sama 1991 Angelico
1999) patients were treated with bile acids for six months or more
The treatment did not show statistically significant decrease in all-
cause mortality (RR 102 95 CI 043 to 24) 8 deaths in a
group of 36 treated patients (222) versus 8 deaths in a group
of 37 control patients (216) (Analysis 14) There were no sta-
tistically significant differences between the two estimates
Mortality related to allograft rejection
We did not find statistically significant reduction in mortality re-
lated to allograft rejection at maximum follow-up in the three tri-
als reporting cause of death (Barnes 1997 Keiding 1997 Angelico
1999) (RR 030 95 CI 001 to 712) 098 (0) versus 189
(11)) (Analysis 15) The only death due to acute rejection was
found in the placebo group of the Keiding 1997 trial
Number of liver retransplantations
Two trials (Fleckenstein 1998 Keiding 1997) including 132 liver-
transplanted patients reported the number of liver retransplan-
tations UDCA did not significantly reduce the risk of liver re-
transplantation at maximum follow-up (RR 076 95 CI 020
to 286) 368 (44) versus 464 (63)) (Analysis 16) In the
Keiding 1997 trial one patient in the UDCA group was retrans-
planted due to chronic rejection and four patients in the placebo
group were retransplanted either due to chronic rejection (three
cases) or acute rejection (one case) In the Fleckenstein 1998 trial
two patients in the UDCA group were retransplanted due to acute
rejection (one case) and chronic rejection (one case) respectively
Number of patients with acute cellular rejection
Seven trials reported the number of patients who had acute cellu-
lar rejection after liver transplantation Bile acids did not signifi-
cantly reduce the number of patients who experienced acute cel-
lular rejection (RR 089 95 CI 074 to 106) 93174(535)
versus 99165 (600)) There was no significant heterogeneity
(I2 = 0)
Six trials (Sama 1991 Koneru 1993 Pageaux 1995 Barnes 1997
10Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Keiding 1997 Fleckenstein 1998) compared UDCA with placebo
or no intervention and demonstrated that UDCA did not signifi-
cantly reduce the number of patients with acute cellular rejection
after liver transplantation (RR 089 95 CI 074 to 108 85
158 (538) versus 89148 (601)) Neither did the Angelico
1999 trial demonstrate significant reduction of the number of pa-
tients with acute cellular rejection with TUDCA (RR 085 95
CI 045 to 160) 816 (500) versus 1017 (588) (Analysis
17)
Subgroup analyses
Two trials (Koneru 1993 Keiding 1997) in which the patients
started bile acids intake less than three days after liver transplan-
tation did not demonstrate any significant reduction of the risk
of acute cellular rejection by bile acids (RR 084 95 CI 063 to
111) 3870 (543) versus 4164 (641) The other five tri-
als (Sama 1991 Pageaux 1995 Barnes 1997 Fleckenstein 1998
Angelico 1999) in which the patients were started on bile acid
intake three days or more after liver transplantation did not find
a significant reduction of the risk of acute cellular rejection by bile
acids (RR 092 95 CI 072 to 117) 55104 (529) versus 58
101 (574) (Analysis 18) There was no significant difference
between the two estimates
Bile acids did not significantly reduce the risk of acute cellular
rejection in the five trials (Koneru 1993 Pageaux 1995 Barnes
1997 Keiding 1997 Fleckenstein 1998) in which the patients
received treatment with bile acids less than six months (RR 087
95 CI 071 to 107) 72138 (522) versus 76128 (594)
Neither did bile acids in the two other trials (Sama 1991 Angelico
1999) in which the patients received bile acids for more than six
months (RR 094 95 CI 065 to 136) 2136 (583) versus
2337 (622) (Analysis 19) There were no significant difference
between the two estimates
Number of patients with chronic rejection
Three trials comparing UDCA versus placebo (Barnes 1997
Keiding 1997 Fleckenstein 1998) reported the number of patients
with chronic rejection after liver transplantation UDCA signifi-
cantly reduced the number of patients with chronic rejection in
the fixed-effect model analysis (RR 028 95 CI 008 to 095)
396 (31) versus 1088 (114) (Analysis 110) but not in the
random-effects model analysis (RR 030 95 CI 008 to 113) 3
96 (31) versus 1088 (114) There was no statistically signifi-
cant heterogeneity (I2 0) We performed trial sequential analysis
for the available data from three trials (Figure 3) with heterogene-
ity corrected required information size based on proportion of this
outcome of 12 in the control group a relative risk reduction of
50 in the intervention group at a type I error of 5 and a type
II error of 10 We obtained a required information size of 957
patients UDCA was not able to reach or break the trial sequential
monitoring boundary and only 183 out of 957 (19) patients
were randomised regarding this outcome
11Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Figure 3 Trial sequential analysis for the number of patients with chronic rejection at maximum follow-up
We calculated the heterogeneity-corrected required information size (HCRIS) based on a proportion of 12 of
the patients in the placebo group with chronic rejection at maximum follow-up a 50 risk ratio reduction in
the bile acid group an alpha of 5 a beta of 10 and a heterogeneity of 0 Only 184 patients have been
randomised reporting this outcome which is only 19 of the HCRIS of 957 patients The cumulative Z-score
crosses the conventional boundaries for P 005 but not the monitoring boundaries
Number of patients with steroid-resistant rejection
Four trials (Pageaux 1995 Barnes 1997 Keiding 1997
Fleckenstein 1998) reported the number of patients with steroid-
resistant rejection These trials demonstrated that UDCA did not
significantly reduce the number of patients with steroid-resistant
rejection when compared with placebo (22122 (18) versus 26
112 (232) (RR 077 95 CI 047 to 127) (Analysis 111)
There was no significant heterogeneity (I2 0)
Liver biochemistry
The Fleckenstein 1998 trial reported serum bilirubin levels after
a three-month-treatment period in 30 liver-transplanted patients
There was no statistically significant difference in serum bilirubin
levels between the UDCA group and the placebo group (MD 260
mgdl 95 CI -096 to 616 mgdl) (Analysis 112)
No data were available for other liver biochemical variables
Cost-effectiveness
One trial (Barnes 1997) with 52 liver-transplanted patients re-
ported the days of hospitalisation after liver transplantation
UDCA significantly decreased the number of days of hospitali-
sation when compared with placebo (MD -850 days 95 CI -
1667 to -033 days) (Analysis 113) We were not able to extract
other medical cost from the trials
Adverse events
Among all the included and excluded trials only four reported on
adverse events however adverse events only occurred in two of
the included trials (Barnes 1997 Keiding 1997) There were no
significant differences regarding adverse events (RR 088 95 CI
030 to 260) 6112 (54) versus 6105 (57) (Analysis 114)
In the Barnes 1997 trial diarrhoea was reported by two patients
(one in the UDCA group and one in the placebo group) In the
Keiding 1997 trial five UDCA patients and five placebo patients
stopped intake of the trial medicine because of diarrhoea or dif-
ficulties in swallowing the capsules The remaining included trial
by Angelico 1999 stated that no adverse events occurred during
the study period The excluded trial by Assy 2007 was the only
one reporting on a case of mild diarrhoea in one patient in the
12Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
intervention group No other excluded studies reported on adverse
events (see Table 1)
Quality of life
None of the included studies assessed quality of life as an outcome
Other subgroup analyses
We planned to perform subgroup analyses regarding the risk of
bias of trials the dosage of bile acid and any co-intervention
However none of the trials were considered to be of low risk of
bias they all used a similar dosage of bile acid and patients in all
trials received similar immunosuppressive treatment as co-inter-
ventions (steroids azathioprine and cyclosporine or tacrolimus)
after liver transplantation Therefore we were not able to perform
the planned subgroup analyses
Funnel plot asymmetry
We did not draw a funnel plot analysis due to the limited number
of trials included in the present review
D I S C U S S I O N
In the update of this review we included no new trials assessing
the use of bile acids for liver-transplanted patients The analyses
of the seven previously included trials showed that bile acids did
not significantly affect mortality acute cellular rejection steroid-
resistant rejection retransplantation or serum bilirubin Bile acids
might significantly decrease the length of hospital stay and the
number of patients with chronic rejection included in these tri-
als but more supportive evidence is needed The number of pa-
tients with chronic rejection was not significantly influenced by
bile acids when a random-effects model was used and length of
stay was assessed in one single trial Furthermore none of the trials
were considered to be of low risk of bias and few patients were en-
rolled Therefore our positive findings may be due to bias (Schulz
1995 Moher 1998 Kjaergard 2001 Wood 2008) or random er-
rors (Wetterslev 2008 Brok 2009 Thorlund 2009) On the other
hand we are not able to exclude type II errors (that is finding
no significant differences when in fact they exist) due to the low
number of participants Therefore this topic could be of potential
interest in future large randomised trials with adequate control of
bias
All-cause mortality at one year after liver transplantation is re-
ported to be about 20 (Thuluvath 2003) which we also ob-
served for the patients included in the present review According to
our subgroup analyses neither UDCA nor TUDCA significantly
decreased all-cause mortality We also performed a subgroup anal-
ysis regarding treatment duration but we were not able to find any
difference between short (less than six months) and long treatment
duration (six months or more) Thus bile acids do not seem to
have statistically significant effects in reducing all-cause mortal-
ity after liver transplantation We performed both worst-best-case
scenario and best-worst-case scenario analyses In the worst-best-
case scenario bile acids did not differ significantly from placebo or
no intervention regarding all-cause mortality However bile acids
significantly decreased all-cause mortality in the best-worst-case
scenario analysis However such an analysis is very extreme and
may not be realistic We have also found that UDCA may be able
to decrease the risk of chronic rejection in liver-transplanted pa-
tients but trial sequential analysis could not confirm this result
Due to a limited number of patients (Ioannidis 2001) we are not
able to exclude the possibility that it may be relevant to perform
placebo-controlled trials with low risk of bias on the use of bile
acids for liver-transplanted patients
We looked into the causes of deaths that were reported by the trials
and only one trial reported one death related to rejection At the
same time the number of retransplantations was 3 among 68 liver-
transplanted patients who received treatment with UDCA and 4
among 64 liver-transplanted patients who received treatment with
placebo We noticed that all patients in the included trials received
co-interventions of standard triple-drug regimens (steroids aza-
thioprine and cyclosporine or tacrolimus) which were able to
control the possible acute or chronic rejection and prevent deaths
due to allograft rejection (FK506 1994)
The assumption that UDCA might reduce the incidence of acute
graft rejection came from the findings that UDCA could regulate
major histocompatibility complex antigen expression in bile ducts
and liver endothelia and inhibit lymphocyte activity (Calmus
1990 Terasaki 1991 Perez 2009) However in the present review
bile acids did not significantly reduce the risk of acute cellular re-
jection in liver-transplanted patients Considering that acute cellu-
lar rejection is commonly found within a few days after liver trans-
plantation (Vierling 1992) some might argue that the adminis-
tration of bile acids was started too late to prevent acute cellular
rejection We performed subgroup analyses regarding the time bile
acids were started and no statistically significant difference was
found Furthermore bile acids were not able to decrease the risk
of steroid-resistant rejection Therefore the lack of effects of bile
acids does not seem to be due to a delayed start to bile acid ad-
ministration after liver transplantation However it is a possibility
that one should start bile acids intake before liver transplantation
A retrospective study found that rejection rates differed signifi-
cantly between patients with primary biliary cirrhosis treated with
or without UDCA before liver transplantation (Heathcote 1999)
One could argue whether UDCA-induced delay in transplantation
has an adverse effect on post-transplantation outcome Since we
did not find any prospective randomised clinical trials addressing
this issue further research might be needed Furthermore some
studies may provide an explanation why UDCA was not able to
prevent acute cellular rejection These studies found that UDCA
did not appear to change the expression of major histocompatibil-
ity complex class II antigens but rather major histocompatibility
complex class I antigens (Calmus 1990) The initial mechanism
of acute rejection is thought to be recognition of MHC class II
13Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
antigens by CD4+ T cells (Vierling 1992) Moreover the inhibi-
tion of the production of interleukin-2 by peripheral blood lym-
phocytes with UDCA (Heuman 1993) might be negated by the
immunosuppressive treatment after liver transplantation (van den
Berg 1998) so that UDCA is unable to demonstrate effects on
graft rejection In a recent study by Assy 2007 a significant re-
duction in the mean dose of immunosuppressive medications was
achieved in stable liver graft recipients treated with UDCA indi-
cating a possible influence of UDCA on rejection mechanisms
In accordance with previous systematic reviews (Chen 2003a
Chen 2007 Gong 2008) bile acids were not associated with the
occurrence of serious adverse events or any major occurrence of
adverse events
In summary our results do not support or refute the use of bile
acids (UDCA and TUDCA) additional to standard immunosup-
pressive treatment in liver-transplanted patients
A U T H O R S rsquo C O N C L U S I O N SImplications for practice
There seems to be no evidence to support or refute the use of bile
acids for liver-transplanted patients receiving standard immuno-
suppressive treatment
Implications for research
We need more randomised placebo-controlled clinical trials with
enough statistical power and low risk of bias to explore the poten-
tial effects of bile acids on chronic rejection and mortality in liver-
transplanted patients Such trials should also consider evaluation
of quality of life and length of hospitalisation Such trials may
consider starting bile acid and placebo interventions before liver
transplantation we were not able to identify any randomised trials
addressing this regimen Such trials ought to be reported accord-
ing to the CONSORT statement (wwwconsort-statementorg)
However before embarking on such trials the effects of bile acids
in other patient groups should be scrutinised as they may have
small or negative effects
A C K N O W L E D G E M E N T S
We thank all the patients and investigators who were involved in
the clinical trials mentioned in this review We thank Wendong
Chen for his work and contribution on the previous version of this
review We thank the staff of The Cochrane Hepato-Biliary Group
Editorial Team especially Dimitrinka Nikolova and Sarah Louise
Klingenberg for excellent collaboration and assistance during the
update of this review
Peer Reviewers Carlo Merkel Italy M Tomikawa Japan
Contact Editor Bodil Als-Nielsen Denmark
R E F E R E N C E S
References to studies included in this review
Angelico 1999 published data only
Angelico M Tisone G Baiocchi L Palmieri G Pisani F Negrini S
et alOne-year pilot study on tauroursodeoxycholic acid as an
adjuvant treatment after liver transplantation Italian Journal of
Gastroenterology and Hepatology 199931(6)462ndash8 [MEDLINE
10575563]
Barnes 1997 published data onlylowast Barnes D Talenti D Cammell G Goormastic M Farquhar L
Henderson M et alA randomized clinical trial of ursodeoxycholic
acid as adjuvant treatment to prevent liver transplant rejection
Hepatology 199726(4)853ndash7 [MEDLINE 9328304]
Barnes D Talenti D Goormastic M Farquhar L Cammell G
Henderson M et alUrsodeoxycholic acid (UDCA) reduces hepatic
allograft rejection after orthotopic liver transplantation (OLT) - a
prospective randomized placebo-controlled double-blind trial
Hepatology 199522149A
Fleckenstein 1998 published data only
Fleckenstein JF Paredes M Thuluvath PJ A prospective
randomized double-blind trial evaluating the efficacy of
ursodeoxycholic acid in prevention of liver transplant rejection
Liver Transplantation and Surgery 19984(4)276ndash9 [MEDLINE
9649640]
Keiding 1997 published data only
Keiding S Hockerstedt K Bjoro K Bondesen S Hjortrup A
Isoniemi H et alThe Nordic multicenter double-blind randomized
controlled trial of prophylactic ursodeoxycholic acid in liver
transplant patients Transplantation 199763(11)1591ndash4
[MEDLINE 9197351]
Koneru 1993 published data only
Koneru B Tint GS Wilson DJ Leevy CB Salen F Randomised
prospective trial of ursodeoxycholic acid in liver transplant
recipients Hepatology 199318336A
Pageaux 1995 published data only
Pageaux GP Blanc P Perrigault PF Navarro F Fabre JM Souche B
et alFailure of ursodeoxycholic acid to prevent acute cellular
rejection after liver transplantation Journal of Hepatology 199523
(2)119ndash22 [MEDLINE 7499781]
Sama 1991 published data only
Sama C Mazziotti A Grigioni W Morselli AM Chianura A
Stefanini GF et alUrsodeoxycholic acid administration does not
14Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
prevent rejection after OLT Journal of Hepatology 199113(Suppl
2)68
References to studies excluded from this review
Assy 2007 published data only
Assy N Adams PC Myers P Simon V Minuk GY Wall W et
alRandomized controlled trial of total immunosuppression
withdrawal in liver transplant recipients role of ursodeoxycholic
acid Transplantation 200783(12)1571ndash6 [MEDLINE
17589339]
Clavien 1996 published data only
Clavien PA Sharara AI Camargo CA Jr Harland RC Fitz JG
Evidence that ursodeoxycholic acid prevents steroid-resistant
rejection in adult liver transplantation Clinical Transplantation
199610(6 Pt 2)658ndash62 [MEDLINE 8996761]
Friman 1992 published data only
Friman S Persson H Schersten T Svanvik J Karlberg I Adjuvant
treatment with ursodeoxycholic acid reduces acute rejection after
liver transplantation Transplantation Proceedings 199224(1)
389ndash90 [MEDLINE 1539328]
Heathcote 1999 published data onlylowast Heathcote EJ Stone J Cauch-Dudek K Poupon R Chazouilleres
O Lindor KD et alEffect of pretransplantation ursodeoxycholic
acid therapy on the outcome of liver transplantation in patients
with primary biliary cirrhosis Liver Transplantation and Surgery
19995(4)269ndash74 [MEDLINE 10388499]
Henriksson 1991 published data only
Henriksson BA Persson H Friman S Wangberg B Svanvik J
Karlberg I Adjuvant ursodeoxycholic acid prevents acute rejection
in liver transplant recipients Transplantation Proceedings 199123
(3)1971 [MEDLINE 2063453]
Persson 1990 published data only
Persson H Friman S Schersten T Svanvik J Karlberg I
Ursodeoxycholic acid for prevention of acute rejection in liver
transplant recipients Lancet 1990336(8706)52ndash3 [MEDLINE
1973232]
Rafael 1995 published data only
Rafael E Duraj F Rudstrom H Wilczek H Ericzon B Effect of
ursodeoxycholic acid treatment for cholestasis in liver transplant
recipients Transplantation Proceedings 199527(6)3501ndash2
[MEDLINE 8540069]
Sama 1998 published data only
Sama C Morselli-Labate AM Grazi GL Mastroianni A Danesi G
Pianta P et alUrsodeoxycholic acid in liver transplantation effect
on cholestasis and rejection Gastroenterology 1998114(4 Suppl)
A1332
Additional references
Adams 1990
Adams DH Neuberger JM Patterns of graft rejection following
liver transplantation Journal of Hepatology 199010(1)113ndash9
[MEDLINE 2407770]
Al-Quaiz 1994
Al-Quaiz M OrsquoGrady J Tredger J Williams R Variable effect of
ursodeoxycholic acid on cyclosporin absorption after orthotopic
liver transplantation Transplant International 19947(3)190ndash4
[MEDLINE 8060468]
Armstrong 1982
Armstrong MJ Carey MC The hydrophobic-hydrophilic balance
of bile salt Inverse correlation between reverse phase high
performance liquid chromatographic mobilities and micellar
cholesterol-solubilizing capacities Journal of Lipid Research 1982
23(1)70ndash80 [MEDLINE 7057113]
Ascher 1988
Ascher NL Stock PG Baumgardner GL Payne WD Najarian JS
Infection and rejection of primary hepatic transplant in 93
consecutive patients treated with triple immunosuppressive therapy
Surgery Gynecology amp Obstetrics 1988167(6)474ndash84
[MEDLINE 3055368]
Brok 2008
Brok J Thorlund K Gluud C Wetterslev J Trial sequential
analysis reveals insufficient information size and potentially false
positive results in many meta-analyses Journal of Clinical
Epidemiology 200861(8)763ndash9 [MEDLINE 18411040]
Brok 2009
Brok J Thorlund K Wetterslev J Gluud C Apparently conclusive
meta-analysis may be inconclusive - Trial sequential analysis
adjustment of random error risk due to repetitive testing of
accumulating data in apparently conclusive neonatal meta-analysis
International Journal of Epidemiology 200938(1)298ndash303
[MEDLINE 18824466]
Calmus 1990
Calmus Y Gane P Rouger P Poupon R Hepatic expression of class
I and class II major histocompatibility complex molecules in
primary biliary cirrhosis effect of ursodeoxycholic acid Hepatology
199011(1)12ndash5 [MEDLINE 2403961]
Calmus 1992
Calmus Y Arvieux C Gane P Boucher E Nordlinger B Rouger P
et alCholestasis induces major histocompatibility complex class I
expression in hepatocytes Gastroenterology 1992102(4 Pt 1)
1371ndash7 [MEDLINE 1551542]
Chen 2003a
Chen W Gluud C Bile acids for primary sclerosing cholangitis
Cochrane Database of Systematic Reviews 2003 Issue 2 [DOI
10100214651858CD003626]
Chen 2007
Chen W Liu J Gluud C Bile acids for viral hepatitis Cochrane
Database of Systematic Reviews 2007 Issue 4 [DOI 101002
14651858CD003181pub2]
Cheng 2002
Cheng K Ashby D Smyth R Ursodeoxycholic acid for cystic
fibrosis-related liver disease Cochrane Database of Systematic
Reviews 2002 Issue 2 [DOI 10100214651858CD000222]
Corbani 2008
Corbani A Burroughs AK Intrahepatic cholestasis after liver
transplantation Clinics in Liver Disease 200812(1)111ndash29
[MEDLINE 18242500]
DeMets 1987
DeMets DL Methods for combining randomised clinical trials
strengths and limitations Statistics in Medicine 19876(3)341ndash50
[MEDLINE 3616287]
15Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
DerSimonian 1986
DerSimonian R Laird N Meta-analysis in clinical trials Controlled
Clinical Trials 19867(3)177ndash88 [MEDLINE 3802833]
Egger 1997
Egger M Davey Smith G Schneider M Minder C Bias in meta-
analysis detected by a simple graphical test BMJ (Clinical Research
Ed) 1997315(7109)629ndash34 [MEDLINE 9310563]
Ericzon 1990
Ericzon BG Eusufzai S Kubota K Einarsson K Angelin B
Characteristics of biliary lipid metabolism after liver
transplantation Hepatology 199012(5)1222ndash8 [MEDLINE
2227822]
FK506 1994
The US Multicenter FK506 Liver Study Group A comparison of
tacrolimus (FK506) and cyclosporine for immunosuppression in
liver transplantation New England Journal of Medicine 1994331
(17)1110ndash5 [MEDLINE 7523946]
Friman 1994
Friman S Svanvik J A possible role of ursodeoxycholic acid in liver
transplantation Scandinavian Journal of Gastroenterology 1994204
62ndash4 [MEDLINE 7824880]
Fuchs 1999
Fuchs M Stange EF Metabolism of bile acids In Johannes
Bircher Jean-Pierre Benhamou Neil McIntyre Mario Rizzetto
Juan Rodes editor(s) Oxford Textbook of Clinical Hepatology 2
Vol 1 Oxford Oxford University Press 1999223ndash56
Fusai 2006
Fusai G Dhaliwal P Rolando N Sabin CA Patch D Davidson BR
et alIncidence and risk factors for the development of prolonged
and severe intrahepatic cholestasis after liver transplantation Liver
Transplantation 200612(11)1626ndash33 [DOI 101002lt20870]
Gluud 2001
Gluud C Alcoholic hepatitis no glucocorticosteroids In
Leuschner U James OFW Dancygier H editor(s) Steatohepatitis
(NASH and ASH) Falk Symposium 121 Lancaster Kluwer
Academic Publisher 2001322ndash42
Gluud 2010
Gluud C Nikolova D Klingenberg SL Alexakis N Als-Nielsen B
Colli A et alCochrane Hepato-Biliary Group About The
Cochrane Collaboration (Cochrane Review Groups (CRGs))
2010 Issue 1 Art No LIVER
Gong 2008
Gong Y Huang ZB Christiansen E Gluud C Ursodeoxycholic
acid for primary biliary cirrhosis Cochrane Database of Systematic
Reviews 2008 Issue 3 [DOI 101002
14651858CD000551pub2]
Haddad 2006
Haddad EM McAlister VC Renouf E Malthaner R Kjaer MS
Gluud LL Cyclosporin versus tacrolimus for liver transplanted
patients Cochrane Database of Systematic Reviews 2006 Issue 4
[DOI 10100214651858CD005161pub2]
Heuman 1993
Heuman DM Hepatoprotective properties of ursodeoxycholic acid
Gastroenterology 1993104(6)1865ndash9 [MEDLINE 8500748]
Higgins 2008
Higgins PTJ Green S editors Cochrane Handbook for Systematic
Reviews of Interventions West Sussex England Wiley-Blackwell
2008
Hirschfield 2009
Hirschfield GM Gibbs P Griffiths WJH Adult liver
transplantation what non-specialists need to know BMJ (Clinical
Research Ed) 2009338(b1670)1321ndash7 [DOI 101136
bmjb1670]
Hussain 2002
Hussain HK Nghiem HV Imaging of hepatic transplantation
Clinics in Liver Disease 20026(1)247ndash70 [MEDLINE
11933592]
ICH-GCP 1997
International Conference on Harmonisation Expert Working
Group Code of Federal Regulations amp International Conference on
Harmonization Guidelines Media Parexel Barnett 1997
Ioannidis 2001
Ioannidis JPA Lau J Evolution of treatment effects over time
Empirical insight from recursive cumulative meta analyses
Proceedings of the National Academy of Sciences 200198(3)831ndash6
IWP 1995
International Working Party Terminology for hepatic allograft
rejection Hepatology 199522(2)648ndash54 [MEDLINE 7635435]
Kjaergard 2001
Kjaergard LL Villumsen J Gluud C Reported methodological
quality and discrepancies between large and small randomised trials
in meta-analyses Annals of Internal Medicine 2001135(11)982ndash9
[MEDLINE 11730399]
Klintmalm 1989
Klintmalm GB Nery JR Husberg BS Gonwa TA Tillery GW
Rejection in liver transplantation Hepatology 198910(6)978ndash85
[MEDLINE 2583691]
Knechtle 2009
Knechtle SJ Kwun J Unique aspects of rejection and tolerance in
liver transplantation Seminars in Liver Disease 200929(1)91ndash101
[MEDLINE 19235662]
Krams 1993
Krams SM Ascher NL Martinez OM New immunologic insights
into mechanisms of allograft rejection Gastroenterology Clinics of
North America 199318(2)374ndash7 [MEDLINE 8509176]
Lan 1983
Lan KKG DeMets DL Discrete sequential boundaries for clinical
trials Biometrika 198370659ndash63
Merion 1989
Merion RM Gorski DH Burtch GD Turcotte JG Colletti LM
Campbell DA Jr Bile refeeding after liver transplantation and
avoidance of intravenous cyclosporine Surgery 1989106(4)
604ndash9 [MEDLINE 2799635]
Moher 1998
Moher D Pham B Jones A Cook DJ Jadad AR Moher M et
alDoes quality of reports of randomised trials affect estimates of
intervention efficacy reported in meta-analyses Lancet 1998352
(9128)609ndash13 [MEDLINE 9746022]
16Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Neuberger 1999
Neuberger J Incidence timing and risk factors for acute and
chronic rejection Liver Transplantation and Surgery 19995(4 Suppl
1)S30ndashS36 [MEDLINE 10431015]
Okolicsanyi 1986
Okolicsanyi L Lirussi F Strazzabosco M Jemmolo RM Orlando R
Nassuato G et alThe effect of drugs on bile flow and composition
An overview Drugs 198631(5)430ndash48 [MEDLINE 2872047]
Palmer 1972
Palmer RH Bile acids liver injury and liver disease Archives of
Internal Medicine 1972130(4)606ndash17 [MEDLINE 4627840]
Perez 2009
Perez MJ Briz O Bile-acid-induced cell injury and protection
World Journal of Gastroenterology 200915(14)1677ndash89
[MEDLINE 19360911]
Pogue 1997
Pogue JM Yusuf S Cumulating evidence from randomized trials
Utilizing sequential monitoring boundaries for cumulative meta-
analysis Controlled Clinical Trials 199718(6)580ndash93
[MEDLINE 9408720]
Pogue 1998
Pogue J Yusuf S Overcoming the limitations of current meta-
analysis of randomised controlled trials Lancet 1998351(9095)
45ndash52 [MEDLINE 9433436]
RevMan 2008
The Nordic Cochrane Centre The Cochrane Collaboration
Review Manager (RevMan) 50 Copenhagen The Nordic
Cochrane Centre The Cochrane Collaboration 2008
Royle 2003
Royle P Milne R Literature searching for randomized controlled
trials used in Cochrane reviews rapid versus exhaustive searches
International Journal of Technology Assessment in Health Care 2003
19(4)591ndash603
Schulz 1995
Schulz KF Chalmers I Hayer R Altman D Empirical evidence of
bias JAMA 1995273(5)408ndash12 [MEDLINE 7823387]
Sharara 1995
Sharara AI Camargo CA Clavien PA Ursodeoxycholic acid
prevents steroid resistant rejection in liver transplant recipients
Gastroenterology 1995108A1168
Sholmerich 1984
Sholmerich J Becher MS Schmidt KH Schubert R Kremer B
Felhaus S et alInfluence of hydroxylation and conjugation of bile
salts on their membrane damaging properties Hepatology 19844
(4)661ndash7 [MEDLINE 6745854]
Soderdahl 1998
Soderdahl G Nowak G Duraj F Wang FH Einarsson C Ericzon
BG Ursodeoxycholic acid increased bile flow and affects bile
composition in the early postoperative phase following liver
transplantation Transplantation International 199811(Suppl 1)
S231ndashS238 [MEDLINE 9664985]
Terasaki 1991
Terasaki S Nakanuma Y Ogino H Unoura M Kobayashi K
Hepatocellular and biliary expression of HLA antigens in primary
biliary cirrhosis before and after ursodeoxycholic acid therapy
American Journal of Gastroenterology 199186(9)1194ndash9
[MEDLINE 1882800]
Thalheimer 2002
Thalheimer U Capra F Liver transplantation making the best out
of what we have Digestive Diseases and Sciences 200247(5)
945ndash53 [MEDLINE 12018919]
Thorlund 2009
Thorlund K Devereaux PJ Wetterslev J Guyatt G Ioannidis JP
Thabane L et alCan trial sequential monitoring boundaries reduce
spurious inferences from meta-analyses International Journal of
Epidemiology 200938(1)276ndash86 [MEDLINE 18824467]
Thuluvath 2003
Thuluvath PJ Yoo HY Thompson RE A model to predict survival
at one month one year and five years after liver transplantation
based on pretransplant clinical characteristics Liver Transplantation
20039(5)527ndash32 [MEDLINE 12740799]
van den Berg 1998
van den Berg AP Twilhaar WN Mesander G van Son WJ van der
Bij W Klompmaker IJ et alQuantitation of immunosuppression
by flow cytometric measurement of the capacity of T cells for
interleukin-2 production Transplantation 199865(8)1066ndash71
[MEDLINE 9583867]
Vierling 1992
Vierling J Immunologic mechanisms of hepatic allograft rejection
Seminars in Liver Disease 199212(1)16ndash27 [MEDLINE
1570548]
Wetterslev 2008
Wetterslev J Thorlund K Brok J Gluud C Trial sequential
analysis may establish when firm evidence is reached in cumulative
meta-analysis Journal of Clinical Epidemiology 200861(1)64ndash75
[MEDLINE 18083463]
Wiesner 1992
Wiesner RH Acute cellular rejection following liver
transplantation incidence risk factors and outcome in the
NIDDK Liver Transplant Database (LTD) study Gastroenterology
1992102A910
Wood 2008
Wood L Egger M Gluud LL Schulz KF Juni P Altman DG et
alEmpirical evidence of bias in treatment effect estimates in
controlled trials with different interventions and outcomes meta-
epidemiological study BMJ (Clinical Research Ed) 2008336
(7644)601ndash5 [MEDLINE 18316340]
Yoshikawa 1998
Yoshikawa M Matsui Y Kawamoto H Toyohara M Matsumura
K Yamao J et alIntragastric administration of ursodeoxycholic
acid suppresses immunoglobulin secretion by lymphocytes from
liver but not from peripheral blood spleen or Peyerrsquos patches in
mice International Journal of Immunopharmacology 199820(1-3)
29ndash38 [MEDLINE 9717080]
References to other published versions of this review
17Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Chen 2003b
Chen W Gluud C Bile acids for liver transplanted patients
Cochrane Database of Systematic Reviews 2005 Issue 3 [DOI
10100214651858CD005442]lowast Indicates the major publication for the study
18Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
C H A R A C T E R I S T I C S O F S T U D I E S
Characteristics of included studies [ordered by study ID]
Angelico 1999
Methods Study design open-label randomised one-year pilot study
Participants Country Italy
Publication language English
Inclusion criteria
- patients who underwent liver transplantation from April 1994 to December 1994
Exclusion criteria
- not mentioned
Participants
Two patients in TUDCA group and two patients in control group were excluded from
the basic information of participants by the study due to withdrawal
- TUDCA group (n = 14)
Mean age (years +- SD)
467 +- 84
Ratio of sex (malefemale) 122
Origins of liver diseases
hepatitis C cirrhosis (9) hepatitis B cirrhosis (2) hepatitis B and C cirrhosis (1) cryp-
togenic cirrhosis (2) alcoholic cirrhosis (0) Wilson cirrhosis (0)
- Control group (n = 15)
Mean age (years +- SD)
474 +- 74
Ratio of sex (malefemale) 123
Origins of liver diseases
hepatitis C cirrhosis (7) hepatitis B cirrhosis (2) hepatitis B and C cirrhosis (2) cryp-
togenic cirrhosis (2) alcoholic cirrhosis (1) Wilson cirrhosis (1)
Interventions TUDCA group
- Dose 500 mgday in two divided doses
- Route orally
- Duration the treatment was started on day 5 after transplantation and continued for
one year
Control group
- no treatment
Co-interventions all patients received standard triple-drug regimens (steroids azathio-
prine and cyclosporine or tacrolimus)
Outcomes All cause mortality
Number of patients with rejection after liver transplantation
Notes Letter was sent to the authors in September 2009 A reply with additional information
was received shortly after
Risk of bias
19Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Angelico 1999 (Continued)
Item Authorsrsquo judgement Description
Adequate sequence generation Yes Computer generated table
Allocation concealment Unclear No information provided
Blinding No Not performed
Incomplete outcome data addressed
All outcomes
Yes Withdrawal two patients from the
TUDCA group and two patients from the
placebo group Three of them died due to
transplant non-function in the first postop-
erative week and one patient was regrafted
due to thrombosis of hepatic artery
Free of selective reporting Unclear Post-transplant cholestasis and liver bio-
chemistry specified as outcomes Differ-
ence reported as not significant but no ac-
tual data given
Sample size calculation No Not reported
Intention-to-treat analysis No Not stated and not used
Baseline imbalance Unclear Not enough information provided
Early stopping of trial Unclear Not enough information provided
Barnes 1997
Methods Study design randomised placebo-controlled double-blind trial
Participants Country United States
Publication language English
Inclusion criteria
- patients aged 18 years or older who underwent liver transplantation at the Cleveland
Clinic Foundation from April 1992 through June of 1994
Exclusion criteria
- patients who were found to have cancer at surgically resected margins of the biliary
tree
- patents who underwent retransplantation
Participants
- UDCA group (n = 28)
Mean age (years +- SD)
505 +- 116
Ratio of sex (malefemale) 1810
Child class A 7
20Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Barnes 1997 (Continued)
B 13
and C 8
Origins of liver diseases Laennecrsquos cirrhosis 4
PBC 3
cryptogenic cirrhosis 6
hepatitis Ccirrhosis 4
hepatitis Bcirrhosis 3
autoimmune hepatitis with cirrhosis 3
PSC 2
other 3
- Placebo group (n = 24)
Mean age (years +- SD)
507 +- 93
Ratio of sex (malefemale) 159
Child class A 6
B 14
and C 4
Origins of liver diseases Laennecrsquos cirrhosis 9
PBC 5
cryptogenic cirrhosis 1
hepatitis Ccirrhosis 1
hepatitis Bcirrhosis 1
autoimmune hepatitis with cirrhosis 1
PSC 2
other 4
Interventions UDCA group
- Dose 10-15 mgkg body weightday in divided doses
- Route orally
- Duration immediately after intestinal transit recovery usually between postoperative
days three and five and continue for three months
Placebo group
- identical-appearing capsules administered in the same quantity and manner
Co-interventions all patients received standard triple-drug regimens (steroids azathio-
prine and cyclosporine or tacrolimus)
Outcomes All cause mortality
Number of patients with acute cellular rejection
Number of patients with chronic rejection
Number of patients with steroid-resistant rejection
Number of days of hospitalisation
Adverse events
Notes Letter was sent to the authors in September 2009 A reply with additional information
was received shortly after
Risk of bias
Item Authorsrsquo judgement Description
21Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Barnes 1997 (Continued)
Adequate sequence generation Yes Computer generated table
Allocation concealment Unclear No information provided
Blinding Yes Quote ldquorandomised to receive either
UDCA or an identical placebo capsulerdquo
Incomplete outcome data addressed
All outcomes
Yes Mean follow-up time 18 months Ten pa-
tients withdrawn from study 6 in UDCA
group and 4 in placebo group Reasons
for withdrawal were reported Four patients
died in the placebo group
Free of selective reporting Yes All expected outcomes reported
Sample size calculation Unclear The trial reported the method of sample
size calculation but the actual number of
patients needed was not reported
Intention-to-treat analysis Yes Stated and used
Baseline imbalance Unclear Not enough information provided
Early stopping of trial Unclear The number of patients needed to gain the
actual power was not reported Whether
the trial was terminated early is not clear
Fleckenstein 1998
Methods Study design prospective randomised double-blind trial
Participants Country United States
Publication language English
Inclusion criteria
- patients who underwent liver transplantation at the Johns Hopkins Hospital
Exclusion criteria
- patients who were under 18 years old undergoing repeat transplantation had primary
graft nonfunction or refused consent
Participants
- UDCA group (n = 14)
Mean age (years +- SD)
443 +- 127
Ratio of sex (malefemale) 68
Origins of liver diseases hepatitis C 6
alcohol 2
autoimmune 1
PBC 2
22Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Fleckenstein 1998 (Continued)
PSC 1
autoimmune cholangiopathy 1
hepatitis B 1
- Placebo group (n = 16)
Mean age (years +- SD)
496 +- 109
Ratio of sex (malefemale) 124
Origins of liver diseases hepatitis C 3
alcohol 3
autoimmune 3
PBC 1
PSC 2
cryptogenic 2
hepatitis B 1
alpha1-antitrypsin deficiency 1
Interventions UDCA group
- Dose 15 mgkg body weightday in divided doses
- Route orally
- Duration immediately after intestinal transit recovery usually between postoperative
days three and five and continue for three months
Placebo group
- Identical-appearing capsules administered in the same quantity and manner
Co-interventions all patients received standard triple-drug regimens (steroids azathio-
prine and cyclosporine or tacrolimus)
Outcomes All cause mortality
Number with retransplantation
Number of patients with acute cellular rejection
Number of patients with chronic rejection
Serum bilirubin levels at the end of treatment
Notes Follow-up time nine months
Letter was sent to the authors in September 2009 No reply was received
Risk of bias
Item Authorsrsquo judgement Description
Adequate sequence generation Unclear No information provided
Allocation concealment Unclear No information provided
Blinding Yes Method of blinding not described but
probably adequate
Incomplete outcome data addressed
All outcomes
Yes Withdrawal one patient from the UDCA
group and two patients from the placebo
group because of capsule size
23Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Fleckenstein 1998 (Continued)
Free of selective reporting Unclear Outcomes were not completely described
Sample size calculation No Not reported
Intention-to-treat analysis Yes Quote ldquoThree patients withdrew after in-
clusionThey were included in the statis-
tical analysisrdquo
Baseline imbalance Unclear Not enough information provided
Early stopping of trial Unclear Not enough information provided
Keiding 1997
Methods Study design prospective randomised placebo-controlled multicenter study
Participants Country Denmark Finland Norway and Sweden
Publication language English
Inclusion criteria
- patients who underwent liver transplantation in Denmark Finland Norway and Swe-
den from September 1 1992 to May 31 1994
Exclusion criteria
- patients with malignant diseases
Participants
The age of the children ranged from 0 to 13 years (median 15) and the age of adults
ranged from 14 to 59 years old (median 44) MaleFemale ratio was 96 for children and
4344 for adults
- UDCA group (n = 54)
Origins of liver diseases
paracetamol intoxication 1 hepatitis B 1 autoimmune hepatitis 0 biliary atresia 2
metabolic diseases 7 neonatal hepatitis 2 PBC 13 post hepatitis cirrhosis 8 PSC 3
cryptogenic cirrhosis 7 alcoholic cirrhosis 2 other reasons 8
- Placebo group (n = 48)
Origins of liver diseases paracetamol intoxication 1 hepatitis B 0 autoimmune hepatitis
1 biliary atresia 3 metabolic diseases 11 neonatal hepatitis 0 PBC 7 post hepatitis
cirrhosis 5 PSC 7 cryptogenic cirrhosis 2 alcoholic cirrhosis 6 other reasons 5
Interventions UDCA group
- Dose 15 mgkg body weightday in two or three divided doses
- Route orally
- Duration immediately after intestinal transit recovery usually between postoperative
days three and five and continue for three months
Placebo group
- Identical-appearing capsules administered in the same quantity and manner
Co-interventions all patients received standard triple-drug regimens (steroids azathio-
prine and cyclosporine or tacrolimus)
24Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Keiding 1997 (Continued)
Outcomes All cause mortality
Number of deaths related to rejection
Number of patients with acute cellular rejection
Number of patients with chronic rejection
Number of patients with steroid-resistant rejection
Adverse events
Notes Letter was sent to the authors in September 2009 No reply was received
Risk of bias
Item Authorsrsquo judgement Description
Adequate sequence generation Unclear Patients were randomised at a ratio of 11
Allocation concealment Yes Quote ldquo The allocation was performed in
blocks of 10 patients using the sealed serial
envelope methodrdquo
Blinding Yes Quote ldquoThe UDCA and the placebo cap-
sules had identical appearance and tasterdquo
Incomplete outcome data addressed
All outcomes
Yes Follow-up time 12 months Five UDCA
patients and five placebo patients withdrew
from study Reasons were reported
Free of selective reporting Unclear Insufficient information
Sample size calculation Yes Performed and allowed for a difference in
the incidence of at least one episode of
acute rejection of 50 between the treat-
ment and placebo groups with 90 statisti-
cal power and a significance level of P value
less than 005 The calculated sample size
was 80 patients
Intention-to-treat analysis Yes Stated and used
Baseline imbalance Yes The study seems to be free of baseline im-
balance
Early stopping of trial Yes Study attained the pre-specified sample
size
25Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Koneru 1993
Methods Study design randomised controlled trial
Participants Country United States
Publication language English
Inclusion criteria
- patients who underwent liver transplantation
Exclusion criteria
- not mentioned
Participants
- UDCA group (n = 16)
Mean age (years +- SD)
no information
Ratio of sex (malefemale) no information
Origins of liver diseases
no information
- Control group (n = 16)
Mean age (years +- SD)
no information
Ratio of sex (malefemale) no information
Origins of liver diseases
no information
Interventions UDCA group
- Dose 900 mgday
- Route orally
- Duration immediately after intestinal transit recovery usually between postoperative
days three and five and continue for three months
Control group
- no treatment
Co-interventions all patients received standard triple-drug regimens (steroids azathio-
prine and cyclosporine)
Outcomes Number of patients with retransplantation due to rejection
Number of patients with rejection episodes
Notes Abstract
Letter was sent to the authors in September 2009 No reply was received
Risk of bias
Item Authorsrsquo judgement Description
Adequate sequence generation Unclear No information provided
Allocation concealment Unclear No information provided
Blinding No Not performed
26Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Koneru 1993 (Continued)
Incomplete outcome data addressed
All outcomes
Unclear The study gives the impression that there
were no withdrawals but this was not ex-
plicitly stated
Free of selective reporting Unclear Insufficient information provided
Sample size calculation No Not performed
Intention-to-treat analysis Unclear No information provided
Baseline imbalance Unclear Not enough information provided
Early stopping of trial Unclear Not enough information provided
Pageaux 1995
Methods Study design double-blind randomised study
Participants Country France
Publication language English
Inclusion criteria
- patients who underwent liver transplantation
Exclusion criteria
- not mentioned
Participants
- UDCA group (n=26)
Mean age (years +- SD)
47 +- 10
Ratio of sex (malefemale) 179
Origins of liver diseases alcoholic cirrhosis 14
post-hepatic B cirrhosis 2
post-hepatitis C cirrhosis 4
PBC 2
liver cancer 2
fulminant hepatitis 1
miscellaneous 1
- Placebo group (n = 24)
Mean age (years +- SD)
51+- 9
Ratio of sex (malefemale) 159
Origins of liver diseases alcoholic cirrhosis 10
post-hepatic B cirrhosis 0
post-hepatic C cirrhosis 6
PBC 3
liver cancer 4
fulminant hepatitis 0
miscellaneous 1
27Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Pageaux 1995 (Continued)
Interventions UDCA group
- Dose 600 mgday in three divided doses
- Route orally
- Duration immediately after intestinal transit recovery usually between postoperative
days three and five and continue for two months
Placebo group
- identical-appearing capsules administered in the same quantity and manner
Co-interventions all patients received standard triple-drug regimens (steroids azathio-
prine and cyclosporine or tacrolimus)
Outcomes Number of patients with acute cellular rejection
Number of patients with steroid-resistant rejection
Notes Letter was sent to the authors in September 2009 No reply was received
Risk of bias
Item Authorsrsquo judgement Description
Adequate sequence generation Unclear No information provided
Allocation concealment Unclear No information provided
Blinding Unclear Method of blinding not described
Incomplete outcome data addressed
All outcomes
Yes Five patients died from non-immunologi-
cal causes before the end of the first month
and were excluded from the study Reasons
were reported
Free of selective reporting Unclear Not enough information provided
Sample size calculation No Not performed
Intention-to-treat analysis No Not stated and not used
Baseline imbalance Unclear Not enough information provided
Early stopping of trial Unclear Not enough information provided
Sama 1991
Methods Study design randomised controlled trial
Participants Country Italy
Publication language English
Inclusion criteria
28Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Sama 1991 (Continued)
- patients who underwent liver transplantation
Exclusion criteria
- not mentioned
Participants
- UDCA group (n = 20)
Mean age (years +- SD)
no information
Ratio of sex (malefemale) no information
Origins of liver diseases
no information
- Control group (n = 20)
Mean age (years +- SD)
no information
Ratio of sex (malefemale) no information
Origins of liver diseases
no information
Interventions UDCA group
- Dose 600 mgday in two divided doses
- Route orally
- Duration immediately after intestinal transit recovery usually between postoperative
day five and day seven and continue for six months
Control group
- no treatment
Co-interventions all patients received standard immunosuppressive treatment (steroids
and cyclosporine)
Outcomes All cause mortality
Number of patients with acute cellular rejection
Notes Abstract
Letter was sent to the authors in September 2009 No reply was received
Risk of bias
Item Authorsrsquo judgement Description
Adequate sequence generation Unclear A randomisation list was performed before
patients were admitted to the trial (infor-
mation from principal author)
Allocation concealment Unclear No information provided
Blinding Unclear The principle author provided information
that the study was made according to a
single-blind randomised protocol The pri-
mary outcome was the occurrence of biopsy
proven rejection episodes The pathologists
were blind but the patients were not
29Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Sama 1991 (Continued)
Incomplete outcome data addressed
All outcomes
Unclear Five patients from the UDCA group and
six patients from the placebo group were
excluded Reasons for exclusion were not
fully stated
Free of selective reporting No Data about survival of patients were not
adequately reported
Sample size calculation No Not performed
Intention-to-treat analysis No Not stated and not used
Baseline imbalance Unclear Basic characteristics of patients not re-
ported
Early stopping of trial Unclear Not enough information provided
UDCA = ursodeoxycholic acid
TUDCA = tauroursodeoxycholic acid
PBC = primary biliary cirrhosis
PSC = primary sclerosing cholangitis
OKT3 = anti-CD3 monoclonal antibody
Characteristics of excluded studies [ordered by study ID]
Assy 2007 A randomised controlled trial that included only recipients of liver transplantation with stable graft function and
no episodes of rejection for at least 2 years that were then offered total immunosuppression withdrawal Fourteen
patients received UDCA (15 mgkg body weightday) and 12 received placebo Rejection occurred in 43 and
75 of patients respectively (no significant difference) None developed chronic rejection After follow-up two
patients were free of immunosuppression 80 were steroid free and 50 were able to reduce their dose of
cyclosporine
Clavien 1996 Case series Fifty consecutive liver-transplanted patients were treated with a standard cyclosporine immunosup-
pressive regimen Twenty three of the 43 survivors developed an episode of rejection and UDCA (10 mgkg
weightday) was initiated Only one patient had a second episode of rejection
Friman 1992 Observational study Thirty-three liver-transplanted patients received 10 mg UDCAkg body weightday for
median of 10 months (range four to 21 months) Eight historical liver-transplanted patients served as control
group The rejection incidence was significantly lower in the patients who received the treatment with UDCA
Biochemistry one month after transplantation demonstrated significantly lower average values of aminotrans-
ferases and alkaline phosphatases in patients treated with UDCA than in the control group
30Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
Heathcote 1999 Observational study From 1987 to 1996 37 UDCA treated and 53 placebo treated patients with primary biliary
cirrhosis were referred for transplantation Posttransplantation survival rates at one month were 939 in the
UDCA group and 884 in the placebo group and one year survival rates were 903 and 784 respectively
(no significant differences) However rejection (type not defined - a secondary outcome measure) occurred
significantly less often in the UDCA group (429) than in placebo group (688)
Henriksson 1991 Observational study All patients in this study were given sequential quadruple immunosuppression with anti-
lymphocyte globulin azathioprine steroids and cyclosporine All patients with primary graft function (n = 11)
were treated with 10 mg UDCAkg body weightday starting during the first postoperative week Patients who
received liver transplantation in the first 6 months of 1989 (n = 8) served as controls In the control group one
patient died after 9 months with chronic graft dysfunction and six patients had rejection episodes during the
first postoperative month All patients in the UDCA group were alive without rejection episodes
Persson 1990 Observational study All 11 adult patients transplanted between August 1989 and January 1990 with primary
graft function were treated with 10 mg UDCA kg body weightday Eight patients transplanted during the first
half of 1989 served as control UDCA was started during the first postoperative week and the treatment was
continued for six months All patients in the UDCA treated group survived with satisfactory graft function In
the control group six patients had at least one rejection episode needing treatment during the first postoperative
month
Rafael 1995 Observational study Seventeen patients who underwent liver transplantation between February 1990 and April
1993 and developed biliary complications after transplantation were retrospectively analysed regarding treatment
with UDCA UDCA was given in a dose of 500 to 1000 mgday Ten patients were treated for at least one year while
seven patients were treated for 14 to 250 days UDCA significantly improved gammaglutamyl transpeptidase in
liver graft recipients with biliary complications There was also a trend towards improvement in serum bilirubin
and alanine transaminase values
Sama 1998 Observational study Thirty-four patients who underwent liver transplantation between January 1995 and June
1996 were included in the study Seventeen were treated with UDCA 10 mgkg body weightday during 6
months while 17 served as controls on the basis of having undergone liver transplantation closest to UDCA
patients A significant decrease in serum bilirubin levels was observed in UDCA patients There was a significantly
higher incidence of recurrent hepatitis in the control group
UDCA ursodeoxycholic acid
31Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
D A T A A N D A N A L Y S E S
Comparison 1 Bile acids for liver-transplanted patients
Outcome or subgroup titleNo of
studies
No of
participants Statistical method Effect size
1 All-cause mortality at maximum
follow-up
5 257 Risk Ratio (M-H Fixed 95 CI) 085 [053 136]
11 UDCA versus placebo or
no treatment
4 224 Risk Ratio (M-H Fixed 95 CI) 080 [049 130]
12 TUDCA versus no
treatment
1 33 Risk Ratio (M-H Fixed 95 CI) 159 [030 833]
2 All-cause mortality worst-best
case and best-worst case
scenarios
5 Risk Ratio (M-H Fixed 95 CI) Subtotals only
21 Worst-best case scenario 5 257 Risk Ratio (M-H Fixed 95 CI) 130 [086 196]
22 Best-worst case scenario 5 257 Risk Ratio (M-H Fixed 95 CI) 058 [038 090]
3 Subgroup analyses all-cause
mortality at maximum
follow-up according to time of
start of bile acids
5 257 Risk Ratio (M-H Fixed 95 CI) 085 [053 136]
31 Less than three days after
transplantation
1 102 Risk Ratio (M-H Fixed 95 CI) 124 [061 254]
32 Three days or more after
transplantation
4 155 Risk Ratio (M-H Fixed 95 CI) 063 [033 120]
4 Subgroup analyses all cause
mortality at maximum
follow-up according to
treatment duration
5 257 Risk Ratio (M-H Fixed 95 CI) 085 [053 136]
41 Less than six months 3 184 Risk Ratio (M-H Fixed 95 CI) 078 [045 138]
42 Six months or more 2 73 Risk Ratio (M-H Fixed 95 CI) 102 [043 240]
5 Number of deaths related
to rejection at maximum
follow-up
1 102 Risk Ratio (M-H Fixed 95 CI) 030 [001 712]
51 UDCA versus placebo 1 102 Risk Ratio (M-H Fixed 95 CI) 030 [001 712]
6 Number of retransplantations at
maximum follow-up
2 132 Risk Ratio (M-H Fixed 95 CI) 076 [020 286]
7 Number of patients with acute
cellular rejection at maximum
follow-up
7 339 Risk Ratio (M-H Fixed 95 CI) 089 [074 106]
71 UDCA versus placebo or
no treatment
6 306 Risk Ratio (M-H Fixed 95 CI) 089 [074 108]
72 TUDCA versus no
treatment
1 33 Risk Ratio (M-H Fixed 95 CI) 085 [045 160]
8 Subgroup analysis number of
patients with acute cellular
rejection according to time of
start of bile acid
7 339 Risk Ratio (M-H Fixed 95 CI) 089 [074 106]
32Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
81 Less than three days after
transplantation
2 134 Risk Ratio (M-H Fixed 95 CI) 084 [063 111]
82 Three days or more after
liver transplantation
5 205 Risk Ratio (M-H Fixed 95 CI) 092 [072 117]
9 Subgroup analysis number
of patients with acute
cellular rejection according to
treatment duration
7 339 Risk Ratio (M-H Fixed 95 CI) 089 [074 106]
91 Less than six months 5 266 Risk Ratio (M-H Fixed 95 CI) 087 [071 107]
92 Six months or more 2 73 Risk Ratio (M-H Fixed 95 CI) 094 [065 136]
10 Number of patients with
chronic rejection at maximum
follow-up
3 184 Risk Ratio (M-H Fixed 95 CI) 028 [008 095]
11 Number of patients with
steroid-resistant rejection at
maximum follow-up
4 234 Risk Ratio (M-H Fixed 95 CI) 077 [047 127]
12 Serum bilirubin (mgdl) at the
end of treatment
1 30 Mean Difference (IV Fixed 95 CI) 26 [-096 616]
13 Number of days of
hospitalisation after liver
transplantation
1 52 Mean Difference (IV Fixed 95 CI) -85 [-1667 -033]
14 Adverse events 3 187 Risk Ratio (M-H Fixed 95 CI) 088 [030 260]
Analysis 11 Comparison 1 Bile acids for liver-transplanted patients Outcome 1 All-cause mortality at
maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 1 All-cause mortality at maximum follow-up
Study or subgroup Favours bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 UDCA versus placebo or no treatment
Barnes 1997 228 724 253 024 [ 006 107 ]
Fleckenstein 1998 214 416 125 057 [ 012 266 ]
Keiding 1997 1454 1048 355 124 [ 061 254 ]
Sama 1991 520 620 201 083 [ 030 229 ]
Subtotal (95 CI) 116 108 935 080 [ 049 130 ]
Total events 23 (Favours bile acids) 27 (Control)
Heterogeneity Chi2 = 416 df = 3 (P = 025) I2 =28
Test for overall effect Z = 091 (P = 036)
01 02 05 1 2 5 10
Favours bile acids Favours control
(Continued )
33Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Favours bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
2 TUDCA versus no treatment
Angelico 1999 316 217 65 159 [ 030 833 ]
Subtotal (95 CI) 16 17 65 159 [ 030 833 ]
Total events 3 (Favours bile acids) 2 (Control)
Heterogeneity not applicable
Test for overall effect Z = 055 (P = 058)
Total (95 CI) 132 125 1000 085 [ 053 136 ]
Total events 26 (Favours bile acids) 29 (Control)
Heterogeneity Chi2 = 466 df = 4 (P = 032) I2 =14
Test for overall effect Z = 069 (P = 049)
01 02 05 1 2 5 10
Favours bile acids Favours control
Analysis 12 Comparison 1 Bile acids for liver-transplanted patients Outcome 2 All-cause mortality worst-
best case and best-worst case scenarios
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 2 All-cause mortality worst-best case and best-worst case scenarios
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 Worst-best case scenario
Angelico 1999 516 217 65 266 [ 060 1180 ]
Barnes 1997 828 724 253 098 [ 042 230 ]
Fleckenstein 1998 314 416 125 086 [ 023 319 ]
Keiding 1997 1954 1048 355 169 [ 087 327 ]
Sama 1991 520 620 201 083 [ 030 229 ]
Subtotal (95 CI) 132 125 1000 130 [ 086 196 ]
Total events 40 (Bile acids) 29 (Control)
Heterogeneity Chi2 = 303 df = 4 (P = 055) I2 =00
Test for overall effect Z = 123 (P = 022)
2 Best-worst case scenario
005 02 1 5 20
Favours bile acids Favours control
(Continued )
34Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Angelico 1999 316 417 90 080 [ 021 302 ]
Barnes 1997 228 1124 274 016 [ 004 063 ]
Fleckenstein 1998 214 616 130 038 [ 009 159 ]
Keiding 1997 1454 1548 368 083 [ 045 154 ]
Sama 1991 520 620 139 083 [ 030 229 ]
Subtotal (95 CI) 132 125 1000 058 [ 038 090 ]
Total events 26 (Bile acids) 42 (Control)
Heterogeneity Chi2 = 567 df = 4 (P = 023) I2 =29
Test for overall effect Z = 247 (P = 0014)
005 02 1 5 20
Favours bile acids Favours control
Analysis 13 Comparison 1 Bile acids for liver-transplanted patients Outcome 3 Subgroup analyses all-
cause mortality at maximum follow-up according to time of start of bile acids
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 3 Subgroup analyses all-cause mortality at maximum follow-up according to time of start of bile acids
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 Less than three days after transplantation
Keiding 1997 1454 1048 355 124 [ 061 254 ]
Subtotal (95 CI) 54 48 355 124 [ 061 254 ]
Total events 14 (Bile acids) 10 (Control)
Heterogeneity not applicable
Test for overall effect Z = 060 (P = 055)
2 Three days or more after transplantation
Angelico 1999 316 217 65 159 [ 030 833 ]
Barnes 1997 228 724 253 024 [ 006 107 ]
Fleckenstein 1998 214 416 125 057 [ 012 266 ]
Sama 1991 520 620 201 083 [ 030 229 ]
005 02 1 5 20
Favours bile acids Favours control
(Continued )
35Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Subtotal (95 CI) 78 77 645 063 [ 033 120 ]
Total events 12 (Bile acids) 19 (Control)
Heterogeneity Chi2 = 310 df = 3 (P = 038) I2 =3
Test for overall effect Z = 141 (P = 016)
Total (95 CI) 132 125 1000 085 [ 053 136 ]
Total events 26 (Bile acids) 29 (Control)
Heterogeneity Chi2 = 466 df = 4 (P = 032) I2 =14
Test for overall effect Z = 069 (P = 049)
005 02 1 5 20
Favours bile acids Favours control
Analysis 14 Comparison 1 Bile acids for liver-transplanted patients Outcome 4 Subgroup analyses all
cause mortality at maximum follow-up according to treatment duration
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 4 Subgroup analyses all cause mortality at maximum follow-up according to treatment duration
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 Less than six months
Barnes 1997 228 724 253 024 [ 006 107 ]
Fleckenstein 1998 214 416 125 057 [ 012 266 ]
Keiding 1997 1454 1048 355 124 [ 061 254 ]
Subtotal (95 CI) 96 88 734 078 [ 045 138 ]
Total events 18 (Bile acids) 21 (Control)
Heterogeneity Chi2 = 417 df = 2 (P = 012) I2 =52
Test for overall effect Z = 084 (P = 040)
2 Six months or more
Angelico 1999 316 217 65 159 [ 030 833 ]
Sama 1991 520 620 201 083 [ 030 229 ]
Subtotal (95 CI) 36 37 266 102 [ 043 240 ]
Total events 8 (Bile acids) 8 (Control)
Heterogeneity Chi2 = 043 df = 1 (P = 051) I2 =00
005 02 1 5 20
Favours bile acids Favours control
(Continued )
36Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Test for overall effect Z = 004 (P = 097)
Total (95 CI) 132 125 1000 085 [ 053 136 ]
Total events 26 (Bile acids) 29 (Control)
Heterogeneity Chi2 = 466 df = 4 (P = 032) I2 =14
Test for overall effect Z = 069 (P = 049)
005 02 1 5 20
Favours bile acids Favours control
Analysis 15 Comparison 1 Bile acids for liver-transplanted patients Outcome 5 Number of deaths related
to rejection at maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 5 Number of deaths related to rejection at maximum follow-up
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 UDCA versus placebo
Keiding 1997 054 148 1000 030 [ 001 712 ]
Total (95 CI) 54 48 1000 030 [ 001 712 ]
Total events 0 (Bile acids) 1 (Control)
Heterogeneity not applicable
Test for overall effect Z = 075 (P = 045)
0001 001 01 1 10 100 1000
Favours bile acids Favours control
37Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 16 Comparison 1 Bile acids for liver-transplanted patients Outcome 6 Number of
retransplantations at maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 6 Number of retransplantations at maximum follow-up
Study or subgroup Bile acids Placebo Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Fleckenstein 1998 214 016 100 567 [ 029 10891 ]
Keiding 1997 154 448 900 022 [ 003 192 ]
Total (95 CI) 68 64 1000 076 [ 020 286 ]
Total events 3 (Bile acids) 4 (Placebo)
Heterogeneity Chi2 = 303 df = 1 (P = 008) I2 =67
Test for overall effect Z = 040 (P = 069)
0001 001 01 1 10 100 1000
Favours bile acids Favours placebo
Analysis 17 Comparison 1 Bile acids for liver-transplanted patients Outcome 7 Number of patients with
acute cellular rejection at maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 7 Number of patients with acute cellular rejection at maximum follow-up
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 UDCA versus placebo or no treatment
Barnes 1997 1728 1724 180 086 [ 058 127 ]
Fleckenstein 1998 814 916 83 102 [ 054 190 ]
Keiding 1997 3554 3248 333 097 [ 073 129 ]
Koneru 1993 316 916 89 033 [ 011 101 ]
Pageaux 1995 926 924 92 092 [ 044 193 ]
Sama 1991 1320 1320 128 100 [ 063 158 ]
Subtotal (95 CI) 158 148 905 089 [ 074 108 ]
01 02 05 1 2 5 10
Favours bile acids Favours control
(Continued )
38Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Total events 85 (Bile acids) 89 (Control)
Heterogeneity Chi2 = 387 df = 5 (P = 057) I2 =00
Test for overall effect Z = 120 (P = 023)
2 TUDCA versus no treatment
Angelico 1999 816 1017 95 085 [ 045 160 ]
Subtotal (95 CI) 16 17 95 085 [ 045 160 ]
Total events 8 (Bile acids) 10 (Control)
Heterogeneity not applicable
Test for overall effect Z = 050 (P = 061)
Total (95 CI) 174 165 1000 089 [ 074 106 ]
Total events 93 (Bile acids) 99 (Control)
Heterogeneity Chi2 = 392 df = 6 (P = 069) I2 =00
Test for overall effect Z = 130 (P = 019)
01 02 05 1 2 5 10
Favours bile acids Favours control
Analysis 18 Comparison 1 Bile acids for liver-transplanted patients Outcome 8 Subgroup analysis
number of patients with acute cellular rejection according to time of start of bile acid
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 8 Subgroup analysis number of patients with acute cellular rejection according to time of start of bile acid
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 Less than three days after transplantation
Keiding 1997 3554 3248 333 097 [ 073 129 ]
Koneru 1993 316 916 89 033 [ 011 101 ]
Subtotal (95 CI) 70 64 422 084 [ 063 111 ]
Total events 38 (Bile acids) 41 (Control)
Heterogeneity Chi2 = 374 df = 1 (P = 005) I2 =73
Test for overall effect Z = 124 (P = 022)
2 Three days or more after liver transplantation
Angelico 1999 816 1017 95 085 [ 045 160 ]
01 02 05 1 2 5 10
Favours bile acids Favours control
(Continued )
39Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Barnes 1997 1728 1724 180 086 [ 058 127 ]
Fleckenstein 1998 814 916 83 102 [ 054 190 ]
Pageaux 1995 926 924 92 092 [ 044 193 ]
Sama 1991 1320 1320 128 100 [ 063 158 ]
Subtotal (95 CI) 104 101 578 092 [ 072 117 ]
Total events 55 (Bile acids) 58 (Control)
Heterogeneity Chi2 = 041 df = 4 (P = 098) I2 =00
Test for overall effect Z = 067 (P = 050)
Total (95 CI) 174 165 1000 089 [ 074 106 ]
Total events 93 (Bile acids) 99 (Control)
Heterogeneity Chi2 = 392 df = 6 (P = 069) I2 =00
Test for overall effect Z = 130 (P = 019)
01 02 05 1 2 5 10
Favours bile acids Favours control
40Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 19 Comparison 1 Bile acids for liver-transplanted patients Outcome 9 Subgroup analysis
number of patients with acute cellular rejection according to treatment duration
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 9 Subgroup analysis number of patients with acute cellular rejection according to treatment duration
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 Less than six months
Barnes 1997 1728 1724 180 086 [ 058 127 ]
Fleckenstein 1998 814 916 83 102 [ 054 190 ]
Keiding 1997 3554 3248 333 097 [ 073 129 ]
Koneru 1993 316 916 89 033 [ 011 101 ]
Pageaux 1995 926 924 92 092 [ 044 193 ]
Subtotal (95 CI) 138 128 777 087 [ 071 107 ]
Total events 72 (Bile acids) 76 (Control)
Heterogeneity Chi2 = 374 df = 4 (P = 044) I2 =00
Test for overall effect Z = 129 (P = 020)
2 Six months or more
Angelico 1999 816 1017 95 085 [ 045 160 ]
Sama 1991 1320 1320 128 100 [ 063 158 ]
Subtotal (95 CI) 36 37 223 094 [ 065 136 ]
Total events 21 (Bile acids) 23 (Control)
Heterogeneity Chi2 = 017 df = 1 (P = 068) I2 =00
Test for overall effect Z = 035 (P = 073)
Total (95 CI) 174 165 1000 089 [ 074 106 ]
Total events 93 (Bile acids) 99 (Control)
Heterogeneity Chi2 = 392 df = 6 (P = 069) I2 =00
Test for overall effect Z = 130 (P = 019)
01 02 05 1 2 5 10
Favours bile acids Favours control
41Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 110 Comparison 1 Bile acids for liver-transplanted patients Outcome 10 Number of patients
with chronic rejection at maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 10 Number of patients with chronic rejection at maximum follow-up
Study or subgroup Bile acids Placebo Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Barnes 1997 128 624 611 014 [ 002 110 ]
Fleckenstein 1998 114 116 88 114 [ 008 1663 ]
Keiding 1997 154 348 300 030 [ 003 275 ]
Total (95 CI) 96 88 1000 028 [ 008 095 ]
Total events 3 (Bile acids) 10 (Placebo)
Heterogeneity Chi2 = 148 df = 2 (P = 048) I2 =00
Test for overall effect Z = 204 (P = 0041)
0001 001 01 1 10 100 1000
Favours bile acids Favours placebo
Analysis 111 Comparison 1 Bile acids for liver-transplanted patients Outcome 11 Number of patients
with steroid-resistant rejection at maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 11 Number of patients with steroid-resistant rejection at maximum follow-up
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Barnes 1997 328 724 277 037 [ 011 127 ]
Fleckenstein 1998 314 316 103 114 [ 027 478 ]
Keiding 1997 1454 1548 583 083 [ 045 154 ]
Pageaux 1995 226 124 38 185 [ 018 1908 ]
Total (95 CI) 122 112 1000 077 [ 047 127 ]
Total events 22 (Bile acids) 26 (Control)
Heterogeneity Chi2 = 226 df = 3 (P = 052) I2 =00
Test for overall effect Z = 102 (P = 031)
001 01 1 10 100
Favours bile acids Favours placebo
42Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 112 Comparison 1 Bile acids for liver-transplanted patients Outcome 12 Serum bilirubin (mgdl)
at the end of treatment
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 12 Serum bilirubin (mgdl) at the end of treatment
Study or subgroup Bile acids Placebo Mean Difference Weight Mean Difference
N Mean(SD) N Mean(SD) IVFixed95 CI IVFixed95 CI
Fleckenstein 1998 14 319 (68) 16 059 (022) 1000 260 [ -096 616 ]
Total (95 CI) 14 16 1000 260 [ -096 616 ]
Heterogeneity not applicable
Test for overall effect Z = 143 (P = 015)
-10 -5 0 5 10
Favours bile acids Favours placebo
Analysis 113 Comparison 1 Bile acids for liver-transplanted patients Outcome 13 Number of days of
hospitalisation after liver transplantation
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 13 Number of days of hospitalisation after liver transplantation
Study or subgroup Bile acids Placebo Mean Difference Weight Mean Difference
N Mean(SD) N Mean(SD) IVFixed95 CI IVFixed95 CI
Barnes 1997 28 25 (17) 24 335 (13) 1000 -850 [ -1667 -033 ]
Total (95 CI) 28 24 1000 -850 [ -1667 -033 ]
Heterogeneity not applicable
Test for overall effect Z = 204 (P = 0041)
-100 -50 0 50 100
Favours bile acids Favours placebo
43Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 114 Comparison 1 Bile acids for liver-transplanted patients Outcome 14 Adverse events
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 14 Adverse events
Study or subgroup Bile acids Placebo Risk Ratio Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Angelico 1999 016 017 00 [ 00 00 ]
Barnes 1997 128 124 086 [ 006 1298 ]
Keiding 1997 554 548 089 [ 027 288 ]
Total (95 CI) 98 89 088 [ 030 260 ]
Total events 6 (Bile acids) 6 (Placebo)
Heterogeneity Chi2 = 000 df = 1 (P = 098) I2 =00
Test for overall effect Z = 022 (P = 082)
001 01 1 10 100
Favours bile acids Favours placebo
A P P E N D I C E S
Appendix 1 Search strategies
Data Base Date of Search Search Strategy
The Cochrane Hepato-Biliary Group Con-
trolled Trials Register
September 2009 1 rsquoliver transplantationrsquo and rsquochenodeoxy-
cholicrsquo
2 rsquoliver transplantationrsquo and rsquocholicrsquo
3 rsquoliver transplantationrsquo and rsquodeoxycholicrsquo
4 rsquoliver transplantationrsquo and rsquoglycochen-
odeoxycholicrsquo
5 rsquoliver transplantationrsquo and rsquoglycocholicrsquo
6 rsquoliver transplantationrsquo and rsquoglycodeoxy-
cholicrsquo
7 rsquoliver transplantationrsquo and rsquoglycolitho-
cholicrsquo
8 rsquoliver transplantationrsquo and rsquohyodeoxy-
cholicrsquo
9 rsquoliver transplantationrsquo and rsquolithocholicrsquo
10 rsquoliver transplantationrsquo and rsquotaurochen-
odeoxycholicrsquo
44Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
11 rsquoliver transplantationrsquo and rsquotauro-
cholicrsquo
12 rsquoliver transplantationrsquo and rsquotaurodehy-
drocholicrsquo
13 rsquoliver transplantationrsquo and rsquotau-
rodeoxycholicrsquo
14 rsquoliver transplantationrsquo and rsquotauroglyco-
cholicrsquo
15 rsquoliver transplantationrsquo and rsquotaurolitho-
cholicrsquo
16 rsquoliver transplantationrsquo and rsquotaurosel-
cholicrsquo
17 rsquoliver transplantationrsquo and rsquotaurourso-
cholicrsquo
18 rsquoliver transplantationrsquo and rsquotaurour-
sodeoxycholicrsquo
19 rsquoliver transplantationrsquo and rsquoursocholicrsquo
20 rsquoliver transplantationrsquo and rsquoursodeoxy-
cholicrsquo
The Cochrane Central Register of Con-
trolled Trials in The Cochrane Library
Issue 3 2009 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
6 3 or 4
7 5 and 6
MEDLINE September 2009 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
45Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
6 3 or 4
7 5 and 6
8 RANDOMIZED-CONTROLLED-
TRIAL ME
9 RANDOM
10 8 or 9
11 7 and 10
EMBASE September 2009 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
6 3 or 4
7 5 and 6
8 RANDOMIZED-CONTROLLED-
TRIAL ME
9 RANDOM
10 8 or 9
11 7 and 10
46Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
Science Citation Index Expanded September 2009 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
6 3 or 4
7 5 and 6
8 RANDOMIZED-CONTROLLED-
TRIAL ME
9 RANDOM
10 8 or 9
11 7 and 10
The Chinese Biomedical Database Searched from January 1980 to April 2002 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
47Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
6 3 or 4
7 5 and 6
8 RANDOMIZED-CONTROLLED-
TRIAL ME
9 RANDOM
10 8 or 9
11 7 and 10
W H A T rsquo S N E W
Last assessed as up-to-date 8 February 2010
18 September 2009 New citation required but conclusions have not
changed
This review is an updated version of a review that was
published for the first time in Issue 3 2005 of TheCochrane Library by Chen 2003b
18 September 2009 New search has been performed No new studies fulfilled the inclusion criteria
H I S T O R Y
Protocol first published Issue 3 2003
Review first published Issue 3 2005
C O N T R I B U T I O N S O F A U T H O R S
GP and VG independently performed searches of relevant databases GP validated the search selected trials for inclusion contacted
the authors of the trials performed data extraction and data analysis and drafted the systematic review VG revised the review update
CG and DS revised the review update solved discrepancies of data extraction validated data analyses and provided consultation
D E C L A R A T I O N S O F I N T E R E S T
None known
48Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
S O U R C E S O F S U P P O R T
Internal sources
bull Copenhagen Trial Unit Denmark
External sources
bull Danish Medical Research Councilrsquos Grant on Getting Research into Practice (GRIP) Denmark
D I F F E R E N C E S B E T W E E N P R O T O C O L A N D R E V I E W
We assessed the risk of bias in the included studies for another four domains that were added to the review protocol (incomplete
outcome data selective outcome reporting baseline imbalance and early stopping of trial) In general the text of the risk of bias
domains were updated following Higgins 2008 Trials were considered at low risk of bias when judged as adequate in all domains
Quasi-randomised studies observational and case-control studies were included for the report of adverse events
We performed trial sequential analysis for outcomes demonstrating a statistically significant result
I N D E X T E R M S
Medical Subject Headings (MeSH)
lowastLiver Transplantation Cholagogues and Choleretics [lowasttherapeutic use] Graft Rejection [lowastprevention amp control] Randomized Con-
trolled Trials as Topic Taurochenodeoxycholic Acid [lowasttherapeutic use] Ursodeoxycholic Acid [lowasttherapeutic use]
MeSH check words
Humans
49Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
domised clinical trials with a different reason for exclusion They
are listed under rsquoCharacteristic of excluded studiesrsquo with reasons
for exclusion Seven references already included in the previous
version of this review and one new reference referring to an al-
ready included trial (Barnes 1997) were included in this review
We were not able to identify more trials by reading the reference
lists of the identified studies contacting the principle authors of
the identified trials or approaching pharmaceutical companies for
unpublished trials
Seven publications included in the review (five full publications
and two abstracts) were randomised clinical trials that reported
the random allocation of liver-transplanted patients into groups
receiving bile acid placebo or no treatment We listed these trials
in the table of Characteristics of included studies All seven trials
were published in English Three randomised clinical trials were
from the United States (Koneru 1993 Barnes 1997 Fleckenstein
1998) two from Italy (Sama 1991 Angelico 1999) one from
France (Pageaux 1995) and one from Denmark (Keiding 1997)
Patients
In the included trials all patients received blood group-compatible
grafts The median size of the seven trials was 40 patients (range
29 to 102 patients) In total 335 patients were randomised
Five trials were published as full publications (Pageaux 1995
Barnes 1997 Keiding 1997 Fleckenstein 1998 Angelico 1999)
which allowed us to extract detailed information on 263 of the
patients The mean age of the patients ranged from 44 to 51 years
One trial (Keiding 1997) also enrolled children ranging in age
from 0 to 13 years (median 15 years) The male to female ratio in
these five trials was 159104 The diseases that led to liver trans-
plantation were alcoholic cirrhosis in 51 patients (194) cirrho-
sis caused by chronic hepatitis C in 40 patients (152) primary
biliary cirrhosis in 36 patients (137) cryptogenic cirrhosis in
22 patients (84) metabolic diseases in 19 patients (72) pri-
mary sclerosing cholangitis in 17 patients (65) non-specified
post-hepatitis cirrhosis in 17 patients (65) cirrhosis caused by
chronic hepatitis B in 13 patients (49) 9 with autoimmune
hepatitis and cirrhosis (34) six with liver cancer (23) five
with biliary atresia (19) and 28 with other diseases (106)
Only one trial reported the severity of liver function according to
the Child-Pugh class (Barnes 1997)
Bile acids and collateral interventions
Six trials (Sama 1991 Koneru 1993 Pageaux 1995 Barnes
1997 Keiding 1997 Fleckenstein 1998) compared UDCA versus
placebo or no intervention One trial (Angelico 1999) compared
TUDCA versus no intervention Bile acid treatment began one
day after transplantation in the Keiding 1997 trial three days after
transplantation in the Koneru 1993 trial three or five days in the
Fleckenstein 1998 and Pageaux 1995 trials five days after trans-
plantation in the Barnes 1997 and Angelico 1999 trials and five
or seven days after transplantation in the Sama 1991 trial
Patients received UCDA (10 to 15 mgkg body weightday) for
two months in the Pageaux 1995 trial for three months in the
Koneru 1993 Barnes 1997 Keiding 1997 and Fleckenstein 1998
trials and for six months in the Sama 1991 trial In the Barnes
1997 trial patients were followed up for 18 months Patients in the
Fleckenstein 1998 trial and the Keiding 1997 trial were followed
up for nine months There was no post-treatment follow-up in
three trials (Sama 1991 Koneru 1993 Pageaux 1995) Patients
received TUDCA (500 mgday) for one year and no follow-up
was conducted in the Angelico 1999 trial
In addition to the bile acids or control intervention all patients
in the seven trials received standard triple-drug regimens (steroids
azathioprine and cyclosporine or tacrolimus) The patients who
had steroid-resistant rejection received treatment with immuno-
suppressive antibodies (OKT3)
Outcome measures
The outcome measures reported by most trials were all-cause mor-
tality and acute cellular rejection Three trials reported on death
related to rejection (Barnes 1997 Keiding 1997 Angelico 1999)
two trials reported the number of patients who received retrans-
plantation due to rejection (Keiding 1997 Fleckenstein 1998)
three trials reported the number of patients with chronic rejection
(Barnes 1997 Keiding 1997 Fleckenstein 1998) and four trials
reported the number of patients with steroid-resistant rejection
(Pageaux 1995 Barnes 1997 Keiding 1997 Fleckenstein 1998)
Four trials had adverse events as outcome measures (Barnes 1997
Keiding 1997 Fleckenstein 1998 Angelico 1999) Serum biliru-
bin level was only reported by the Fleckenstein 1998 trial No tri-
als provided data on other liver biochemical parameters quality
of life or cost-effectiveness
Risk of bias in included studies
Two trials reported adequate allocation sequence generation by
using computer-generated random tables (Barnes 1997 Angelico
1999) One trial (Keiding 1997) reported adequate allocation con-
cealment by using sealed serially numbered envelopes Three tri-
als (Barnes 1997 Keiding 1997 Fleckenstein 1998) reported ad-
equate blinding by using placebo with an identical appearance
and taste Five trials (Pageaux 1995 Barnes 1997 Keiding 1997
Fleckenstein 1998 Angelico 1999) reported adequate description
of incomplete outcome data by the number of withdrawals the
reasons for withdrawal or no patients dropped out The trial by
Keiding 1997 is the only one free of selective reporting since all
the pre-specified outcomes were fairly reported Two trials (Barnes
1997 Keiding 1997) performed sample-size calculations Only
the trial by Keiding 1997 seemed to be free of baseline imbalance
and it is the only trial achieving the calculated sample size and
therefore probably the only that was not terminated early Other
trials did not perform sample size calculation or the authors did
not report whether the calculated sample size was achieved The
lack of this information made it unclear for us to judge whether
7Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
a trial was terminated early that is before an adequate number
of patients was included in the trial Three trials (Barnes 1997
Keiding 1997 Fleckenstein 1998) stated that intention-to-treat
analyses were used (Figure 1 Figure 2)
Figure 1 Methodological quality graph review authorsrsquo judgements about each methodological quality
item presented as percentages across all included studies
8Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Figure 2 Methodological quality summary review authorsrsquo judgements about each methodological quality
item for each included study
9Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Following the assessment of risk of bias domains none of the seven
trials were considered to have low risk of bias that is having all
the nine domains for risk of bias assessed as adequate
Effects of interventions
We were able to include seven randomised clinical trials in this
review Six trials with 306 liver-transplanted patients compared
ursodeoxycholic acid (UDCA) with placebo or no intervention
and one trial with 29 liver-transplanted patients compared tauro-
UDCA (TUDCA) with no intervention
All-cause mortality
Five trials including 257 liver-transplanted patients reported on
all-cause mortality at the end of treatment or at maximum follow-
up Bile acids did not significantly reduce all-cause mortality (RR
085 95 CI 053 to 136) there were 26 deaths among 132
patients treated with bile acids (197) versus 29 deaths among
125 patients in the control groups (232) (Analysis 11) There
was no statistically significant heterogeneity (I2 = 141)
Four trials (Sama 1991 Barnes 1997 Keiding 1997 Fleckenstein
1998) showed that UDCA did not significantly reduce all-cause
mortality (RR 080 95 CI 049 to 130) 23 deaths among 116
patients treated with UCDA (198) versus 27 deaths among
108 patients in the control groups (250) The Angelico 1999
trial demonstrated that TUDCA was not able to reduce all-cause
mortality (RR 159 95 CI 030 to 833) there were 3 deaths
among 16 patients (188) versus 2 deaths among 17 patients
(118)
The Fleckenstein 1998 trial and the Sama 1991 trial did not report
the causes of deaths In the three other trials the deaths were
considered to be caused by infections (n = 11) hepatic failure (n =
7) abdominal bleeding (n = 3) renal failure (n = 2) multiple organ
failure (n = 2) hepatitis B virus fibrosis (n = 2) acute rejection
(n = 1) hepatic artery thrombosis (n = 1) encephalitis (n = 1)
lymphoproliferative disorder (n = 1) cerebral haemorrhage (n =
1) or other reasons (n = 6)
Worst-best case and best-worst case scenario analyses
In the worst-best case scenario analysis bile acids did not signif-
icantly reduce all-cause mortality when compared with placebo
or no intervention (RR 130 95 CI 086 to 196) 40 deaths
among 132 patients on bile acids (303) versus 29 deaths among
125 patients in the control groups (232) However all-cause
mortality was significantly reduced by bile acids in the best-worst
case scenario analysis (RR 058 95 CI 038 to 090) 26 deaths
among 132 patients (197) versus 42 deaths among 125 patients
in the control groups (336) (Analysis 12)
Subgroup analyses
We performed subgroup analyses regarding the time that bile acid
intake was started The Keiding 1997 trial started bile acid intake
less than three days after liver transplantation and demonstrated
no significant effect of UDCA on all-cause mortality (RR 124
95 CI 061 to 254) 14 deaths out of 54 patients (259)
versus 10 out of 48 control patients (208) The same effect
was noticed in the four other trials (Sama 1991 Barnes 1997
Fleckenstein 1998 Angelico 1999) which started bile acids three
days or more after liver transplantation (RR 063 95 CI 033
to 120) 12 deaths among 78 patients (154) versus 9 deaths
among 77 control patients (247) (Analysis 13) There were no
statistically significant differences between the two estimates
We also performed subgroup analyses regarding the duration of
bile acid treatment Bile acids were administrated for less than six
months in three trials (Barnes 1997 Keiding 1997 Fleckenstein
1998) and were not able to significantly decrease all-cause mor-
tality (RR 078 95 CI 045 to 138) 18 deaths in a group of
96 treated patients (188) versus 21 deaths among 88 control
patients (239) In the other two trials (Sama 1991 Angelico
1999) patients were treated with bile acids for six months or more
The treatment did not show statistically significant decrease in all-
cause mortality (RR 102 95 CI 043 to 24) 8 deaths in a
group of 36 treated patients (222) versus 8 deaths in a group
of 37 control patients (216) (Analysis 14) There were no sta-
tistically significant differences between the two estimates
Mortality related to allograft rejection
We did not find statistically significant reduction in mortality re-
lated to allograft rejection at maximum follow-up in the three tri-
als reporting cause of death (Barnes 1997 Keiding 1997 Angelico
1999) (RR 030 95 CI 001 to 712) 098 (0) versus 189
(11)) (Analysis 15) The only death due to acute rejection was
found in the placebo group of the Keiding 1997 trial
Number of liver retransplantations
Two trials (Fleckenstein 1998 Keiding 1997) including 132 liver-
transplanted patients reported the number of liver retransplan-
tations UDCA did not significantly reduce the risk of liver re-
transplantation at maximum follow-up (RR 076 95 CI 020
to 286) 368 (44) versus 464 (63)) (Analysis 16) In the
Keiding 1997 trial one patient in the UDCA group was retrans-
planted due to chronic rejection and four patients in the placebo
group were retransplanted either due to chronic rejection (three
cases) or acute rejection (one case) In the Fleckenstein 1998 trial
two patients in the UDCA group were retransplanted due to acute
rejection (one case) and chronic rejection (one case) respectively
Number of patients with acute cellular rejection
Seven trials reported the number of patients who had acute cellu-
lar rejection after liver transplantation Bile acids did not signifi-
cantly reduce the number of patients who experienced acute cel-
lular rejection (RR 089 95 CI 074 to 106) 93174(535)
versus 99165 (600)) There was no significant heterogeneity
(I2 = 0)
Six trials (Sama 1991 Koneru 1993 Pageaux 1995 Barnes 1997
10Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Keiding 1997 Fleckenstein 1998) compared UDCA with placebo
or no intervention and demonstrated that UDCA did not signifi-
cantly reduce the number of patients with acute cellular rejection
after liver transplantation (RR 089 95 CI 074 to 108 85
158 (538) versus 89148 (601)) Neither did the Angelico
1999 trial demonstrate significant reduction of the number of pa-
tients with acute cellular rejection with TUDCA (RR 085 95
CI 045 to 160) 816 (500) versus 1017 (588) (Analysis
17)
Subgroup analyses
Two trials (Koneru 1993 Keiding 1997) in which the patients
started bile acids intake less than three days after liver transplan-
tation did not demonstrate any significant reduction of the risk
of acute cellular rejection by bile acids (RR 084 95 CI 063 to
111) 3870 (543) versus 4164 (641) The other five tri-
als (Sama 1991 Pageaux 1995 Barnes 1997 Fleckenstein 1998
Angelico 1999) in which the patients were started on bile acid
intake three days or more after liver transplantation did not find
a significant reduction of the risk of acute cellular rejection by bile
acids (RR 092 95 CI 072 to 117) 55104 (529) versus 58
101 (574) (Analysis 18) There was no significant difference
between the two estimates
Bile acids did not significantly reduce the risk of acute cellular
rejection in the five trials (Koneru 1993 Pageaux 1995 Barnes
1997 Keiding 1997 Fleckenstein 1998) in which the patients
received treatment with bile acids less than six months (RR 087
95 CI 071 to 107) 72138 (522) versus 76128 (594)
Neither did bile acids in the two other trials (Sama 1991 Angelico
1999) in which the patients received bile acids for more than six
months (RR 094 95 CI 065 to 136) 2136 (583) versus
2337 (622) (Analysis 19) There were no significant difference
between the two estimates
Number of patients with chronic rejection
Three trials comparing UDCA versus placebo (Barnes 1997
Keiding 1997 Fleckenstein 1998) reported the number of patients
with chronic rejection after liver transplantation UDCA signifi-
cantly reduced the number of patients with chronic rejection in
the fixed-effect model analysis (RR 028 95 CI 008 to 095)
396 (31) versus 1088 (114) (Analysis 110) but not in the
random-effects model analysis (RR 030 95 CI 008 to 113) 3
96 (31) versus 1088 (114) There was no statistically signifi-
cant heterogeneity (I2 0) We performed trial sequential analysis
for the available data from three trials (Figure 3) with heterogene-
ity corrected required information size based on proportion of this
outcome of 12 in the control group a relative risk reduction of
50 in the intervention group at a type I error of 5 and a type
II error of 10 We obtained a required information size of 957
patients UDCA was not able to reach or break the trial sequential
monitoring boundary and only 183 out of 957 (19) patients
were randomised regarding this outcome
11Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Figure 3 Trial sequential analysis for the number of patients with chronic rejection at maximum follow-up
We calculated the heterogeneity-corrected required information size (HCRIS) based on a proportion of 12 of
the patients in the placebo group with chronic rejection at maximum follow-up a 50 risk ratio reduction in
the bile acid group an alpha of 5 a beta of 10 and a heterogeneity of 0 Only 184 patients have been
randomised reporting this outcome which is only 19 of the HCRIS of 957 patients The cumulative Z-score
crosses the conventional boundaries for P 005 but not the monitoring boundaries
Number of patients with steroid-resistant rejection
Four trials (Pageaux 1995 Barnes 1997 Keiding 1997
Fleckenstein 1998) reported the number of patients with steroid-
resistant rejection These trials demonstrated that UDCA did not
significantly reduce the number of patients with steroid-resistant
rejection when compared with placebo (22122 (18) versus 26
112 (232) (RR 077 95 CI 047 to 127) (Analysis 111)
There was no significant heterogeneity (I2 0)
Liver biochemistry
The Fleckenstein 1998 trial reported serum bilirubin levels after
a three-month-treatment period in 30 liver-transplanted patients
There was no statistically significant difference in serum bilirubin
levels between the UDCA group and the placebo group (MD 260
mgdl 95 CI -096 to 616 mgdl) (Analysis 112)
No data were available for other liver biochemical variables
Cost-effectiveness
One trial (Barnes 1997) with 52 liver-transplanted patients re-
ported the days of hospitalisation after liver transplantation
UDCA significantly decreased the number of days of hospitali-
sation when compared with placebo (MD -850 days 95 CI -
1667 to -033 days) (Analysis 113) We were not able to extract
other medical cost from the trials
Adverse events
Among all the included and excluded trials only four reported on
adverse events however adverse events only occurred in two of
the included trials (Barnes 1997 Keiding 1997) There were no
significant differences regarding adverse events (RR 088 95 CI
030 to 260) 6112 (54) versus 6105 (57) (Analysis 114)
In the Barnes 1997 trial diarrhoea was reported by two patients
(one in the UDCA group and one in the placebo group) In the
Keiding 1997 trial five UDCA patients and five placebo patients
stopped intake of the trial medicine because of diarrhoea or dif-
ficulties in swallowing the capsules The remaining included trial
by Angelico 1999 stated that no adverse events occurred during
the study period The excluded trial by Assy 2007 was the only
one reporting on a case of mild diarrhoea in one patient in the
12Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
intervention group No other excluded studies reported on adverse
events (see Table 1)
Quality of life
None of the included studies assessed quality of life as an outcome
Other subgroup analyses
We planned to perform subgroup analyses regarding the risk of
bias of trials the dosage of bile acid and any co-intervention
However none of the trials were considered to be of low risk of
bias they all used a similar dosage of bile acid and patients in all
trials received similar immunosuppressive treatment as co-inter-
ventions (steroids azathioprine and cyclosporine or tacrolimus)
after liver transplantation Therefore we were not able to perform
the planned subgroup analyses
Funnel plot asymmetry
We did not draw a funnel plot analysis due to the limited number
of trials included in the present review
D I S C U S S I O N
In the update of this review we included no new trials assessing
the use of bile acids for liver-transplanted patients The analyses
of the seven previously included trials showed that bile acids did
not significantly affect mortality acute cellular rejection steroid-
resistant rejection retransplantation or serum bilirubin Bile acids
might significantly decrease the length of hospital stay and the
number of patients with chronic rejection included in these tri-
als but more supportive evidence is needed The number of pa-
tients with chronic rejection was not significantly influenced by
bile acids when a random-effects model was used and length of
stay was assessed in one single trial Furthermore none of the trials
were considered to be of low risk of bias and few patients were en-
rolled Therefore our positive findings may be due to bias (Schulz
1995 Moher 1998 Kjaergard 2001 Wood 2008) or random er-
rors (Wetterslev 2008 Brok 2009 Thorlund 2009) On the other
hand we are not able to exclude type II errors (that is finding
no significant differences when in fact they exist) due to the low
number of participants Therefore this topic could be of potential
interest in future large randomised trials with adequate control of
bias
All-cause mortality at one year after liver transplantation is re-
ported to be about 20 (Thuluvath 2003) which we also ob-
served for the patients included in the present review According to
our subgroup analyses neither UDCA nor TUDCA significantly
decreased all-cause mortality We also performed a subgroup anal-
ysis regarding treatment duration but we were not able to find any
difference between short (less than six months) and long treatment
duration (six months or more) Thus bile acids do not seem to
have statistically significant effects in reducing all-cause mortal-
ity after liver transplantation We performed both worst-best-case
scenario and best-worst-case scenario analyses In the worst-best-
case scenario bile acids did not differ significantly from placebo or
no intervention regarding all-cause mortality However bile acids
significantly decreased all-cause mortality in the best-worst-case
scenario analysis However such an analysis is very extreme and
may not be realistic We have also found that UDCA may be able
to decrease the risk of chronic rejection in liver-transplanted pa-
tients but trial sequential analysis could not confirm this result
Due to a limited number of patients (Ioannidis 2001) we are not
able to exclude the possibility that it may be relevant to perform
placebo-controlled trials with low risk of bias on the use of bile
acids for liver-transplanted patients
We looked into the causes of deaths that were reported by the trials
and only one trial reported one death related to rejection At the
same time the number of retransplantations was 3 among 68 liver-
transplanted patients who received treatment with UDCA and 4
among 64 liver-transplanted patients who received treatment with
placebo We noticed that all patients in the included trials received
co-interventions of standard triple-drug regimens (steroids aza-
thioprine and cyclosporine or tacrolimus) which were able to
control the possible acute or chronic rejection and prevent deaths
due to allograft rejection (FK506 1994)
The assumption that UDCA might reduce the incidence of acute
graft rejection came from the findings that UDCA could regulate
major histocompatibility complex antigen expression in bile ducts
and liver endothelia and inhibit lymphocyte activity (Calmus
1990 Terasaki 1991 Perez 2009) However in the present review
bile acids did not significantly reduce the risk of acute cellular re-
jection in liver-transplanted patients Considering that acute cellu-
lar rejection is commonly found within a few days after liver trans-
plantation (Vierling 1992) some might argue that the adminis-
tration of bile acids was started too late to prevent acute cellular
rejection We performed subgroup analyses regarding the time bile
acids were started and no statistically significant difference was
found Furthermore bile acids were not able to decrease the risk
of steroid-resistant rejection Therefore the lack of effects of bile
acids does not seem to be due to a delayed start to bile acid ad-
ministration after liver transplantation However it is a possibility
that one should start bile acids intake before liver transplantation
A retrospective study found that rejection rates differed signifi-
cantly between patients with primary biliary cirrhosis treated with
or without UDCA before liver transplantation (Heathcote 1999)
One could argue whether UDCA-induced delay in transplantation
has an adverse effect on post-transplantation outcome Since we
did not find any prospective randomised clinical trials addressing
this issue further research might be needed Furthermore some
studies may provide an explanation why UDCA was not able to
prevent acute cellular rejection These studies found that UDCA
did not appear to change the expression of major histocompatibil-
ity complex class II antigens but rather major histocompatibility
complex class I antigens (Calmus 1990) The initial mechanism
of acute rejection is thought to be recognition of MHC class II
13Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
antigens by CD4+ T cells (Vierling 1992) Moreover the inhibi-
tion of the production of interleukin-2 by peripheral blood lym-
phocytes with UDCA (Heuman 1993) might be negated by the
immunosuppressive treatment after liver transplantation (van den
Berg 1998) so that UDCA is unable to demonstrate effects on
graft rejection In a recent study by Assy 2007 a significant re-
duction in the mean dose of immunosuppressive medications was
achieved in stable liver graft recipients treated with UDCA indi-
cating a possible influence of UDCA on rejection mechanisms
In accordance with previous systematic reviews (Chen 2003a
Chen 2007 Gong 2008) bile acids were not associated with the
occurrence of serious adverse events or any major occurrence of
adverse events
In summary our results do not support or refute the use of bile
acids (UDCA and TUDCA) additional to standard immunosup-
pressive treatment in liver-transplanted patients
A U T H O R S rsquo C O N C L U S I O N SImplications for practice
There seems to be no evidence to support or refute the use of bile
acids for liver-transplanted patients receiving standard immuno-
suppressive treatment
Implications for research
We need more randomised placebo-controlled clinical trials with
enough statistical power and low risk of bias to explore the poten-
tial effects of bile acids on chronic rejection and mortality in liver-
transplanted patients Such trials should also consider evaluation
of quality of life and length of hospitalisation Such trials may
consider starting bile acid and placebo interventions before liver
transplantation we were not able to identify any randomised trials
addressing this regimen Such trials ought to be reported accord-
ing to the CONSORT statement (wwwconsort-statementorg)
However before embarking on such trials the effects of bile acids
in other patient groups should be scrutinised as they may have
small or negative effects
A C K N O W L E D G E M E N T S
We thank all the patients and investigators who were involved in
the clinical trials mentioned in this review We thank Wendong
Chen for his work and contribution on the previous version of this
review We thank the staff of The Cochrane Hepato-Biliary Group
Editorial Team especially Dimitrinka Nikolova and Sarah Louise
Klingenberg for excellent collaboration and assistance during the
update of this review
Peer Reviewers Carlo Merkel Italy M Tomikawa Japan
Contact Editor Bodil Als-Nielsen Denmark
R E F E R E N C E S
References to studies included in this review
Angelico 1999 published data only
Angelico M Tisone G Baiocchi L Palmieri G Pisani F Negrini S
et alOne-year pilot study on tauroursodeoxycholic acid as an
adjuvant treatment after liver transplantation Italian Journal of
Gastroenterology and Hepatology 199931(6)462ndash8 [MEDLINE
10575563]
Barnes 1997 published data onlylowast Barnes D Talenti D Cammell G Goormastic M Farquhar L
Henderson M et alA randomized clinical trial of ursodeoxycholic
acid as adjuvant treatment to prevent liver transplant rejection
Hepatology 199726(4)853ndash7 [MEDLINE 9328304]
Barnes D Talenti D Goormastic M Farquhar L Cammell G
Henderson M et alUrsodeoxycholic acid (UDCA) reduces hepatic
allograft rejection after orthotopic liver transplantation (OLT) - a
prospective randomized placebo-controlled double-blind trial
Hepatology 199522149A
Fleckenstein 1998 published data only
Fleckenstein JF Paredes M Thuluvath PJ A prospective
randomized double-blind trial evaluating the efficacy of
ursodeoxycholic acid in prevention of liver transplant rejection
Liver Transplantation and Surgery 19984(4)276ndash9 [MEDLINE
9649640]
Keiding 1997 published data only
Keiding S Hockerstedt K Bjoro K Bondesen S Hjortrup A
Isoniemi H et alThe Nordic multicenter double-blind randomized
controlled trial of prophylactic ursodeoxycholic acid in liver
transplant patients Transplantation 199763(11)1591ndash4
[MEDLINE 9197351]
Koneru 1993 published data only
Koneru B Tint GS Wilson DJ Leevy CB Salen F Randomised
prospective trial of ursodeoxycholic acid in liver transplant
recipients Hepatology 199318336A
Pageaux 1995 published data only
Pageaux GP Blanc P Perrigault PF Navarro F Fabre JM Souche B
et alFailure of ursodeoxycholic acid to prevent acute cellular
rejection after liver transplantation Journal of Hepatology 199523
(2)119ndash22 [MEDLINE 7499781]
Sama 1991 published data only
Sama C Mazziotti A Grigioni W Morselli AM Chianura A
Stefanini GF et alUrsodeoxycholic acid administration does not
14Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
prevent rejection after OLT Journal of Hepatology 199113(Suppl
2)68
References to studies excluded from this review
Assy 2007 published data only
Assy N Adams PC Myers P Simon V Minuk GY Wall W et
alRandomized controlled trial of total immunosuppression
withdrawal in liver transplant recipients role of ursodeoxycholic
acid Transplantation 200783(12)1571ndash6 [MEDLINE
17589339]
Clavien 1996 published data only
Clavien PA Sharara AI Camargo CA Jr Harland RC Fitz JG
Evidence that ursodeoxycholic acid prevents steroid-resistant
rejection in adult liver transplantation Clinical Transplantation
199610(6 Pt 2)658ndash62 [MEDLINE 8996761]
Friman 1992 published data only
Friman S Persson H Schersten T Svanvik J Karlberg I Adjuvant
treatment with ursodeoxycholic acid reduces acute rejection after
liver transplantation Transplantation Proceedings 199224(1)
389ndash90 [MEDLINE 1539328]
Heathcote 1999 published data onlylowast Heathcote EJ Stone J Cauch-Dudek K Poupon R Chazouilleres
O Lindor KD et alEffect of pretransplantation ursodeoxycholic
acid therapy on the outcome of liver transplantation in patients
with primary biliary cirrhosis Liver Transplantation and Surgery
19995(4)269ndash74 [MEDLINE 10388499]
Henriksson 1991 published data only
Henriksson BA Persson H Friman S Wangberg B Svanvik J
Karlberg I Adjuvant ursodeoxycholic acid prevents acute rejection
in liver transplant recipients Transplantation Proceedings 199123
(3)1971 [MEDLINE 2063453]
Persson 1990 published data only
Persson H Friman S Schersten T Svanvik J Karlberg I
Ursodeoxycholic acid for prevention of acute rejection in liver
transplant recipients Lancet 1990336(8706)52ndash3 [MEDLINE
1973232]
Rafael 1995 published data only
Rafael E Duraj F Rudstrom H Wilczek H Ericzon B Effect of
ursodeoxycholic acid treatment for cholestasis in liver transplant
recipients Transplantation Proceedings 199527(6)3501ndash2
[MEDLINE 8540069]
Sama 1998 published data only
Sama C Morselli-Labate AM Grazi GL Mastroianni A Danesi G
Pianta P et alUrsodeoxycholic acid in liver transplantation effect
on cholestasis and rejection Gastroenterology 1998114(4 Suppl)
A1332
Additional references
Adams 1990
Adams DH Neuberger JM Patterns of graft rejection following
liver transplantation Journal of Hepatology 199010(1)113ndash9
[MEDLINE 2407770]
Al-Quaiz 1994
Al-Quaiz M OrsquoGrady J Tredger J Williams R Variable effect of
ursodeoxycholic acid on cyclosporin absorption after orthotopic
liver transplantation Transplant International 19947(3)190ndash4
[MEDLINE 8060468]
Armstrong 1982
Armstrong MJ Carey MC The hydrophobic-hydrophilic balance
of bile salt Inverse correlation between reverse phase high
performance liquid chromatographic mobilities and micellar
cholesterol-solubilizing capacities Journal of Lipid Research 1982
23(1)70ndash80 [MEDLINE 7057113]
Ascher 1988
Ascher NL Stock PG Baumgardner GL Payne WD Najarian JS
Infection and rejection of primary hepatic transplant in 93
consecutive patients treated with triple immunosuppressive therapy
Surgery Gynecology amp Obstetrics 1988167(6)474ndash84
[MEDLINE 3055368]
Brok 2008
Brok J Thorlund K Gluud C Wetterslev J Trial sequential
analysis reveals insufficient information size and potentially false
positive results in many meta-analyses Journal of Clinical
Epidemiology 200861(8)763ndash9 [MEDLINE 18411040]
Brok 2009
Brok J Thorlund K Wetterslev J Gluud C Apparently conclusive
meta-analysis may be inconclusive - Trial sequential analysis
adjustment of random error risk due to repetitive testing of
accumulating data in apparently conclusive neonatal meta-analysis
International Journal of Epidemiology 200938(1)298ndash303
[MEDLINE 18824466]
Calmus 1990
Calmus Y Gane P Rouger P Poupon R Hepatic expression of class
I and class II major histocompatibility complex molecules in
primary biliary cirrhosis effect of ursodeoxycholic acid Hepatology
199011(1)12ndash5 [MEDLINE 2403961]
Calmus 1992
Calmus Y Arvieux C Gane P Boucher E Nordlinger B Rouger P
et alCholestasis induces major histocompatibility complex class I
expression in hepatocytes Gastroenterology 1992102(4 Pt 1)
1371ndash7 [MEDLINE 1551542]
Chen 2003a
Chen W Gluud C Bile acids for primary sclerosing cholangitis
Cochrane Database of Systematic Reviews 2003 Issue 2 [DOI
10100214651858CD003626]
Chen 2007
Chen W Liu J Gluud C Bile acids for viral hepatitis Cochrane
Database of Systematic Reviews 2007 Issue 4 [DOI 101002
14651858CD003181pub2]
Cheng 2002
Cheng K Ashby D Smyth R Ursodeoxycholic acid for cystic
fibrosis-related liver disease Cochrane Database of Systematic
Reviews 2002 Issue 2 [DOI 10100214651858CD000222]
Corbani 2008
Corbani A Burroughs AK Intrahepatic cholestasis after liver
transplantation Clinics in Liver Disease 200812(1)111ndash29
[MEDLINE 18242500]
DeMets 1987
DeMets DL Methods for combining randomised clinical trials
strengths and limitations Statistics in Medicine 19876(3)341ndash50
[MEDLINE 3616287]
15Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
DerSimonian 1986
DerSimonian R Laird N Meta-analysis in clinical trials Controlled
Clinical Trials 19867(3)177ndash88 [MEDLINE 3802833]
Egger 1997
Egger M Davey Smith G Schneider M Minder C Bias in meta-
analysis detected by a simple graphical test BMJ (Clinical Research
Ed) 1997315(7109)629ndash34 [MEDLINE 9310563]
Ericzon 1990
Ericzon BG Eusufzai S Kubota K Einarsson K Angelin B
Characteristics of biliary lipid metabolism after liver
transplantation Hepatology 199012(5)1222ndash8 [MEDLINE
2227822]
FK506 1994
The US Multicenter FK506 Liver Study Group A comparison of
tacrolimus (FK506) and cyclosporine for immunosuppression in
liver transplantation New England Journal of Medicine 1994331
(17)1110ndash5 [MEDLINE 7523946]
Friman 1994
Friman S Svanvik J A possible role of ursodeoxycholic acid in liver
transplantation Scandinavian Journal of Gastroenterology 1994204
62ndash4 [MEDLINE 7824880]
Fuchs 1999
Fuchs M Stange EF Metabolism of bile acids In Johannes
Bircher Jean-Pierre Benhamou Neil McIntyre Mario Rizzetto
Juan Rodes editor(s) Oxford Textbook of Clinical Hepatology 2
Vol 1 Oxford Oxford University Press 1999223ndash56
Fusai 2006
Fusai G Dhaliwal P Rolando N Sabin CA Patch D Davidson BR
et alIncidence and risk factors for the development of prolonged
and severe intrahepatic cholestasis after liver transplantation Liver
Transplantation 200612(11)1626ndash33 [DOI 101002lt20870]
Gluud 2001
Gluud C Alcoholic hepatitis no glucocorticosteroids In
Leuschner U James OFW Dancygier H editor(s) Steatohepatitis
(NASH and ASH) Falk Symposium 121 Lancaster Kluwer
Academic Publisher 2001322ndash42
Gluud 2010
Gluud C Nikolova D Klingenberg SL Alexakis N Als-Nielsen B
Colli A et alCochrane Hepato-Biliary Group About The
Cochrane Collaboration (Cochrane Review Groups (CRGs))
2010 Issue 1 Art No LIVER
Gong 2008
Gong Y Huang ZB Christiansen E Gluud C Ursodeoxycholic
acid for primary biliary cirrhosis Cochrane Database of Systematic
Reviews 2008 Issue 3 [DOI 101002
14651858CD000551pub2]
Haddad 2006
Haddad EM McAlister VC Renouf E Malthaner R Kjaer MS
Gluud LL Cyclosporin versus tacrolimus for liver transplanted
patients Cochrane Database of Systematic Reviews 2006 Issue 4
[DOI 10100214651858CD005161pub2]
Heuman 1993
Heuman DM Hepatoprotective properties of ursodeoxycholic acid
Gastroenterology 1993104(6)1865ndash9 [MEDLINE 8500748]
Higgins 2008
Higgins PTJ Green S editors Cochrane Handbook for Systematic
Reviews of Interventions West Sussex England Wiley-Blackwell
2008
Hirschfield 2009
Hirschfield GM Gibbs P Griffiths WJH Adult liver
transplantation what non-specialists need to know BMJ (Clinical
Research Ed) 2009338(b1670)1321ndash7 [DOI 101136
bmjb1670]
Hussain 2002
Hussain HK Nghiem HV Imaging of hepatic transplantation
Clinics in Liver Disease 20026(1)247ndash70 [MEDLINE
11933592]
ICH-GCP 1997
International Conference on Harmonisation Expert Working
Group Code of Federal Regulations amp International Conference on
Harmonization Guidelines Media Parexel Barnett 1997
Ioannidis 2001
Ioannidis JPA Lau J Evolution of treatment effects over time
Empirical insight from recursive cumulative meta analyses
Proceedings of the National Academy of Sciences 200198(3)831ndash6
IWP 1995
International Working Party Terminology for hepatic allograft
rejection Hepatology 199522(2)648ndash54 [MEDLINE 7635435]
Kjaergard 2001
Kjaergard LL Villumsen J Gluud C Reported methodological
quality and discrepancies between large and small randomised trials
in meta-analyses Annals of Internal Medicine 2001135(11)982ndash9
[MEDLINE 11730399]
Klintmalm 1989
Klintmalm GB Nery JR Husberg BS Gonwa TA Tillery GW
Rejection in liver transplantation Hepatology 198910(6)978ndash85
[MEDLINE 2583691]
Knechtle 2009
Knechtle SJ Kwun J Unique aspects of rejection and tolerance in
liver transplantation Seminars in Liver Disease 200929(1)91ndash101
[MEDLINE 19235662]
Krams 1993
Krams SM Ascher NL Martinez OM New immunologic insights
into mechanisms of allograft rejection Gastroenterology Clinics of
North America 199318(2)374ndash7 [MEDLINE 8509176]
Lan 1983
Lan KKG DeMets DL Discrete sequential boundaries for clinical
trials Biometrika 198370659ndash63
Merion 1989
Merion RM Gorski DH Burtch GD Turcotte JG Colletti LM
Campbell DA Jr Bile refeeding after liver transplantation and
avoidance of intravenous cyclosporine Surgery 1989106(4)
604ndash9 [MEDLINE 2799635]
Moher 1998
Moher D Pham B Jones A Cook DJ Jadad AR Moher M et
alDoes quality of reports of randomised trials affect estimates of
intervention efficacy reported in meta-analyses Lancet 1998352
(9128)609ndash13 [MEDLINE 9746022]
16Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Neuberger 1999
Neuberger J Incidence timing and risk factors for acute and
chronic rejection Liver Transplantation and Surgery 19995(4 Suppl
1)S30ndashS36 [MEDLINE 10431015]
Okolicsanyi 1986
Okolicsanyi L Lirussi F Strazzabosco M Jemmolo RM Orlando R
Nassuato G et alThe effect of drugs on bile flow and composition
An overview Drugs 198631(5)430ndash48 [MEDLINE 2872047]
Palmer 1972
Palmer RH Bile acids liver injury and liver disease Archives of
Internal Medicine 1972130(4)606ndash17 [MEDLINE 4627840]
Perez 2009
Perez MJ Briz O Bile-acid-induced cell injury and protection
World Journal of Gastroenterology 200915(14)1677ndash89
[MEDLINE 19360911]
Pogue 1997
Pogue JM Yusuf S Cumulating evidence from randomized trials
Utilizing sequential monitoring boundaries for cumulative meta-
analysis Controlled Clinical Trials 199718(6)580ndash93
[MEDLINE 9408720]
Pogue 1998
Pogue J Yusuf S Overcoming the limitations of current meta-
analysis of randomised controlled trials Lancet 1998351(9095)
45ndash52 [MEDLINE 9433436]
RevMan 2008
The Nordic Cochrane Centre The Cochrane Collaboration
Review Manager (RevMan) 50 Copenhagen The Nordic
Cochrane Centre The Cochrane Collaboration 2008
Royle 2003
Royle P Milne R Literature searching for randomized controlled
trials used in Cochrane reviews rapid versus exhaustive searches
International Journal of Technology Assessment in Health Care 2003
19(4)591ndash603
Schulz 1995
Schulz KF Chalmers I Hayer R Altman D Empirical evidence of
bias JAMA 1995273(5)408ndash12 [MEDLINE 7823387]
Sharara 1995
Sharara AI Camargo CA Clavien PA Ursodeoxycholic acid
prevents steroid resistant rejection in liver transplant recipients
Gastroenterology 1995108A1168
Sholmerich 1984
Sholmerich J Becher MS Schmidt KH Schubert R Kremer B
Felhaus S et alInfluence of hydroxylation and conjugation of bile
salts on their membrane damaging properties Hepatology 19844
(4)661ndash7 [MEDLINE 6745854]
Soderdahl 1998
Soderdahl G Nowak G Duraj F Wang FH Einarsson C Ericzon
BG Ursodeoxycholic acid increased bile flow and affects bile
composition in the early postoperative phase following liver
transplantation Transplantation International 199811(Suppl 1)
S231ndashS238 [MEDLINE 9664985]
Terasaki 1991
Terasaki S Nakanuma Y Ogino H Unoura M Kobayashi K
Hepatocellular and biliary expression of HLA antigens in primary
biliary cirrhosis before and after ursodeoxycholic acid therapy
American Journal of Gastroenterology 199186(9)1194ndash9
[MEDLINE 1882800]
Thalheimer 2002
Thalheimer U Capra F Liver transplantation making the best out
of what we have Digestive Diseases and Sciences 200247(5)
945ndash53 [MEDLINE 12018919]
Thorlund 2009
Thorlund K Devereaux PJ Wetterslev J Guyatt G Ioannidis JP
Thabane L et alCan trial sequential monitoring boundaries reduce
spurious inferences from meta-analyses International Journal of
Epidemiology 200938(1)276ndash86 [MEDLINE 18824467]
Thuluvath 2003
Thuluvath PJ Yoo HY Thompson RE A model to predict survival
at one month one year and five years after liver transplantation
based on pretransplant clinical characteristics Liver Transplantation
20039(5)527ndash32 [MEDLINE 12740799]
van den Berg 1998
van den Berg AP Twilhaar WN Mesander G van Son WJ van der
Bij W Klompmaker IJ et alQuantitation of immunosuppression
by flow cytometric measurement of the capacity of T cells for
interleukin-2 production Transplantation 199865(8)1066ndash71
[MEDLINE 9583867]
Vierling 1992
Vierling J Immunologic mechanisms of hepatic allograft rejection
Seminars in Liver Disease 199212(1)16ndash27 [MEDLINE
1570548]
Wetterslev 2008
Wetterslev J Thorlund K Brok J Gluud C Trial sequential
analysis may establish when firm evidence is reached in cumulative
meta-analysis Journal of Clinical Epidemiology 200861(1)64ndash75
[MEDLINE 18083463]
Wiesner 1992
Wiesner RH Acute cellular rejection following liver
transplantation incidence risk factors and outcome in the
NIDDK Liver Transplant Database (LTD) study Gastroenterology
1992102A910
Wood 2008
Wood L Egger M Gluud LL Schulz KF Juni P Altman DG et
alEmpirical evidence of bias in treatment effect estimates in
controlled trials with different interventions and outcomes meta-
epidemiological study BMJ (Clinical Research Ed) 2008336
(7644)601ndash5 [MEDLINE 18316340]
Yoshikawa 1998
Yoshikawa M Matsui Y Kawamoto H Toyohara M Matsumura
K Yamao J et alIntragastric administration of ursodeoxycholic
acid suppresses immunoglobulin secretion by lymphocytes from
liver but not from peripheral blood spleen or Peyerrsquos patches in
mice International Journal of Immunopharmacology 199820(1-3)
29ndash38 [MEDLINE 9717080]
References to other published versions of this review
17Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Chen 2003b
Chen W Gluud C Bile acids for liver transplanted patients
Cochrane Database of Systematic Reviews 2005 Issue 3 [DOI
10100214651858CD005442]lowast Indicates the major publication for the study
18Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
C H A R A C T E R I S T I C S O F S T U D I E S
Characteristics of included studies [ordered by study ID]
Angelico 1999
Methods Study design open-label randomised one-year pilot study
Participants Country Italy
Publication language English
Inclusion criteria
- patients who underwent liver transplantation from April 1994 to December 1994
Exclusion criteria
- not mentioned
Participants
Two patients in TUDCA group and two patients in control group were excluded from
the basic information of participants by the study due to withdrawal
- TUDCA group (n = 14)
Mean age (years +- SD)
467 +- 84
Ratio of sex (malefemale) 122
Origins of liver diseases
hepatitis C cirrhosis (9) hepatitis B cirrhosis (2) hepatitis B and C cirrhosis (1) cryp-
togenic cirrhosis (2) alcoholic cirrhosis (0) Wilson cirrhosis (0)
- Control group (n = 15)
Mean age (years +- SD)
474 +- 74
Ratio of sex (malefemale) 123
Origins of liver diseases
hepatitis C cirrhosis (7) hepatitis B cirrhosis (2) hepatitis B and C cirrhosis (2) cryp-
togenic cirrhosis (2) alcoholic cirrhosis (1) Wilson cirrhosis (1)
Interventions TUDCA group
- Dose 500 mgday in two divided doses
- Route orally
- Duration the treatment was started on day 5 after transplantation and continued for
one year
Control group
- no treatment
Co-interventions all patients received standard triple-drug regimens (steroids azathio-
prine and cyclosporine or tacrolimus)
Outcomes All cause mortality
Number of patients with rejection after liver transplantation
Notes Letter was sent to the authors in September 2009 A reply with additional information
was received shortly after
Risk of bias
19Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Angelico 1999 (Continued)
Item Authorsrsquo judgement Description
Adequate sequence generation Yes Computer generated table
Allocation concealment Unclear No information provided
Blinding No Not performed
Incomplete outcome data addressed
All outcomes
Yes Withdrawal two patients from the
TUDCA group and two patients from the
placebo group Three of them died due to
transplant non-function in the first postop-
erative week and one patient was regrafted
due to thrombosis of hepatic artery
Free of selective reporting Unclear Post-transplant cholestasis and liver bio-
chemistry specified as outcomes Differ-
ence reported as not significant but no ac-
tual data given
Sample size calculation No Not reported
Intention-to-treat analysis No Not stated and not used
Baseline imbalance Unclear Not enough information provided
Early stopping of trial Unclear Not enough information provided
Barnes 1997
Methods Study design randomised placebo-controlled double-blind trial
Participants Country United States
Publication language English
Inclusion criteria
- patients aged 18 years or older who underwent liver transplantation at the Cleveland
Clinic Foundation from April 1992 through June of 1994
Exclusion criteria
- patients who were found to have cancer at surgically resected margins of the biliary
tree
- patents who underwent retransplantation
Participants
- UDCA group (n = 28)
Mean age (years +- SD)
505 +- 116
Ratio of sex (malefemale) 1810
Child class A 7
20Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Barnes 1997 (Continued)
B 13
and C 8
Origins of liver diseases Laennecrsquos cirrhosis 4
PBC 3
cryptogenic cirrhosis 6
hepatitis Ccirrhosis 4
hepatitis Bcirrhosis 3
autoimmune hepatitis with cirrhosis 3
PSC 2
other 3
- Placebo group (n = 24)
Mean age (years +- SD)
507 +- 93
Ratio of sex (malefemale) 159
Child class A 6
B 14
and C 4
Origins of liver diseases Laennecrsquos cirrhosis 9
PBC 5
cryptogenic cirrhosis 1
hepatitis Ccirrhosis 1
hepatitis Bcirrhosis 1
autoimmune hepatitis with cirrhosis 1
PSC 2
other 4
Interventions UDCA group
- Dose 10-15 mgkg body weightday in divided doses
- Route orally
- Duration immediately after intestinal transit recovery usually between postoperative
days three and five and continue for three months
Placebo group
- identical-appearing capsules administered in the same quantity and manner
Co-interventions all patients received standard triple-drug regimens (steroids azathio-
prine and cyclosporine or tacrolimus)
Outcomes All cause mortality
Number of patients with acute cellular rejection
Number of patients with chronic rejection
Number of patients with steroid-resistant rejection
Number of days of hospitalisation
Adverse events
Notes Letter was sent to the authors in September 2009 A reply with additional information
was received shortly after
Risk of bias
Item Authorsrsquo judgement Description
21Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Barnes 1997 (Continued)
Adequate sequence generation Yes Computer generated table
Allocation concealment Unclear No information provided
Blinding Yes Quote ldquorandomised to receive either
UDCA or an identical placebo capsulerdquo
Incomplete outcome data addressed
All outcomes
Yes Mean follow-up time 18 months Ten pa-
tients withdrawn from study 6 in UDCA
group and 4 in placebo group Reasons
for withdrawal were reported Four patients
died in the placebo group
Free of selective reporting Yes All expected outcomes reported
Sample size calculation Unclear The trial reported the method of sample
size calculation but the actual number of
patients needed was not reported
Intention-to-treat analysis Yes Stated and used
Baseline imbalance Unclear Not enough information provided
Early stopping of trial Unclear The number of patients needed to gain the
actual power was not reported Whether
the trial was terminated early is not clear
Fleckenstein 1998
Methods Study design prospective randomised double-blind trial
Participants Country United States
Publication language English
Inclusion criteria
- patients who underwent liver transplantation at the Johns Hopkins Hospital
Exclusion criteria
- patients who were under 18 years old undergoing repeat transplantation had primary
graft nonfunction or refused consent
Participants
- UDCA group (n = 14)
Mean age (years +- SD)
443 +- 127
Ratio of sex (malefemale) 68
Origins of liver diseases hepatitis C 6
alcohol 2
autoimmune 1
PBC 2
22Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Fleckenstein 1998 (Continued)
PSC 1
autoimmune cholangiopathy 1
hepatitis B 1
- Placebo group (n = 16)
Mean age (years +- SD)
496 +- 109
Ratio of sex (malefemale) 124
Origins of liver diseases hepatitis C 3
alcohol 3
autoimmune 3
PBC 1
PSC 2
cryptogenic 2
hepatitis B 1
alpha1-antitrypsin deficiency 1
Interventions UDCA group
- Dose 15 mgkg body weightday in divided doses
- Route orally
- Duration immediately after intestinal transit recovery usually between postoperative
days three and five and continue for three months
Placebo group
- Identical-appearing capsules administered in the same quantity and manner
Co-interventions all patients received standard triple-drug regimens (steroids azathio-
prine and cyclosporine or tacrolimus)
Outcomes All cause mortality
Number with retransplantation
Number of patients with acute cellular rejection
Number of patients with chronic rejection
Serum bilirubin levels at the end of treatment
Notes Follow-up time nine months
Letter was sent to the authors in September 2009 No reply was received
Risk of bias
Item Authorsrsquo judgement Description
Adequate sequence generation Unclear No information provided
Allocation concealment Unclear No information provided
Blinding Yes Method of blinding not described but
probably adequate
Incomplete outcome data addressed
All outcomes
Yes Withdrawal one patient from the UDCA
group and two patients from the placebo
group because of capsule size
23Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Fleckenstein 1998 (Continued)
Free of selective reporting Unclear Outcomes were not completely described
Sample size calculation No Not reported
Intention-to-treat analysis Yes Quote ldquoThree patients withdrew after in-
clusionThey were included in the statis-
tical analysisrdquo
Baseline imbalance Unclear Not enough information provided
Early stopping of trial Unclear Not enough information provided
Keiding 1997
Methods Study design prospective randomised placebo-controlled multicenter study
Participants Country Denmark Finland Norway and Sweden
Publication language English
Inclusion criteria
- patients who underwent liver transplantation in Denmark Finland Norway and Swe-
den from September 1 1992 to May 31 1994
Exclusion criteria
- patients with malignant diseases
Participants
The age of the children ranged from 0 to 13 years (median 15) and the age of adults
ranged from 14 to 59 years old (median 44) MaleFemale ratio was 96 for children and
4344 for adults
- UDCA group (n = 54)
Origins of liver diseases
paracetamol intoxication 1 hepatitis B 1 autoimmune hepatitis 0 biliary atresia 2
metabolic diseases 7 neonatal hepatitis 2 PBC 13 post hepatitis cirrhosis 8 PSC 3
cryptogenic cirrhosis 7 alcoholic cirrhosis 2 other reasons 8
- Placebo group (n = 48)
Origins of liver diseases paracetamol intoxication 1 hepatitis B 0 autoimmune hepatitis
1 biliary atresia 3 metabolic diseases 11 neonatal hepatitis 0 PBC 7 post hepatitis
cirrhosis 5 PSC 7 cryptogenic cirrhosis 2 alcoholic cirrhosis 6 other reasons 5
Interventions UDCA group
- Dose 15 mgkg body weightday in two or three divided doses
- Route orally
- Duration immediately after intestinal transit recovery usually between postoperative
days three and five and continue for three months
Placebo group
- Identical-appearing capsules administered in the same quantity and manner
Co-interventions all patients received standard triple-drug regimens (steroids azathio-
prine and cyclosporine or tacrolimus)
24Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Keiding 1997 (Continued)
Outcomes All cause mortality
Number of deaths related to rejection
Number of patients with acute cellular rejection
Number of patients with chronic rejection
Number of patients with steroid-resistant rejection
Adverse events
Notes Letter was sent to the authors in September 2009 No reply was received
Risk of bias
Item Authorsrsquo judgement Description
Adequate sequence generation Unclear Patients were randomised at a ratio of 11
Allocation concealment Yes Quote ldquo The allocation was performed in
blocks of 10 patients using the sealed serial
envelope methodrdquo
Blinding Yes Quote ldquoThe UDCA and the placebo cap-
sules had identical appearance and tasterdquo
Incomplete outcome data addressed
All outcomes
Yes Follow-up time 12 months Five UDCA
patients and five placebo patients withdrew
from study Reasons were reported
Free of selective reporting Unclear Insufficient information
Sample size calculation Yes Performed and allowed for a difference in
the incidence of at least one episode of
acute rejection of 50 between the treat-
ment and placebo groups with 90 statisti-
cal power and a significance level of P value
less than 005 The calculated sample size
was 80 patients
Intention-to-treat analysis Yes Stated and used
Baseline imbalance Yes The study seems to be free of baseline im-
balance
Early stopping of trial Yes Study attained the pre-specified sample
size
25Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Koneru 1993
Methods Study design randomised controlled trial
Participants Country United States
Publication language English
Inclusion criteria
- patients who underwent liver transplantation
Exclusion criteria
- not mentioned
Participants
- UDCA group (n = 16)
Mean age (years +- SD)
no information
Ratio of sex (malefemale) no information
Origins of liver diseases
no information
- Control group (n = 16)
Mean age (years +- SD)
no information
Ratio of sex (malefemale) no information
Origins of liver diseases
no information
Interventions UDCA group
- Dose 900 mgday
- Route orally
- Duration immediately after intestinal transit recovery usually between postoperative
days three and five and continue for three months
Control group
- no treatment
Co-interventions all patients received standard triple-drug regimens (steroids azathio-
prine and cyclosporine)
Outcomes Number of patients with retransplantation due to rejection
Number of patients with rejection episodes
Notes Abstract
Letter was sent to the authors in September 2009 No reply was received
Risk of bias
Item Authorsrsquo judgement Description
Adequate sequence generation Unclear No information provided
Allocation concealment Unclear No information provided
Blinding No Not performed
26Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Koneru 1993 (Continued)
Incomplete outcome data addressed
All outcomes
Unclear The study gives the impression that there
were no withdrawals but this was not ex-
plicitly stated
Free of selective reporting Unclear Insufficient information provided
Sample size calculation No Not performed
Intention-to-treat analysis Unclear No information provided
Baseline imbalance Unclear Not enough information provided
Early stopping of trial Unclear Not enough information provided
Pageaux 1995
Methods Study design double-blind randomised study
Participants Country France
Publication language English
Inclusion criteria
- patients who underwent liver transplantation
Exclusion criteria
- not mentioned
Participants
- UDCA group (n=26)
Mean age (years +- SD)
47 +- 10
Ratio of sex (malefemale) 179
Origins of liver diseases alcoholic cirrhosis 14
post-hepatic B cirrhosis 2
post-hepatitis C cirrhosis 4
PBC 2
liver cancer 2
fulminant hepatitis 1
miscellaneous 1
- Placebo group (n = 24)
Mean age (years +- SD)
51+- 9
Ratio of sex (malefemale) 159
Origins of liver diseases alcoholic cirrhosis 10
post-hepatic B cirrhosis 0
post-hepatic C cirrhosis 6
PBC 3
liver cancer 4
fulminant hepatitis 0
miscellaneous 1
27Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Pageaux 1995 (Continued)
Interventions UDCA group
- Dose 600 mgday in three divided doses
- Route orally
- Duration immediately after intestinal transit recovery usually between postoperative
days three and five and continue for two months
Placebo group
- identical-appearing capsules administered in the same quantity and manner
Co-interventions all patients received standard triple-drug regimens (steroids azathio-
prine and cyclosporine or tacrolimus)
Outcomes Number of patients with acute cellular rejection
Number of patients with steroid-resistant rejection
Notes Letter was sent to the authors in September 2009 No reply was received
Risk of bias
Item Authorsrsquo judgement Description
Adequate sequence generation Unclear No information provided
Allocation concealment Unclear No information provided
Blinding Unclear Method of blinding not described
Incomplete outcome data addressed
All outcomes
Yes Five patients died from non-immunologi-
cal causes before the end of the first month
and were excluded from the study Reasons
were reported
Free of selective reporting Unclear Not enough information provided
Sample size calculation No Not performed
Intention-to-treat analysis No Not stated and not used
Baseline imbalance Unclear Not enough information provided
Early stopping of trial Unclear Not enough information provided
Sama 1991
Methods Study design randomised controlled trial
Participants Country Italy
Publication language English
Inclusion criteria
28Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Sama 1991 (Continued)
- patients who underwent liver transplantation
Exclusion criteria
- not mentioned
Participants
- UDCA group (n = 20)
Mean age (years +- SD)
no information
Ratio of sex (malefemale) no information
Origins of liver diseases
no information
- Control group (n = 20)
Mean age (years +- SD)
no information
Ratio of sex (malefemale) no information
Origins of liver diseases
no information
Interventions UDCA group
- Dose 600 mgday in two divided doses
- Route orally
- Duration immediately after intestinal transit recovery usually between postoperative
day five and day seven and continue for six months
Control group
- no treatment
Co-interventions all patients received standard immunosuppressive treatment (steroids
and cyclosporine)
Outcomes All cause mortality
Number of patients with acute cellular rejection
Notes Abstract
Letter was sent to the authors in September 2009 No reply was received
Risk of bias
Item Authorsrsquo judgement Description
Adequate sequence generation Unclear A randomisation list was performed before
patients were admitted to the trial (infor-
mation from principal author)
Allocation concealment Unclear No information provided
Blinding Unclear The principle author provided information
that the study was made according to a
single-blind randomised protocol The pri-
mary outcome was the occurrence of biopsy
proven rejection episodes The pathologists
were blind but the patients were not
29Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Sama 1991 (Continued)
Incomplete outcome data addressed
All outcomes
Unclear Five patients from the UDCA group and
six patients from the placebo group were
excluded Reasons for exclusion were not
fully stated
Free of selective reporting No Data about survival of patients were not
adequately reported
Sample size calculation No Not performed
Intention-to-treat analysis No Not stated and not used
Baseline imbalance Unclear Basic characteristics of patients not re-
ported
Early stopping of trial Unclear Not enough information provided
UDCA = ursodeoxycholic acid
TUDCA = tauroursodeoxycholic acid
PBC = primary biliary cirrhosis
PSC = primary sclerosing cholangitis
OKT3 = anti-CD3 monoclonal antibody
Characteristics of excluded studies [ordered by study ID]
Assy 2007 A randomised controlled trial that included only recipients of liver transplantation with stable graft function and
no episodes of rejection for at least 2 years that were then offered total immunosuppression withdrawal Fourteen
patients received UDCA (15 mgkg body weightday) and 12 received placebo Rejection occurred in 43 and
75 of patients respectively (no significant difference) None developed chronic rejection After follow-up two
patients were free of immunosuppression 80 were steroid free and 50 were able to reduce their dose of
cyclosporine
Clavien 1996 Case series Fifty consecutive liver-transplanted patients were treated with a standard cyclosporine immunosup-
pressive regimen Twenty three of the 43 survivors developed an episode of rejection and UDCA (10 mgkg
weightday) was initiated Only one patient had a second episode of rejection
Friman 1992 Observational study Thirty-three liver-transplanted patients received 10 mg UDCAkg body weightday for
median of 10 months (range four to 21 months) Eight historical liver-transplanted patients served as control
group The rejection incidence was significantly lower in the patients who received the treatment with UDCA
Biochemistry one month after transplantation demonstrated significantly lower average values of aminotrans-
ferases and alkaline phosphatases in patients treated with UDCA than in the control group
30Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
Heathcote 1999 Observational study From 1987 to 1996 37 UDCA treated and 53 placebo treated patients with primary biliary
cirrhosis were referred for transplantation Posttransplantation survival rates at one month were 939 in the
UDCA group and 884 in the placebo group and one year survival rates were 903 and 784 respectively
(no significant differences) However rejection (type not defined - a secondary outcome measure) occurred
significantly less often in the UDCA group (429) than in placebo group (688)
Henriksson 1991 Observational study All patients in this study were given sequential quadruple immunosuppression with anti-
lymphocyte globulin azathioprine steroids and cyclosporine All patients with primary graft function (n = 11)
were treated with 10 mg UDCAkg body weightday starting during the first postoperative week Patients who
received liver transplantation in the first 6 months of 1989 (n = 8) served as controls In the control group one
patient died after 9 months with chronic graft dysfunction and six patients had rejection episodes during the
first postoperative month All patients in the UDCA group were alive without rejection episodes
Persson 1990 Observational study All 11 adult patients transplanted between August 1989 and January 1990 with primary
graft function were treated with 10 mg UDCA kg body weightday Eight patients transplanted during the first
half of 1989 served as control UDCA was started during the first postoperative week and the treatment was
continued for six months All patients in the UDCA treated group survived with satisfactory graft function In
the control group six patients had at least one rejection episode needing treatment during the first postoperative
month
Rafael 1995 Observational study Seventeen patients who underwent liver transplantation between February 1990 and April
1993 and developed biliary complications after transplantation were retrospectively analysed regarding treatment
with UDCA UDCA was given in a dose of 500 to 1000 mgday Ten patients were treated for at least one year while
seven patients were treated for 14 to 250 days UDCA significantly improved gammaglutamyl transpeptidase in
liver graft recipients with biliary complications There was also a trend towards improvement in serum bilirubin
and alanine transaminase values
Sama 1998 Observational study Thirty-four patients who underwent liver transplantation between January 1995 and June
1996 were included in the study Seventeen were treated with UDCA 10 mgkg body weightday during 6
months while 17 served as controls on the basis of having undergone liver transplantation closest to UDCA
patients A significant decrease in serum bilirubin levels was observed in UDCA patients There was a significantly
higher incidence of recurrent hepatitis in the control group
UDCA ursodeoxycholic acid
31Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
D A T A A N D A N A L Y S E S
Comparison 1 Bile acids for liver-transplanted patients
Outcome or subgroup titleNo of
studies
No of
participants Statistical method Effect size
1 All-cause mortality at maximum
follow-up
5 257 Risk Ratio (M-H Fixed 95 CI) 085 [053 136]
11 UDCA versus placebo or
no treatment
4 224 Risk Ratio (M-H Fixed 95 CI) 080 [049 130]
12 TUDCA versus no
treatment
1 33 Risk Ratio (M-H Fixed 95 CI) 159 [030 833]
2 All-cause mortality worst-best
case and best-worst case
scenarios
5 Risk Ratio (M-H Fixed 95 CI) Subtotals only
21 Worst-best case scenario 5 257 Risk Ratio (M-H Fixed 95 CI) 130 [086 196]
22 Best-worst case scenario 5 257 Risk Ratio (M-H Fixed 95 CI) 058 [038 090]
3 Subgroup analyses all-cause
mortality at maximum
follow-up according to time of
start of bile acids
5 257 Risk Ratio (M-H Fixed 95 CI) 085 [053 136]
31 Less than three days after
transplantation
1 102 Risk Ratio (M-H Fixed 95 CI) 124 [061 254]
32 Three days or more after
transplantation
4 155 Risk Ratio (M-H Fixed 95 CI) 063 [033 120]
4 Subgroup analyses all cause
mortality at maximum
follow-up according to
treatment duration
5 257 Risk Ratio (M-H Fixed 95 CI) 085 [053 136]
41 Less than six months 3 184 Risk Ratio (M-H Fixed 95 CI) 078 [045 138]
42 Six months or more 2 73 Risk Ratio (M-H Fixed 95 CI) 102 [043 240]
5 Number of deaths related
to rejection at maximum
follow-up
1 102 Risk Ratio (M-H Fixed 95 CI) 030 [001 712]
51 UDCA versus placebo 1 102 Risk Ratio (M-H Fixed 95 CI) 030 [001 712]
6 Number of retransplantations at
maximum follow-up
2 132 Risk Ratio (M-H Fixed 95 CI) 076 [020 286]
7 Number of patients with acute
cellular rejection at maximum
follow-up
7 339 Risk Ratio (M-H Fixed 95 CI) 089 [074 106]
71 UDCA versus placebo or
no treatment
6 306 Risk Ratio (M-H Fixed 95 CI) 089 [074 108]
72 TUDCA versus no
treatment
1 33 Risk Ratio (M-H Fixed 95 CI) 085 [045 160]
8 Subgroup analysis number of
patients with acute cellular
rejection according to time of
start of bile acid
7 339 Risk Ratio (M-H Fixed 95 CI) 089 [074 106]
32Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
81 Less than three days after
transplantation
2 134 Risk Ratio (M-H Fixed 95 CI) 084 [063 111]
82 Three days or more after
liver transplantation
5 205 Risk Ratio (M-H Fixed 95 CI) 092 [072 117]
9 Subgroup analysis number
of patients with acute
cellular rejection according to
treatment duration
7 339 Risk Ratio (M-H Fixed 95 CI) 089 [074 106]
91 Less than six months 5 266 Risk Ratio (M-H Fixed 95 CI) 087 [071 107]
92 Six months or more 2 73 Risk Ratio (M-H Fixed 95 CI) 094 [065 136]
10 Number of patients with
chronic rejection at maximum
follow-up
3 184 Risk Ratio (M-H Fixed 95 CI) 028 [008 095]
11 Number of patients with
steroid-resistant rejection at
maximum follow-up
4 234 Risk Ratio (M-H Fixed 95 CI) 077 [047 127]
12 Serum bilirubin (mgdl) at the
end of treatment
1 30 Mean Difference (IV Fixed 95 CI) 26 [-096 616]
13 Number of days of
hospitalisation after liver
transplantation
1 52 Mean Difference (IV Fixed 95 CI) -85 [-1667 -033]
14 Adverse events 3 187 Risk Ratio (M-H Fixed 95 CI) 088 [030 260]
Analysis 11 Comparison 1 Bile acids for liver-transplanted patients Outcome 1 All-cause mortality at
maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 1 All-cause mortality at maximum follow-up
Study or subgroup Favours bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 UDCA versus placebo or no treatment
Barnes 1997 228 724 253 024 [ 006 107 ]
Fleckenstein 1998 214 416 125 057 [ 012 266 ]
Keiding 1997 1454 1048 355 124 [ 061 254 ]
Sama 1991 520 620 201 083 [ 030 229 ]
Subtotal (95 CI) 116 108 935 080 [ 049 130 ]
Total events 23 (Favours bile acids) 27 (Control)
Heterogeneity Chi2 = 416 df = 3 (P = 025) I2 =28
Test for overall effect Z = 091 (P = 036)
01 02 05 1 2 5 10
Favours bile acids Favours control
(Continued )
33Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Favours bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
2 TUDCA versus no treatment
Angelico 1999 316 217 65 159 [ 030 833 ]
Subtotal (95 CI) 16 17 65 159 [ 030 833 ]
Total events 3 (Favours bile acids) 2 (Control)
Heterogeneity not applicable
Test for overall effect Z = 055 (P = 058)
Total (95 CI) 132 125 1000 085 [ 053 136 ]
Total events 26 (Favours bile acids) 29 (Control)
Heterogeneity Chi2 = 466 df = 4 (P = 032) I2 =14
Test for overall effect Z = 069 (P = 049)
01 02 05 1 2 5 10
Favours bile acids Favours control
Analysis 12 Comparison 1 Bile acids for liver-transplanted patients Outcome 2 All-cause mortality worst-
best case and best-worst case scenarios
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 2 All-cause mortality worst-best case and best-worst case scenarios
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 Worst-best case scenario
Angelico 1999 516 217 65 266 [ 060 1180 ]
Barnes 1997 828 724 253 098 [ 042 230 ]
Fleckenstein 1998 314 416 125 086 [ 023 319 ]
Keiding 1997 1954 1048 355 169 [ 087 327 ]
Sama 1991 520 620 201 083 [ 030 229 ]
Subtotal (95 CI) 132 125 1000 130 [ 086 196 ]
Total events 40 (Bile acids) 29 (Control)
Heterogeneity Chi2 = 303 df = 4 (P = 055) I2 =00
Test for overall effect Z = 123 (P = 022)
2 Best-worst case scenario
005 02 1 5 20
Favours bile acids Favours control
(Continued )
34Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Angelico 1999 316 417 90 080 [ 021 302 ]
Barnes 1997 228 1124 274 016 [ 004 063 ]
Fleckenstein 1998 214 616 130 038 [ 009 159 ]
Keiding 1997 1454 1548 368 083 [ 045 154 ]
Sama 1991 520 620 139 083 [ 030 229 ]
Subtotal (95 CI) 132 125 1000 058 [ 038 090 ]
Total events 26 (Bile acids) 42 (Control)
Heterogeneity Chi2 = 567 df = 4 (P = 023) I2 =29
Test for overall effect Z = 247 (P = 0014)
005 02 1 5 20
Favours bile acids Favours control
Analysis 13 Comparison 1 Bile acids for liver-transplanted patients Outcome 3 Subgroup analyses all-
cause mortality at maximum follow-up according to time of start of bile acids
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 3 Subgroup analyses all-cause mortality at maximum follow-up according to time of start of bile acids
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 Less than three days after transplantation
Keiding 1997 1454 1048 355 124 [ 061 254 ]
Subtotal (95 CI) 54 48 355 124 [ 061 254 ]
Total events 14 (Bile acids) 10 (Control)
Heterogeneity not applicable
Test for overall effect Z = 060 (P = 055)
2 Three days or more after transplantation
Angelico 1999 316 217 65 159 [ 030 833 ]
Barnes 1997 228 724 253 024 [ 006 107 ]
Fleckenstein 1998 214 416 125 057 [ 012 266 ]
Sama 1991 520 620 201 083 [ 030 229 ]
005 02 1 5 20
Favours bile acids Favours control
(Continued )
35Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Subtotal (95 CI) 78 77 645 063 [ 033 120 ]
Total events 12 (Bile acids) 19 (Control)
Heterogeneity Chi2 = 310 df = 3 (P = 038) I2 =3
Test for overall effect Z = 141 (P = 016)
Total (95 CI) 132 125 1000 085 [ 053 136 ]
Total events 26 (Bile acids) 29 (Control)
Heterogeneity Chi2 = 466 df = 4 (P = 032) I2 =14
Test for overall effect Z = 069 (P = 049)
005 02 1 5 20
Favours bile acids Favours control
Analysis 14 Comparison 1 Bile acids for liver-transplanted patients Outcome 4 Subgroup analyses all
cause mortality at maximum follow-up according to treatment duration
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 4 Subgroup analyses all cause mortality at maximum follow-up according to treatment duration
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 Less than six months
Barnes 1997 228 724 253 024 [ 006 107 ]
Fleckenstein 1998 214 416 125 057 [ 012 266 ]
Keiding 1997 1454 1048 355 124 [ 061 254 ]
Subtotal (95 CI) 96 88 734 078 [ 045 138 ]
Total events 18 (Bile acids) 21 (Control)
Heterogeneity Chi2 = 417 df = 2 (P = 012) I2 =52
Test for overall effect Z = 084 (P = 040)
2 Six months or more
Angelico 1999 316 217 65 159 [ 030 833 ]
Sama 1991 520 620 201 083 [ 030 229 ]
Subtotal (95 CI) 36 37 266 102 [ 043 240 ]
Total events 8 (Bile acids) 8 (Control)
Heterogeneity Chi2 = 043 df = 1 (P = 051) I2 =00
005 02 1 5 20
Favours bile acids Favours control
(Continued )
36Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Test for overall effect Z = 004 (P = 097)
Total (95 CI) 132 125 1000 085 [ 053 136 ]
Total events 26 (Bile acids) 29 (Control)
Heterogeneity Chi2 = 466 df = 4 (P = 032) I2 =14
Test for overall effect Z = 069 (P = 049)
005 02 1 5 20
Favours bile acids Favours control
Analysis 15 Comparison 1 Bile acids for liver-transplanted patients Outcome 5 Number of deaths related
to rejection at maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 5 Number of deaths related to rejection at maximum follow-up
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 UDCA versus placebo
Keiding 1997 054 148 1000 030 [ 001 712 ]
Total (95 CI) 54 48 1000 030 [ 001 712 ]
Total events 0 (Bile acids) 1 (Control)
Heterogeneity not applicable
Test for overall effect Z = 075 (P = 045)
0001 001 01 1 10 100 1000
Favours bile acids Favours control
37Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 16 Comparison 1 Bile acids for liver-transplanted patients Outcome 6 Number of
retransplantations at maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 6 Number of retransplantations at maximum follow-up
Study or subgroup Bile acids Placebo Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Fleckenstein 1998 214 016 100 567 [ 029 10891 ]
Keiding 1997 154 448 900 022 [ 003 192 ]
Total (95 CI) 68 64 1000 076 [ 020 286 ]
Total events 3 (Bile acids) 4 (Placebo)
Heterogeneity Chi2 = 303 df = 1 (P = 008) I2 =67
Test for overall effect Z = 040 (P = 069)
0001 001 01 1 10 100 1000
Favours bile acids Favours placebo
Analysis 17 Comparison 1 Bile acids for liver-transplanted patients Outcome 7 Number of patients with
acute cellular rejection at maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 7 Number of patients with acute cellular rejection at maximum follow-up
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 UDCA versus placebo or no treatment
Barnes 1997 1728 1724 180 086 [ 058 127 ]
Fleckenstein 1998 814 916 83 102 [ 054 190 ]
Keiding 1997 3554 3248 333 097 [ 073 129 ]
Koneru 1993 316 916 89 033 [ 011 101 ]
Pageaux 1995 926 924 92 092 [ 044 193 ]
Sama 1991 1320 1320 128 100 [ 063 158 ]
Subtotal (95 CI) 158 148 905 089 [ 074 108 ]
01 02 05 1 2 5 10
Favours bile acids Favours control
(Continued )
38Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Total events 85 (Bile acids) 89 (Control)
Heterogeneity Chi2 = 387 df = 5 (P = 057) I2 =00
Test for overall effect Z = 120 (P = 023)
2 TUDCA versus no treatment
Angelico 1999 816 1017 95 085 [ 045 160 ]
Subtotal (95 CI) 16 17 95 085 [ 045 160 ]
Total events 8 (Bile acids) 10 (Control)
Heterogeneity not applicable
Test for overall effect Z = 050 (P = 061)
Total (95 CI) 174 165 1000 089 [ 074 106 ]
Total events 93 (Bile acids) 99 (Control)
Heterogeneity Chi2 = 392 df = 6 (P = 069) I2 =00
Test for overall effect Z = 130 (P = 019)
01 02 05 1 2 5 10
Favours bile acids Favours control
Analysis 18 Comparison 1 Bile acids for liver-transplanted patients Outcome 8 Subgroup analysis
number of patients with acute cellular rejection according to time of start of bile acid
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 8 Subgroup analysis number of patients with acute cellular rejection according to time of start of bile acid
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 Less than three days after transplantation
Keiding 1997 3554 3248 333 097 [ 073 129 ]
Koneru 1993 316 916 89 033 [ 011 101 ]
Subtotal (95 CI) 70 64 422 084 [ 063 111 ]
Total events 38 (Bile acids) 41 (Control)
Heterogeneity Chi2 = 374 df = 1 (P = 005) I2 =73
Test for overall effect Z = 124 (P = 022)
2 Three days or more after liver transplantation
Angelico 1999 816 1017 95 085 [ 045 160 ]
01 02 05 1 2 5 10
Favours bile acids Favours control
(Continued )
39Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Barnes 1997 1728 1724 180 086 [ 058 127 ]
Fleckenstein 1998 814 916 83 102 [ 054 190 ]
Pageaux 1995 926 924 92 092 [ 044 193 ]
Sama 1991 1320 1320 128 100 [ 063 158 ]
Subtotal (95 CI) 104 101 578 092 [ 072 117 ]
Total events 55 (Bile acids) 58 (Control)
Heterogeneity Chi2 = 041 df = 4 (P = 098) I2 =00
Test for overall effect Z = 067 (P = 050)
Total (95 CI) 174 165 1000 089 [ 074 106 ]
Total events 93 (Bile acids) 99 (Control)
Heterogeneity Chi2 = 392 df = 6 (P = 069) I2 =00
Test for overall effect Z = 130 (P = 019)
01 02 05 1 2 5 10
Favours bile acids Favours control
40Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 19 Comparison 1 Bile acids for liver-transplanted patients Outcome 9 Subgroup analysis
number of patients with acute cellular rejection according to treatment duration
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 9 Subgroup analysis number of patients with acute cellular rejection according to treatment duration
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 Less than six months
Barnes 1997 1728 1724 180 086 [ 058 127 ]
Fleckenstein 1998 814 916 83 102 [ 054 190 ]
Keiding 1997 3554 3248 333 097 [ 073 129 ]
Koneru 1993 316 916 89 033 [ 011 101 ]
Pageaux 1995 926 924 92 092 [ 044 193 ]
Subtotal (95 CI) 138 128 777 087 [ 071 107 ]
Total events 72 (Bile acids) 76 (Control)
Heterogeneity Chi2 = 374 df = 4 (P = 044) I2 =00
Test for overall effect Z = 129 (P = 020)
2 Six months or more
Angelico 1999 816 1017 95 085 [ 045 160 ]
Sama 1991 1320 1320 128 100 [ 063 158 ]
Subtotal (95 CI) 36 37 223 094 [ 065 136 ]
Total events 21 (Bile acids) 23 (Control)
Heterogeneity Chi2 = 017 df = 1 (P = 068) I2 =00
Test for overall effect Z = 035 (P = 073)
Total (95 CI) 174 165 1000 089 [ 074 106 ]
Total events 93 (Bile acids) 99 (Control)
Heterogeneity Chi2 = 392 df = 6 (P = 069) I2 =00
Test for overall effect Z = 130 (P = 019)
01 02 05 1 2 5 10
Favours bile acids Favours control
41Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 110 Comparison 1 Bile acids for liver-transplanted patients Outcome 10 Number of patients
with chronic rejection at maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 10 Number of patients with chronic rejection at maximum follow-up
Study or subgroup Bile acids Placebo Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Barnes 1997 128 624 611 014 [ 002 110 ]
Fleckenstein 1998 114 116 88 114 [ 008 1663 ]
Keiding 1997 154 348 300 030 [ 003 275 ]
Total (95 CI) 96 88 1000 028 [ 008 095 ]
Total events 3 (Bile acids) 10 (Placebo)
Heterogeneity Chi2 = 148 df = 2 (P = 048) I2 =00
Test for overall effect Z = 204 (P = 0041)
0001 001 01 1 10 100 1000
Favours bile acids Favours placebo
Analysis 111 Comparison 1 Bile acids for liver-transplanted patients Outcome 11 Number of patients
with steroid-resistant rejection at maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 11 Number of patients with steroid-resistant rejection at maximum follow-up
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Barnes 1997 328 724 277 037 [ 011 127 ]
Fleckenstein 1998 314 316 103 114 [ 027 478 ]
Keiding 1997 1454 1548 583 083 [ 045 154 ]
Pageaux 1995 226 124 38 185 [ 018 1908 ]
Total (95 CI) 122 112 1000 077 [ 047 127 ]
Total events 22 (Bile acids) 26 (Control)
Heterogeneity Chi2 = 226 df = 3 (P = 052) I2 =00
Test for overall effect Z = 102 (P = 031)
001 01 1 10 100
Favours bile acids Favours placebo
42Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 112 Comparison 1 Bile acids for liver-transplanted patients Outcome 12 Serum bilirubin (mgdl)
at the end of treatment
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 12 Serum bilirubin (mgdl) at the end of treatment
Study or subgroup Bile acids Placebo Mean Difference Weight Mean Difference
N Mean(SD) N Mean(SD) IVFixed95 CI IVFixed95 CI
Fleckenstein 1998 14 319 (68) 16 059 (022) 1000 260 [ -096 616 ]
Total (95 CI) 14 16 1000 260 [ -096 616 ]
Heterogeneity not applicable
Test for overall effect Z = 143 (P = 015)
-10 -5 0 5 10
Favours bile acids Favours placebo
Analysis 113 Comparison 1 Bile acids for liver-transplanted patients Outcome 13 Number of days of
hospitalisation after liver transplantation
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 13 Number of days of hospitalisation after liver transplantation
Study or subgroup Bile acids Placebo Mean Difference Weight Mean Difference
N Mean(SD) N Mean(SD) IVFixed95 CI IVFixed95 CI
Barnes 1997 28 25 (17) 24 335 (13) 1000 -850 [ -1667 -033 ]
Total (95 CI) 28 24 1000 -850 [ -1667 -033 ]
Heterogeneity not applicable
Test for overall effect Z = 204 (P = 0041)
-100 -50 0 50 100
Favours bile acids Favours placebo
43Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 114 Comparison 1 Bile acids for liver-transplanted patients Outcome 14 Adverse events
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 14 Adverse events
Study or subgroup Bile acids Placebo Risk Ratio Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Angelico 1999 016 017 00 [ 00 00 ]
Barnes 1997 128 124 086 [ 006 1298 ]
Keiding 1997 554 548 089 [ 027 288 ]
Total (95 CI) 98 89 088 [ 030 260 ]
Total events 6 (Bile acids) 6 (Placebo)
Heterogeneity Chi2 = 000 df = 1 (P = 098) I2 =00
Test for overall effect Z = 022 (P = 082)
001 01 1 10 100
Favours bile acids Favours placebo
A P P E N D I C E S
Appendix 1 Search strategies
Data Base Date of Search Search Strategy
The Cochrane Hepato-Biliary Group Con-
trolled Trials Register
September 2009 1 rsquoliver transplantationrsquo and rsquochenodeoxy-
cholicrsquo
2 rsquoliver transplantationrsquo and rsquocholicrsquo
3 rsquoliver transplantationrsquo and rsquodeoxycholicrsquo
4 rsquoliver transplantationrsquo and rsquoglycochen-
odeoxycholicrsquo
5 rsquoliver transplantationrsquo and rsquoglycocholicrsquo
6 rsquoliver transplantationrsquo and rsquoglycodeoxy-
cholicrsquo
7 rsquoliver transplantationrsquo and rsquoglycolitho-
cholicrsquo
8 rsquoliver transplantationrsquo and rsquohyodeoxy-
cholicrsquo
9 rsquoliver transplantationrsquo and rsquolithocholicrsquo
10 rsquoliver transplantationrsquo and rsquotaurochen-
odeoxycholicrsquo
44Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
11 rsquoliver transplantationrsquo and rsquotauro-
cholicrsquo
12 rsquoliver transplantationrsquo and rsquotaurodehy-
drocholicrsquo
13 rsquoliver transplantationrsquo and rsquotau-
rodeoxycholicrsquo
14 rsquoliver transplantationrsquo and rsquotauroglyco-
cholicrsquo
15 rsquoliver transplantationrsquo and rsquotaurolitho-
cholicrsquo
16 rsquoliver transplantationrsquo and rsquotaurosel-
cholicrsquo
17 rsquoliver transplantationrsquo and rsquotaurourso-
cholicrsquo
18 rsquoliver transplantationrsquo and rsquotaurour-
sodeoxycholicrsquo
19 rsquoliver transplantationrsquo and rsquoursocholicrsquo
20 rsquoliver transplantationrsquo and rsquoursodeoxy-
cholicrsquo
The Cochrane Central Register of Con-
trolled Trials in The Cochrane Library
Issue 3 2009 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
6 3 or 4
7 5 and 6
MEDLINE September 2009 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
45Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
6 3 or 4
7 5 and 6
8 RANDOMIZED-CONTROLLED-
TRIAL ME
9 RANDOM
10 8 or 9
11 7 and 10
EMBASE September 2009 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
6 3 or 4
7 5 and 6
8 RANDOMIZED-CONTROLLED-
TRIAL ME
9 RANDOM
10 8 or 9
11 7 and 10
46Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
Science Citation Index Expanded September 2009 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
6 3 or 4
7 5 and 6
8 RANDOMIZED-CONTROLLED-
TRIAL ME
9 RANDOM
10 8 or 9
11 7 and 10
The Chinese Biomedical Database Searched from January 1980 to April 2002 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
47Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
6 3 or 4
7 5 and 6
8 RANDOMIZED-CONTROLLED-
TRIAL ME
9 RANDOM
10 8 or 9
11 7 and 10
W H A T rsquo S N E W
Last assessed as up-to-date 8 February 2010
18 September 2009 New citation required but conclusions have not
changed
This review is an updated version of a review that was
published for the first time in Issue 3 2005 of TheCochrane Library by Chen 2003b
18 September 2009 New search has been performed No new studies fulfilled the inclusion criteria
H I S T O R Y
Protocol first published Issue 3 2003
Review first published Issue 3 2005
C O N T R I B U T I O N S O F A U T H O R S
GP and VG independently performed searches of relevant databases GP validated the search selected trials for inclusion contacted
the authors of the trials performed data extraction and data analysis and drafted the systematic review VG revised the review update
CG and DS revised the review update solved discrepancies of data extraction validated data analyses and provided consultation
D E C L A R A T I O N S O F I N T E R E S T
None known
48Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
S O U R C E S O F S U P P O R T
Internal sources
bull Copenhagen Trial Unit Denmark
External sources
bull Danish Medical Research Councilrsquos Grant on Getting Research into Practice (GRIP) Denmark
D I F F E R E N C E S B E T W E E N P R O T O C O L A N D R E V I E W
We assessed the risk of bias in the included studies for another four domains that were added to the review protocol (incomplete
outcome data selective outcome reporting baseline imbalance and early stopping of trial) In general the text of the risk of bias
domains were updated following Higgins 2008 Trials were considered at low risk of bias when judged as adequate in all domains
Quasi-randomised studies observational and case-control studies were included for the report of adverse events
We performed trial sequential analysis for outcomes demonstrating a statistically significant result
I N D E X T E R M S
Medical Subject Headings (MeSH)
lowastLiver Transplantation Cholagogues and Choleretics [lowasttherapeutic use] Graft Rejection [lowastprevention amp control] Randomized Con-
trolled Trials as Topic Taurochenodeoxycholic Acid [lowasttherapeutic use] Ursodeoxycholic Acid [lowasttherapeutic use]
MeSH check words
Humans
49Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
a trial was terminated early that is before an adequate number
of patients was included in the trial Three trials (Barnes 1997
Keiding 1997 Fleckenstein 1998) stated that intention-to-treat
analyses were used (Figure 1 Figure 2)
Figure 1 Methodological quality graph review authorsrsquo judgements about each methodological quality
item presented as percentages across all included studies
8Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Figure 2 Methodological quality summary review authorsrsquo judgements about each methodological quality
item for each included study
9Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Following the assessment of risk of bias domains none of the seven
trials were considered to have low risk of bias that is having all
the nine domains for risk of bias assessed as adequate
Effects of interventions
We were able to include seven randomised clinical trials in this
review Six trials with 306 liver-transplanted patients compared
ursodeoxycholic acid (UDCA) with placebo or no intervention
and one trial with 29 liver-transplanted patients compared tauro-
UDCA (TUDCA) with no intervention
All-cause mortality
Five trials including 257 liver-transplanted patients reported on
all-cause mortality at the end of treatment or at maximum follow-
up Bile acids did not significantly reduce all-cause mortality (RR
085 95 CI 053 to 136) there were 26 deaths among 132
patients treated with bile acids (197) versus 29 deaths among
125 patients in the control groups (232) (Analysis 11) There
was no statistically significant heterogeneity (I2 = 141)
Four trials (Sama 1991 Barnes 1997 Keiding 1997 Fleckenstein
1998) showed that UDCA did not significantly reduce all-cause
mortality (RR 080 95 CI 049 to 130) 23 deaths among 116
patients treated with UCDA (198) versus 27 deaths among
108 patients in the control groups (250) The Angelico 1999
trial demonstrated that TUDCA was not able to reduce all-cause
mortality (RR 159 95 CI 030 to 833) there were 3 deaths
among 16 patients (188) versus 2 deaths among 17 patients
(118)
The Fleckenstein 1998 trial and the Sama 1991 trial did not report
the causes of deaths In the three other trials the deaths were
considered to be caused by infections (n = 11) hepatic failure (n =
7) abdominal bleeding (n = 3) renal failure (n = 2) multiple organ
failure (n = 2) hepatitis B virus fibrosis (n = 2) acute rejection
(n = 1) hepatic artery thrombosis (n = 1) encephalitis (n = 1)
lymphoproliferative disorder (n = 1) cerebral haemorrhage (n =
1) or other reasons (n = 6)
Worst-best case and best-worst case scenario analyses
In the worst-best case scenario analysis bile acids did not signif-
icantly reduce all-cause mortality when compared with placebo
or no intervention (RR 130 95 CI 086 to 196) 40 deaths
among 132 patients on bile acids (303) versus 29 deaths among
125 patients in the control groups (232) However all-cause
mortality was significantly reduced by bile acids in the best-worst
case scenario analysis (RR 058 95 CI 038 to 090) 26 deaths
among 132 patients (197) versus 42 deaths among 125 patients
in the control groups (336) (Analysis 12)
Subgroup analyses
We performed subgroup analyses regarding the time that bile acid
intake was started The Keiding 1997 trial started bile acid intake
less than three days after liver transplantation and demonstrated
no significant effect of UDCA on all-cause mortality (RR 124
95 CI 061 to 254) 14 deaths out of 54 patients (259)
versus 10 out of 48 control patients (208) The same effect
was noticed in the four other trials (Sama 1991 Barnes 1997
Fleckenstein 1998 Angelico 1999) which started bile acids three
days or more after liver transplantation (RR 063 95 CI 033
to 120) 12 deaths among 78 patients (154) versus 9 deaths
among 77 control patients (247) (Analysis 13) There were no
statistically significant differences between the two estimates
We also performed subgroup analyses regarding the duration of
bile acid treatment Bile acids were administrated for less than six
months in three trials (Barnes 1997 Keiding 1997 Fleckenstein
1998) and were not able to significantly decrease all-cause mor-
tality (RR 078 95 CI 045 to 138) 18 deaths in a group of
96 treated patients (188) versus 21 deaths among 88 control
patients (239) In the other two trials (Sama 1991 Angelico
1999) patients were treated with bile acids for six months or more
The treatment did not show statistically significant decrease in all-
cause mortality (RR 102 95 CI 043 to 24) 8 deaths in a
group of 36 treated patients (222) versus 8 deaths in a group
of 37 control patients (216) (Analysis 14) There were no sta-
tistically significant differences between the two estimates
Mortality related to allograft rejection
We did not find statistically significant reduction in mortality re-
lated to allograft rejection at maximum follow-up in the three tri-
als reporting cause of death (Barnes 1997 Keiding 1997 Angelico
1999) (RR 030 95 CI 001 to 712) 098 (0) versus 189
(11)) (Analysis 15) The only death due to acute rejection was
found in the placebo group of the Keiding 1997 trial
Number of liver retransplantations
Two trials (Fleckenstein 1998 Keiding 1997) including 132 liver-
transplanted patients reported the number of liver retransplan-
tations UDCA did not significantly reduce the risk of liver re-
transplantation at maximum follow-up (RR 076 95 CI 020
to 286) 368 (44) versus 464 (63)) (Analysis 16) In the
Keiding 1997 trial one patient in the UDCA group was retrans-
planted due to chronic rejection and four patients in the placebo
group were retransplanted either due to chronic rejection (three
cases) or acute rejection (one case) In the Fleckenstein 1998 trial
two patients in the UDCA group were retransplanted due to acute
rejection (one case) and chronic rejection (one case) respectively
Number of patients with acute cellular rejection
Seven trials reported the number of patients who had acute cellu-
lar rejection after liver transplantation Bile acids did not signifi-
cantly reduce the number of patients who experienced acute cel-
lular rejection (RR 089 95 CI 074 to 106) 93174(535)
versus 99165 (600)) There was no significant heterogeneity
(I2 = 0)
Six trials (Sama 1991 Koneru 1993 Pageaux 1995 Barnes 1997
10Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Keiding 1997 Fleckenstein 1998) compared UDCA with placebo
or no intervention and demonstrated that UDCA did not signifi-
cantly reduce the number of patients with acute cellular rejection
after liver transplantation (RR 089 95 CI 074 to 108 85
158 (538) versus 89148 (601)) Neither did the Angelico
1999 trial demonstrate significant reduction of the number of pa-
tients with acute cellular rejection with TUDCA (RR 085 95
CI 045 to 160) 816 (500) versus 1017 (588) (Analysis
17)
Subgroup analyses
Two trials (Koneru 1993 Keiding 1997) in which the patients
started bile acids intake less than three days after liver transplan-
tation did not demonstrate any significant reduction of the risk
of acute cellular rejection by bile acids (RR 084 95 CI 063 to
111) 3870 (543) versus 4164 (641) The other five tri-
als (Sama 1991 Pageaux 1995 Barnes 1997 Fleckenstein 1998
Angelico 1999) in which the patients were started on bile acid
intake three days or more after liver transplantation did not find
a significant reduction of the risk of acute cellular rejection by bile
acids (RR 092 95 CI 072 to 117) 55104 (529) versus 58
101 (574) (Analysis 18) There was no significant difference
between the two estimates
Bile acids did not significantly reduce the risk of acute cellular
rejection in the five trials (Koneru 1993 Pageaux 1995 Barnes
1997 Keiding 1997 Fleckenstein 1998) in which the patients
received treatment with bile acids less than six months (RR 087
95 CI 071 to 107) 72138 (522) versus 76128 (594)
Neither did bile acids in the two other trials (Sama 1991 Angelico
1999) in which the patients received bile acids for more than six
months (RR 094 95 CI 065 to 136) 2136 (583) versus
2337 (622) (Analysis 19) There were no significant difference
between the two estimates
Number of patients with chronic rejection
Three trials comparing UDCA versus placebo (Barnes 1997
Keiding 1997 Fleckenstein 1998) reported the number of patients
with chronic rejection after liver transplantation UDCA signifi-
cantly reduced the number of patients with chronic rejection in
the fixed-effect model analysis (RR 028 95 CI 008 to 095)
396 (31) versus 1088 (114) (Analysis 110) but not in the
random-effects model analysis (RR 030 95 CI 008 to 113) 3
96 (31) versus 1088 (114) There was no statistically signifi-
cant heterogeneity (I2 0) We performed trial sequential analysis
for the available data from three trials (Figure 3) with heterogene-
ity corrected required information size based on proportion of this
outcome of 12 in the control group a relative risk reduction of
50 in the intervention group at a type I error of 5 and a type
II error of 10 We obtained a required information size of 957
patients UDCA was not able to reach or break the trial sequential
monitoring boundary and only 183 out of 957 (19) patients
were randomised regarding this outcome
11Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Figure 3 Trial sequential analysis for the number of patients with chronic rejection at maximum follow-up
We calculated the heterogeneity-corrected required information size (HCRIS) based on a proportion of 12 of
the patients in the placebo group with chronic rejection at maximum follow-up a 50 risk ratio reduction in
the bile acid group an alpha of 5 a beta of 10 and a heterogeneity of 0 Only 184 patients have been
randomised reporting this outcome which is only 19 of the HCRIS of 957 patients The cumulative Z-score
crosses the conventional boundaries for P 005 but not the monitoring boundaries
Number of patients with steroid-resistant rejection
Four trials (Pageaux 1995 Barnes 1997 Keiding 1997
Fleckenstein 1998) reported the number of patients with steroid-
resistant rejection These trials demonstrated that UDCA did not
significantly reduce the number of patients with steroid-resistant
rejection when compared with placebo (22122 (18) versus 26
112 (232) (RR 077 95 CI 047 to 127) (Analysis 111)
There was no significant heterogeneity (I2 0)
Liver biochemistry
The Fleckenstein 1998 trial reported serum bilirubin levels after
a three-month-treatment period in 30 liver-transplanted patients
There was no statistically significant difference in serum bilirubin
levels between the UDCA group and the placebo group (MD 260
mgdl 95 CI -096 to 616 mgdl) (Analysis 112)
No data were available for other liver biochemical variables
Cost-effectiveness
One trial (Barnes 1997) with 52 liver-transplanted patients re-
ported the days of hospitalisation after liver transplantation
UDCA significantly decreased the number of days of hospitali-
sation when compared with placebo (MD -850 days 95 CI -
1667 to -033 days) (Analysis 113) We were not able to extract
other medical cost from the trials
Adverse events
Among all the included and excluded trials only four reported on
adverse events however adverse events only occurred in two of
the included trials (Barnes 1997 Keiding 1997) There were no
significant differences regarding adverse events (RR 088 95 CI
030 to 260) 6112 (54) versus 6105 (57) (Analysis 114)
In the Barnes 1997 trial diarrhoea was reported by two patients
(one in the UDCA group and one in the placebo group) In the
Keiding 1997 trial five UDCA patients and five placebo patients
stopped intake of the trial medicine because of diarrhoea or dif-
ficulties in swallowing the capsules The remaining included trial
by Angelico 1999 stated that no adverse events occurred during
the study period The excluded trial by Assy 2007 was the only
one reporting on a case of mild diarrhoea in one patient in the
12Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
intervention group No other excluded studies reported on adverse
events (see Table 1)
Quality of life
None of the included studies assessed quality of life as an outcome
Other subgroup analyses
We planned to perform subgroup analyses regarding the risk of
bias of trials the dosage of bile acid and any co-intervention
However none of the trials were considered to be of low risk of
bias they all used a similar dosage of bile acid and patients in all
trials received similar immunosuppressive treatment as co-inter-
ventions (steroids azathioprine and cyclosporine or tacrolimus)
after liver transplantation Therefore we were not able to perform
the planned subgroup analyses
Funnel plot asymmetry
We did not draw a funnel plot analysis due to the limited number
of trials included in the present review
D I S C U S S I O N
In the update of this review we included no new trials assessing
the use of bile acids for liver-transplanted patients The analyses
of the seven previously included trials showed that bile acids did
not significantly affect mortality acute cellular rejection steroid-
resistant rejection retransplantation or serum bilirubin Bile acids
might significantly decrease the length of hospital stay and the
number of patients with chronic rejection included in these tri-
als but more supportive evidence is needed The number of pa-
tients with chronic rejection was not significantly influenced by
bile acids when a random-effects model was used and length of
stay was assessed in one single trial Furthermore none of the trials
were considered to be of low risk of bias and few patients were en-
rolled Therefore our positive findings may be due to bias (Schulz
1995 Moher 1998 Kjaergard 2001 Wood 2008) or random er-
rors (Wetterslev 2008 Brok 2009 Thorlund 2009) On the other
hand we are not able to exclude type II errors (that is finding
no significant differences when in fact they exist) due to the low
number of participants Therefore this topic could be of potential
interest in future large randomised trials with adequate control of
bias
All-cause mortality at one year after liver transplantation is re-
ported to be about 20 (Thuluvath 2003) which we also ob-
served for the patients included in the present review According to
our subgroup analyses neither UDCA nor TUDCA significantly
decreased all-cause mortality We also performed a subgroup anal-
ysis regarding treatment duration but we were not able to find any
difference between short (less than six months) and long treatment
duration (six months or more) Thus bile acids do not seem to
have statistically significant effects in reducing all-cause mortal-
ity after liver transplantation We performed both worst-best-case
scenario and best-worst-case scenario analyses In the worst-best-
case scenario bile acids did not differ significantly from placebo or
no intervention regarding all-cause mortality However bile acids
significantly decreased all-cause mortality in the best-worst-case
scenario analysis However such an analysis is very extreme and
may not be realistic We have also found that UDCA may be able
to decrease the risk of chronic rejection in liver-transplanted pa-
tients but trial sequential analysis could not confirm this result
Due to a limited number of patients (Ioannidis 2001) we are not
able to exclude the possibility that it may be relevant to perform
placebo-controlled trials with low risk of bias on the use of bile
acids for liver-transplanted patients
We looked into the causes of deaths that were reported by the trials
and only one trial reported one death related to rejection At the
same time the number of retransplantations was 3 among 68 liver-
transplanted patients who received treatment with UDCA and 4
among 64 liver-transplanted patients who received treatment with
placebo We noticed that all patients in the included trials received
co-interventions of standard triple-drug regimens (steroids aza-
thioprine and cyclosporine or tacrolimus) which were able to
control the possible acute or chronic rejection and prevent deaths
due to allograft rejection (FK506 1994)
The assumption that UDCA might reduce the incidence of acute
graft rejection came from the findings that UDCA could regulate
major histocompatibility complex antigen expression in bile ducts
and liver endothelia and inhibit lymphocyte activity (Calmus
1990 Terasaki 1991 Perez 2009) However in the present review
bile acids did not significantly reduce the risk of acute cellular re-
jection in liver-transplanted patients Considering that acute cellu-
lar rejection is commonly found within a few days after liver trans-
plantation (Vierling 1992) some might argue that the adminis-
tration of bile acids was started too late to prevent acute cellular
rejection We performed subgroup analyses regarding the time bile
acids were started and no statistically significant difference was
found Furthermore bile acids were not able to decrease the risk
of steroid-resistant rejection Therefore the lack of effects of bile
acids does not seem to be due to a delayed start to bile acid ad-
ministration after liver transplantation However it is a possibility
that one should start bile acids intake before liver transplantation
A retrospective study found that rejection rates differed signifi-
cantly between patients with primary biliary cirrhosis treated with
or without UDCA before liver transplantation (Heathcote 1999)
One could argue whether UDCA-induced delay in transplantation
has an adverse effect on post-transplantation outcome Since we
did not find any prospective randomised clinical trials addressing
this issue further research might be needed Furthermore some
studies may provide an explanation why UDCA was not able to
prevent acute cellular rejection These studies found that UDCA
did not appear to change the expression of major histocompatibil-
ity complex class II antigens but rather major histocompatibility
complex class I antigens (Calmus 1990) The initial mechanism
of acute rejection is thought to be recognition of MHC class II
13Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
antigens by CD4+ T cells (Vierling 1992) Moreover the inhibi-
tion of the production of interleukin-2 by peripheral blood lym-
phocytes with UDCA (Heuman 1993) might be negated by the
immunosuppressive treatment after liver transplantation (van den
Berg 1998) so that UDCA is unable to demonstrate effects on
graft rejection In a recent study by Assy 2007 a significant re-
duction in the mean dose of immunosuppressive medications was
achieved in stable liver graft recipients treated with UDCA indi-
cating a possible influence of UDCA on rejection mechanisms
In accordance with previous systematic reviews (Chen 2003a
Chen 2007 Gong 2008) bile acids were not associated with the
occurrence of serious adverse events or any major occurrence of
adverse events
In summary our results do not support or refute the use of bile
acids (UDCA and TUDCA) additional to standard immunosup-
pressive treatment in liver-transplanted patients
A U T H O R S rsquo C O N C L U S I O N SImplications for practice
There seems to be no evidence to support or refute the use of bile
acids for liver-transplanted patients receiving standard immuno-
suppressive treatment
Implications for research
We need more randomised placebo-controlled clinical trials with
enough statistical power and low risk of bias to explore the poten-
tial effects of bile acids on chronic rejection and mortality in liver-
transplanted patients Such trials should also consider evaluation
of quality of life and length of hospitalisation Such trials may
consider starting bile acid and placebo interventions before liver
transplantation we were not able to identify any randomised trials
addressing this regimen Such trials ought to be reported accord-
ing to the CONSORT statement (wwwconsort-statementorg)
However before embarking on such trials the effects of bile acids
in other patient groups should be scrutinised as they may have
small or negative effects
A C K N O W L E D G E M E N T S
We thank all the patients and investigators who were involved in
the clinical trials mentioned in this review We thank Wendong
Chen for his work and contribution on the previous version of this
review We thank the staff of The Cochrane Hepato-Biliary Group
Editorial Team especially Dimitrinka Nikolova and Sarah Louise
Klingenberg for excellent collaboration and assistance during the
update of this review
Peer Reviewers Carlo Merkel Italy M Tomikawa Japan
Contact Editor Bodil Als-Nielsen Denmark
R E F E R E N C E S
References to studies included in this review
Angelico 1999 published data only
Angelico M Tisone G Baiocchi L Palmieri G Pisani F Negrini S
et alOne-year pilot study on tauroursodeoxycholic acid as an
adjuvant treatment after liver transplantation Italian Journal of
Gastroenterology and Hepatology 199931(6)462ndash8 [MEDLINE
10575563]
Barnes 1997 published data onlylowast Barnes D Talenti D Cammell G Goormastic M Farquhar L
Henderson M et alA randomized clinical trial of ursodeoxycholic
acid as adjuvant treatment to prevent liver transplant rejection
Hepatology 199726(4)853ndash7 [MEDLINE 9328304]
Barnes D Talenti D Goormastic M Farquhar L Cammell G
Henderson M et alUrsodeoxycholic acid (UDCA) reduces hepatic
allograft rejection after orthotopic liver transplantation (OLT) - a
prospective randomized placebo-controlled double-blind trial
Hepatology 199522149A
Fleckenstein 1998 published data only
Fleckenstein JF Paredes M Thuluvath PJ A prospective
randomized double-blind trial evaluating the efficacy of
ursodeoxycholic acid in prevention of liver transplant rejection
Liver Transplantation and Surgery 19984(4)276ndash9 [MEDLINE
9649640]
Keiding 1997 published data only
Keiding S Hockerstedt K Bjoro K Bondesen S Hjortrup A
Isoniemi H et alThe Nordic multicenter double-blind randomized
controlled trial of prophylactic ursodeoxycholic acid in liver
transplant patients Transplantation 199763(11)1591ndash4
[MEDLINE 9197351]
Koneru 1993 published data only
Koneru B Tint GS Wilson DJ Leevy CB Salen F Randomised
prospective trial of ursodeoxycholic acid in liver transplant
recipients Hepatology 199318336A
Pageaux 1995 published data only
Pageaux GP Blanc P Perrigault PF Navarro F Fabre JM Souche B
et alFailure of ursodeoxycholic acid to prevent acute cellular
rejection after liver transplantation Journal of Hepatology 199523
(2)119ndash22 [MEDLINE 7499781]
Sama 1991 published data only
Sama C Mazziotti A Grigioni W Morselli AM Chianura A
Stefanini GF et alUrsodeoxycholic acid administration does not
14Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
prevent rejection after OLT Journal of Hepatology 199113(Suppl
2)68
References to studies excluded from this review
Assy 2007 published data only
Assy N Adams PC Myers P Simon V Minuk GY Wall W et
alRandomized controlled trial of total immunosuppression
withdrawal in liver transplant recipients role of ursodeoxycholic
acid Transplantation 200783(12)1571ndash6 [MEDLINE
17589339]
Clavien 1996 published data only
Clavien PA Sharara AI Camargo CA Jr Harland RC Fitz JG
Evidence that ursodeoxycholic acid prevents steroid-resistant
rejection in adult liver transplantation Clinical Transplantation
199610(6 Pt 2)658ndash62 [MEDLINE 8996761]
Friman 1992 published data only
Friman S Persson H Schersten T Svanvik J Karlberg I Adjuvant
treatment with ursodeoxycholic acid reduces acute rejection after
liver transplantation Transplantation Proceedings 199224(1)
389ndash90 [MEDLINE 1539328]
Heathcote 1999 published data onlylowast Heathcote EJ Stone J Cauch-Dudek K Poupon R Chazouilleres
O Lindor KD et alEffect of pretransplantation ursodeoxycholic
acid therapy on the outcome of liver transplantation in patients
with primary biliary cirrhosis Liver Transplantation and Surgery
19995(4)269ndash74 [MEDLINE 10388499]
Henriksson 1991 published data only
Henriksson BA Persson H Friman S Wangberg B Svanvik J
Karlberg I Adjuvant ursodeoxycholic acid prevents acute rejection
in liver transplant recipients Transplantation Proceedings 199123
(3)1971 [MEDLINE 2063453]
Persson 1990 published data only
Persson H Friman S Schersten T Svanvik J Karlberg I
Ursodeoxycholic acid for prevention of acute rejection in liver
transplant recipients Lancet 1990336(8706)52ndash3 [MEDLINE
1973232]
Rafael 1995 published data only
Rafael E Duraj F Rudstrom H Wilczek H Ericzon B Effect of
ursodeoxycholic acid treatment for cholestasis in liver transplant
recipients Transplantation Proceedings 199527(6)3501ndash2
[MEDLINE 8540069]
Sama 1998 published data only
Sama C Morselli-Labate AM Grazi GL Mastroianni A Danesi G
Pianta P et alUrsodeoxycholic acid in liver transplantation effect
on cholestasis and rejection Gastroenterology 1998114(4 Suppl)
A1332
Additional references
Adams 1990
Adams DH Neuberger JM Patterns of graft rejection following
liver transplantation Journal of Hepatology 199010(1)113ndash9
[MEDLINE 2407770]
Al-Quaiz 1994
Al-Quaiz M OrsquoGrady J Tredger J Williams R Variable effect of
ursodeoxycholic acid on cyclosporin absorption after orthotopic
liver transplantation Transplant International 19947(3)190ndash4
[MEDLINE 8060468]
Armstrong 1982
Armstrong MJ Carey MC The hydrophobic-hydrophilic balance
of bile salt Inverse correlation between reverse phase high
performance liquid chromatographic mobilities and micellar
cholesterol-solubilizing capacities Journal of Lipid Research 1982
23(1)70ndash80 [MEDLINE 7057113]
Ascher 1988
Ascher NL Stock PG Baumgardner GL Payne WD Najarian JS
Infection and rejection of primary hepatic transplant in 93
consecutive patients treated with triple immunosuppressive therapy
Surgery Gynecology amp Obstetrics 1988167(6)474ndash84
[MEDLINE 3055368]
Brok 2008
Brok J Thorlund K Gluud C Wetterslev J Trial sequential
analysis reveals insufficient information size and potentially false
positive results in many meta-analyses Journal of Clinical
Epidemiology 200861(8)763ndash9 [MEDLINE 18411040]
Brok 2009
Brok J Thorlund K Wetterslev J Gluud C Apparently conclusive
meta-analysis may be inconclusive - Trial sequential analysis
adjustment of random error risk due to repetitive testing of
accumulating data in apparently conclusive neonatal meta-analysis
International Journal of Epidemiology 200938(1)298ndash303
[MEDLINE 18824466]
Calmus 1990
Calmus Y Gane P Rouger P Poupon R Hepatic expression of class
I and class II major histocompatibility complex molecules in
primary biliary cirrhosis effect of ursodeoxycholic acid Hepatology
199011(1)12ndash5 [MEDLINE 2403961]
Calmus 1992
Calmus Y Arvieux C Gane P Boucher E Nordlinger B Rouger P
et alCholestasis induces major histocompatibility complex class I
expression in hepatocytes Gastroenterology 1992102(4 Pt 1)
1371ndash7 [MEDLINE 1551542]
Chen 2003a
Chen W Gluud C Bile acids for primary sclerosing cholangitis
Cochrane Database of Systematic Reviews 2003 Issue 2 [DOI
10100214651858CD003626]
Chen 2007
Chen W Liu J Gluud C Bile acids for viral hepatitis Cochrane
Database of Systematic Reviews 2007 Issue 4 [DOI 101002
14651858CD003181pub2]
Cheng 2002
Cheng K Ashby D Smyth R Ursodeoxycholic acid for cystic
fibrosis-related liver disease Cochrane Database of Systematic
Reviews 2002 Issue 2 [DOI 10100214651858CD000222]
Corbani 2008
Corbani A Burroughs AK Intrahepatic cholestasis after liver
transplantation Clinics in Liver Disease 200812(1)111ndash29
[MEDLINE 18242500]
DeMets 1987
DeMets DL Methods for combining randomised clinical trials
strengths and limitations Statistics in Medicine 19876(3)341ndash50
[MEDLINE 3616287]
15Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
DerSimonian 1986
DerSimonian R Laird N Meta-analysis in clinical trials Controlled
Clinical Trials 19867(3)177ndash88 [MEDLINE 3802833]
Egger 1997
Egger M Davey Smith G Schneider M Minder C Bias in meta-
analysis detected by a simple graphical test BMJ (Clinical Research
Ed) 1997315(7109)629ndash34 [MEDLINE 9310563]
Ericzon 1990
Ericzon BG Eusufzai S Kubota K Einarsson K Angelin B
Characteristics of biliary lipid metabolism after liver
transplantation Hepatology 199012(5)1222ndash8 [MEDLINE
2227822]
FK506 1994
The US Multicenter FK506 Liver Study Group A comparison of
tacrolimus (FK506) and cyclosporine for immunosuppression in
liver transplantation New England Journal of Medicine 1994331
(17)1110ndash5 [MEDLINE 7523946]
Friman 1994
Friman S Svanvik J A possible role of ursodeoxycholic acid in liver
transplantation Scandinavian Journal of Gastroenterology 1994204
62ndash4 [MEDLINE 7824880]
Fuchs 1999
Fuchs M Stange EF Metabolism of bile acids In Johannes
Bircher Jean-Pierre Benhamou Neil McIntyre Mario Rizzetto
Juan Rodes editor(s) Oxford Textbook of Clinical Hepatology 2
Vol 1 Oxford Oxford University Press 1999223ndash56
Fusai 2006
Fusai G Dhaliwal P Rolando N Sabin CA Patch D Davidson BR
et alIncidence and risk factors for the development of prolonged
and severe intrahepatic cholestasis after liver transplantation Liver
Transplantation 200612(11)1626ndash33 [DOI 101002lt20870]
Gluud 2001
Gluud C Alcoholic hepatitis no glucocorticosteroids In
Leuschner U James OFW Dancygier H editor(s) Steatohepatitis
(NASH and ASH) Falk Symposium 121 Lancaster Kluwer
Academic Publisher 2001322ndash42
Gluud 2010
Gluud C Nikolova D Klingenberg SL Alexakis N Als-Nielsen B
Colli A et alCochrane Hepato-Biliary Group About The
Cochrane Collaboration (Cochrane Review Groups (CRGs))
2010 Issue 1 Art No LIVER
Gong 2008
Gong Y Huang ZB Christiansen E Gluud C Ursodeoxycholic
acid for primary biliary cirrhosis Cochrane Database of Systematic
Reviews 2008 Issue 3 [DOI 101002
14651858CD000551pub2]
Haddad 2006
Haddad EM McAlister VC Renouf E Malthaner R Kjaer MS
Gluud LL Cyclosporin versus tacrolimus for liver transplanted
patients Cochrane Database of Systematic Reviews 2006 Issue 4
[DOI 10100214651858CD005161pub2]
Heuman 1993
Heuman DM Hepatoprotective properties of ursodeoxycholic acid
Gastroenterology 1993104(6)1865ndash9 [MEDLINE 8500748]
Higgins 2008
Higgins PTJ Green S editors Cochrane Handbook for Systematic
Reviews of Interventions West Sussex England Wiley-Blackwell
2008
Hirschfield 2009
Hirschfield GM Gibbs P Griffiths WJH Adult liver
transplantation what non-specialists need to know BMJ (Clinical
Research Ed) 2009338(b1670)1321ndash7 [DOI 101136
bmjb1670]
Hussain 2002
Hussain HK Nghiem HV Imaging of hepatic transplantation
Clinics in Liver Disease 20026(1)247ndash70 [MEDLINE
11933592]
ICH-GCP 1997
International Conference on Harmonisation Expert Working
Group Code of Federal Regulations amp International Conference on
Harmonization Guidelines Media Parexel Barnett 1997
Ioannidis 2001
Ioannidis JPA Lau J Evolution of treatment effects over time
Empirical insight from recursive cumulative meta analyses
Proceedings of the National Academy of Sciences 200198(3)831ndash6
IWP 1995
International Working Party Terminology for hepatic allograft
rejection Hepatology 199522(2)648ndash54 [MEDLINE 7635435]
Kjaergard 2001
Kjaergard LL Villumsen J Gluud C Reported methodological
quality and discrepancies between large and small randomised trials
in meta-analyses Annals of Internal Medicine 2001135(11)982ndash9
[MEDLINE 11730399]
Klintmalm 1989
Klintmalm GB Nery JR Husberg BS Gonwa TA Tillery GW
Rejection in liver transplantation Hepatology 198910(6)978ndash85
[MEDLINE 2583691]
Knechtle 2009
Knechtle SJ Kwun J Unique aspects of rejection and tolerance in
liver transplantation Seminars in Liver Disease 200929(1)91ndash101
[MEDLINE 19235662]
Krams 1993
Krams SM Ascher NL Martinez OM New immunologic insights
into mechanisms of allograft rejection Gastroenterology Clinics of
North America 199318(2)374ndash7 [MEDLINE 8509176]
Lan 1983
Lan KKG DeMets DL Discrete sequential boundaries for clinical
trials Biometrika 198370659ndash63
Merion 1989
Merion RM Gorski DH Burtch GD Turcotte JG Colletti LM
Campbell DA Jr Bile refeeding after liver transplantation and
avoidance of intravenous cyclosporine Surgery 1989106(4)
604ndash9 [MEDLINE 2799635]
Moher 1998
Moher D Pham B Jones A Cook DJ Jadad AR Moher M et
alDoes quality of reports of randomised trials affect estimates of
intervention efficacy reported in meta-analyses Lancet 1998352
(9128)609ndash13 [MEDLINE 9746022]
16Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Neuberger 1999
Neuberger J Incidence timing and risk factors for acute and
chronic rejection Liver Transplantation and Surgery 19995(4 Suppl
1)S30ndashS36 [MEDLINE 10431015]
Okolicsanyi 1986
Okolicsanyi L Lirussi F Strazzabosco M Jemmolo RM Orlando R
Nassuato G et alThe effect of drugs on bile flow and composition
An overview Drugs 198631(5)430ndash48 [MEDLINE 2872047]
Palmer 1972
Palmer RH Bile acids liver injury and liver disease Archives of
Internal Medicine 1972130(4)606ndash17 [MEDLINE 4627840]
Perez 2009
Perez MJ Briz O Bile-acid-induced cell injury and protection
World Journal of Gastroenterology 200915(14)1677ndash89
[MEDLINE 19360911]
Pogue 1997
Pogue JM Yusuf S Cumulating evidence from randomized trials
Utilizing sequential monitoring boundaries for cumulative meta-
analysis Controlled Clinical Trials 199718(6)580ndash93
[MEDLINE 9408720]
Pogue 1998
Pogue J Yusuf S Overcoming the limitations of current meta-
analysis of randomised controlled trials Lancet 1998351(9095)
45ndash52 [MEDLINE 9433436]
RevMan 2008
The Nordic Cochrane Centre The Cochrane Collaboration
Review Manager (RevMan) 50 Copenhagen The Nordic
Cochrane Centre The Cochrane Collaboration 2008
Royle 2003
Royle P Milne R Literature searching for randomized controlled
trials used in Cochrane reviews rapid versus exhaustive searches
International Journal of Technology Assessment in Health Care 2003
19(4)591ndash603
Schulz 1995
Schulz KF Chalmers I Hayer R Altman D Empirical evidence of
bias JAMA 1995273(5)408ndash12 [MEDLINE 7823387]
Sharara 1995
Sharara AI Camargo CA Clavien PA Ursodeoxycholic acid
prevents steroid resistant rejection in liver transplant recipients
Gastroenterology 1995108A1168
Sholmerich 1984
Sholmerich J Becher MS Schmidt KH Schubert R Kremer B
Felhaus S et alInfluence of hydroxylation and conjugation of bile
salts on their membrane damaging properties Hepatology 19844
(4)661ndash7 [MEDLINE 6745854]
Soderdahl 1998
Soderdahl G Nowak G Duraj F Wang FH Einarsson C Ericzon
BG Ursodeoxycholic acid increased bile flow and affects bile
composition in the early postoperative phase following liver
transplantation Transplantation International 199811(Suppl 1)
S231ndashS238 [MEDLINE 9664985]
Terasaki 1991
Terasaki S Nakanuma Y Ogino H Unoura M Kobayashi K
Hepatocellular and biliary expression of HLA antigens in primary
biliary cirrhosis before and after ursodeoxycholic acid therapy
American Journal of Gastroenterology 199186(9)1194ndash9
[MEDLINE 1882800]
Thalheimer 2002
Thalheimer U Capra F Liver transplantation making the best out
of what we have Digestive Diseases and Sciences 200247(5)
945ndash53 [MEDLINE 12018919]
Thorlund 2009
Thorlund K Devereaux PJ Wetterslev J Guyatt G Ioannidis JP
Thabane L et alCan trial sequential monitoring boundaries reduce
spurious inferences from meta-analyses International Journal of
Epidemiology 200938(1)276ndash86 [MEDLINE 18824467]
Thuluvath 2003
Thuluvath PJ Yoo HY Thompson RE A model to predict survival
at one month one year and five years after liver transplantation
based on pretransplant clinical characteristics Liver Transplantation
20039(5)527ndash32 [MEDLINE 12740799]
van den Berg 1998
van den Berg AP Twilhaar WN Mesander G van Son WJ van der
Bij W Klompmaker IJ et alQuantitation of immunosuppression
by flow cytometric measurement of the capacity of T cells for
interleukin-2 production Transplantation 199865(8)1066ndash71
[MEDLINE 9583867]
Vierling 1992
Vierling J Immunologic mechanisms of hepatic allograft rejection
Seminars in Liver Disease 199212(1)16ndash27 [MEDLINE
1570548]
Wetterslev 2008
Wetterslev J Thorlund K Brok J Gluud C Trial sequential
analysis may establish when firm evidence is reached in cumulative
meta-analysis Journal of Clinical Epidemiology 200861(1)64ndash75
[MEDLINE 18083463]
Wiesner 1992
Wiesner RH Acute cellular rejection following liver
transplantation incidence risk factors and outcome in the
NIDDK Liver Transplant Database (LTD) study Gastroenterology
1992102A910
Wood 2008
Wood L Egger M Gluud LL Schulz KF Juni P Altman DG et
alEmpirical evidence of bias in treatment effect estimates in
controlled trials with different interventions and outcomes meta-
epidemiological study BMJ (Clinical Research Ed) 2008336
(7644)601ndash5 [MEDLINE 18316340]
Yoshikawa 1998
Yoshikawa M Matsui Y Kawamoto H Toyohara M Matsumura
K Yamao J et alIntragastric administration of ursodeoxycholic
acid suppresses immunoglobulin secretion by lymphocytes from
liver but not from peripheral blood spleen or Peyerrsquos patches in
mice International Journal of Immunopharmacology 199820(1-3)
29ndash38 [MEDLINE 9717080]
References to other published versions of this review
17Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Chen 2003b
Chen W Gluud C Bile acids for liver transplanted patients
Cochrane Database of Systematic Reviews 2005 Issue 3 [DOI
10100214651858CD005442]lowast Indicates the major publication for the study
18Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
C H A R A C T E R I S T I C S O F S T U D I E S
Characteristics of included studies [ordered by study ID]
Angelico 1999
Methods Study design open-label randomised one-year pilot study
Participants Country Italy
Publication language English
Inclusion criteria
- patients who underwent liver transplantation from April 1994 to December 1994
Exclusion criteria
- not mentioned
Participants
Two patients in TUDCA group and two patients in control group were excluded from
the basic information of participants by the study due to withdrawal
- TUDCA group (n = 14)
Mean age (years +- SD)
467 +- 84
Ratio of sex (malefemale) 122
Origins of liver diseases
hepatitis C cirrhosis (9) hepatitis B cirrhosis (2) hepatitis B and C cirrhosis (1) cryp-
togenic cirrhosis (2) alcoholic cirrhosis (0) Wilson cirrhosis (0)
- Control group (n = 15)
Mean age (years +- SD)
474 +- 74
Ratio of sex (malefemale) 123
Origins of liver diseases
hepatitis C cirrhosis (7) hepatitis B cirrhosis (2) hepatitis B and C cirrhosis (2) cryp-
togenic cirrhosis (2) alcoholic cirrhosis (1) Wilson cirrhosis (1)
Interventions TUDCA group
- Dose 500 mgday in two divided doses
- Route orally
- Duration the treatment was started on day 5 after transplantation and continued for
one year
Control group
- no treatment
Co-interventions all patients received standard triple-drug regimens (steroids azathio-
prine and cyclosporine or tacrolimus)
Outcomes All cause mortality
Number of patients with rejection after liver transplantation
Notes Letter was sent to the authors in September 2009 A reply with additional information
was received shortly after
Risk of bias
19Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Angelico 1999 (Continued)
Item Authorsrsquo judgement Description
Adequate sequence generation Yes Computer generated table
Allocation concealment Unclear No information provided
Blinding No Not performed
Incomplete outcome data addressed
All outcomes
Yes Withdrawal two patients from the
TUDCA group and two patients from the
placebo group Three of them died due to
transplant non-function in the first postop-
erative week and one patient was regrafted
due to thrombosis of hepatic artery
Free of selective reporting Unclear Post-transplant cholestasis and liver bio-
chemistry specified as outcomes Differ-
ence reported as not significant but no ac-
tual data given
Sample size calculation No Not reported
Intention-to-treat analysis No Not stated and not used
Baseline imbalance Unclear Not enough information provided
Early stopping of trial Unclear Not enough information provided
Barnes 1997
Methods Study design randomised placebo-controlled double-blind trial
Participants Country United States
Publication language English
Inclusion criteria
- patients aged 18 years or older who underwent liver transplantation at the Cleveland
Clinic Foundation from April 1992 through June of 1994
Exclusion criteria
- patients who were found to have cancer at surgically resected margins of the biliary
tree
- patents who underwent retransplantation
Participants
- UDCA group (n = 28)
Mean age (years +- SD)
505 +- 116
Ratio of sex (malefemale) 1810
Child class A 7
20Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Barnes 1997 (Continued)
B 13
and C 8
Origins of liver diseases Laennecrsquos cirrhosis 4
PBC 3
cryptogenic cirrhosis 6
hepatitis Ccirrhosis 4
hepatitis Bcirrhosis 3
autoimmune hepatitis with cirrhosis 3
PSC 2
other 3
- Placebo group (n = 24)
Mean age (years +- SD)
507 +- 93
Ratio of sex (malefemale) 159
Child class A 6
B 14
and C 4
Origins of liver diseases Laennecrsquos cirrhosis 9
PBC 5
cryptogenic cirrhosis 1
hepatitis Ccirrhosis 1
hepatitis Bcirrhosis 1
autoimmune hepatitis with cirrhosis 1
PSC 2
other 4
Interventions UDCA group
- Dose 10-15 mgkg body weightday in divided doses
- Route orally
- Duration immediately after intestinal transit recovery usually between postoperative
days three and five and continue for three months
Placebo group
- identical-appearing capsules administered in the same quantity and manner
Co-interventions all patients received standard triple-drug regimens (steroids azathio-
prine and cyclosporine or tacrolimus)
Outcomes All cause mortality
Number of patients with acute cellular rejection
Number of patients with chronic rejection
Number of patients with steroid-resistant rejection
Number of days of hospitalisation
Adverse events
Notes Letter was sent to the authors in September 2009 A reply with additional information
was received shortly after
Risk of bias
Item Authorsrsquo judgement Description
21Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Barnes 1997 (Continued)
Adequate sequence generation Yes Computer generated table
Allocation concealment Unclear No information provided
Blinding Yes Quote ldquorandomised to receive either
UDCA or an identical placebo capsulerdquo
Incomplete outcome data addressed
All outcomes
Yes Mean follow-up time 18 months Ten pa-
tients withdrawn from study 6 in UDCA
group and 4 in placebo group Reasons
for withdrawal were reported Four patients
died in the placebo group
Free of selective reporting Yes All expected outcomes reported
Sample size calculation Unclear The trial reported the method of sample
size calculation but the actual number of
patients needed was not reported
Intention-to-treat analysis Yes Stated and used
Baseline imbalance Unclear Not enough information provided
Early stopping of trial Unclear The number of patients needed to gain the
actual power was not reported Whether
the trial was terminated early is not clear
Fleckenstein 1998
Methods Study design prospective randomised double-blind trial
Participants Country United States
Publication language English
Inclusion criteria
- patients who underwent liver transplantation at the Johns Hopkins Hospital
Exclusion criteria
- patients who were under 18 years old undergoing repeat transplantation had primary
graft nonfunction or refused consent
Participants
- UDCA group (n = 14)
Mean age (years +- SD)
443 +- 127
Ratio of sex (malefemale) 68
Origins of liver diseases hepatitis C 6
alcohol 2
autoimmune 1
PBC 2
22Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Fleckenstein 1998 (Continued)
PSC 1
autoimmune cholangiopathy 1
hepatitis B 1
- Placebo group (n = 16)
Mean age (years +- SD)
496 +- 109
Ratio of sex (malefemale) 124
Origins of liver diseases hepatitis C 3
alcohol 3
autoimmune 3
PBC 1
PSC 2
cryptogenic 2
hepatitis B 1
alpha1-antitrypsin deficiency 1
Interventions UDCA group
- Dose 15 mgkg body weightday in divided doses
- Route orally
- Duration immediately after intestinal transit recovery usually between postoperative
days three and five and continue for three months
Placebo group
- Identical-appearing capsules administered in the same quantity and manner
Co-interventions all patients received standard triple-drug regimens (steroids azathio-
prine and cyclosporine or tacrolimus)
Outcomes All cause mortality
Number with retransplantation
Number of patients with acute cellular rejection
Number of patients with chronic rejection
Serum bilirubin levels at the end of treatment
Notes Follow-up time nine months
Letter was sent to the authors in September 2009 No reply was received
Risk of bias
Item Authorsrsquo judgement Description
Adequate sequence generation Unclear No information provided
Allocation concealment Unclear No information provided
Blinding Yes Method of blinding not described but
probably adequate
Incomplete outcome data addressed
All outcomes
Yes Withdrawal one patient from the UDCA
group and two patients from the placebo
group because of capsule size
23Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Fleckenstein 1998 (Continued)
Free of selective reporting Unclear Outcomes were not completely described
Sample size calculation No Not reported
Intention-to-treat analysis Yes Quote ldquoThree patients withdrew after in-
clusionThey were included in the statis-
tical analysisrdquo
Baseline imbalance Unclear Not enough information provided
Early stopping of trial Unclear Not enough information provided
Keiding 1997
Methods Study design prospective randomised placebo-controlled multicenter study
Participants Country Denmark Finland Norway and Sweden
Publication language English
Inclusion criteria
- patients who underwent liver transplantation in Denmark Finland Norway and Swe-
den from September 1 1992 to May 31 1994
Exclusion criteria
- patients with malignant diseases
Participants
The age of the children ranged from 0 to 13 years (median 15) and the age of adults
ranged from 14 to 59 years old (median 44) MaleFemale ratio was 96 for children and
4344 for adults
- UDCA group (n = 54)
Origins of liver diseases
paracetamol intoxication 1 hepatitis B 1 autoimmune hepatitis 0 biliary atresia 2
metabolic diseases 7 neonatal hepatitis 2 PBC 13 post hepatitis cirrhosis 8 PSC 3
cryptogenic cirrhosis 7 alcoholic cirrhosis 2 other reasons 8
- Placebo group (n = 48)
Origins of liver diseases paracetamol intoxication 1 hepatitis B 0 autoimmune hepatitis
1 biliary atresia 3 metabolic diseases 11 neonatal hepatitis 0 PBC 7 post hepatitis
cirrhosis 5 PSC 7 cryptogenic cirrhosis 2 alcoholic cirrhosis 6 other reasons 5
Interventions UDCA group
- Dose 15 mgkg body weightday in two or three divided doses
- Route orally
- Duration immediately after intestinal transit recovery usually between postoperative
days three and five and continue for three months
Placebo group
- Identical-appearing capsules administered in the same quantity and manner
Co-interventions all patients received standard triple-drug regimens (steroids azathio-
prine and cyclosporine or tacrolimus)
24Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Keiding 1997 (Continued)
Outcomes All cause mortality
Number of deaths related to rejection
Number of patients with acute cellular rejection
Number of patients with chronic rejection
Number of patients with steroid-resistant rejection
Adverse events
Notes Letter was sent to the authors in September 2009 No reply was received
Risk of bias
Item Authorsrsquo judgement Description
Adequate sequence generation Unclear Patients were randomised at a ratio of 11
Allocation concealment Yes Quote ldquo The allocation was performed in
blocks of 10 patients using the sealed serial
envelope methodrdquo
Blinding Yes Quote ldquoThe UDCA and the placebo cap-
sules had identical appearance and tasterdquo
Incomplete outcome data addressed
All outcomes
Yes Follow-up time 12 months Five UDCA
patients and five placebo patients withdrew
from study Reasons were reported
Free of selective reporting Unclear Insufficient information
Sample size calculation Yes Performed and allowed for a difference in
the incidence of at least one episode of
acute rejection of 50 between the treat-
ment and placebo groups with 90 statisti-
cal power and a significance level of P value
less than 005 The calculated sample size
was 80 patients
Intention-to-treat analysis Yes Stated and used
Baseline imbalance Yes The study seems to be free of baseline im-
balance
Early stopping of trial Yes Study attained the pre-specified sample
size
25Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Koneru 1993
Methods Study design randomised controlled trial
Participants Country United States
Publication language English
Inclusion criteria
- patients who underwent liver transplantation
Exclusion criteria
- not mentioned
Participants
- UDCA group (n = 16)
Mean age (years +- SD)
no information
Ratio of sex (malefemale) no information
Origins of liver diseases
no information
- Control group (n = 16)
Mean age (years +- SD)
no information
Ratio of sex (malefemale) no information
Origins of liver diseases
no information
Interventions UDCA group
- Dose 900 mgday
- Route orally
- Duration immediately after intestinal transit recovery usually between postoperative
days three and five and continue for three months
Control group
- no treatment
Co-interventions all patients received standard triple-drug regimens (steroids azathio-
prine and cyclosporine)
Outcomes Number of patients with retransplantation due to rejection
Number of patients with rejection episodes
Notes Abstract
Letter was sent to the authors in September 2009 No reply was received
Risk of bias
Item Authorsrsquo judgement Description
Adequate sequence generation Unclear No information provided
Allocation concealment Unclear No information provided
Blinding No Not performed
26Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Koneru 1993 (Continued)
Incomplete outcome data addressed
All outcomes
Unclear The study gives the impression that there
were no withdrawals but this was not ex-
plicitly stated
Free of selective reporting Unclear Insufficient information provided
Sample size calculation No Not performed
Intention-to-treat analysis Unclear No information provided
Baseline imbalance Unclear Not enough information provided
Early stopping of trial Unclear Not enough information provided
Pageaux 1995
Methods Study design double-blind randomised study
Participants Country France
Publication language English
Inclusion criteria
- patients who underwent liver transplantation
Exclusion criteria
- not mentioned
Participants
- UDCA group (n=26)
Mean age (years +- SD)
47 +- 10
Ratio of sex (malefemale) 179
Origins of liver diseases alcoholic cirrhosis 14
post-hepatic B cirrhosis 2
post-hepatitis C cirrhosis 4
PBC 2
liver cancer 2
fulminant hepatitis 1
miscellaneous 1
- Placebo group (n = 24)
Mean age (years +- SD)
51+- 9
Ratio of sex (malefemale) 159
Origins of liver diseases alcoholic cirrhosis 10
post-hepatic B cirrhosis 0
post-hepatic C cirrhosis 6
PBC 3
liver cancer 4
fulminant hepatitis 0
miscellaneous 1
27Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Pageaux 1995 (Continued)
Interventions UDCA group
- Dose 600 mgday in three divided doses
- Route orally
- Duration immediately after intestinal transit recovery usually between postoperative
days three and five and continue for two months
Placebo group
- identical-appearing capsules administered in the same quantity and manner
Co-interventions all patients received standard triple-drug regimens (steroids azathio-
prine and cyclosporine or tacrolimus)
Outcomes Number of patients with acute cellular rejection
Number of patients with steroid-resistant rejection
Notes Letter was sent to the authors in September 2009 No reply was received
Risk of bias
Item Authorsrsquo judgement Description
Adequate sequence generation Unclear No information provided
Allocation concealment Unclear No information provided
Blinding Unclear Method of blinding not described
Incomplete outcome data addressed
All outcomes
Yes Five patients died from non-immunologi-
cal causes before the end of the first month
and were excluded from the study Reasons
were reported
Free of selective reporting Unclear Not enough information provided
Sample size calculation No Not performed
Intention-to-treat analysis No Not stated and not used
Baseline imbalance Unclear Not enough information provided
Early stopping of trial Unclear Not enough information provided
Sama 1991
Methods Study design randomised controlled trial
Participants Country Italy
Publication language English
Inclusion criteria
28Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Sama 1991 (Continued)
- patients who underwent liver transplantation
Exclusion criteria
- not mentioned
Participants
- UDCA group (n = 20)
Mean age (years +- SD)
no information
Ratio of sex (malefemale) no information
Origins of liver diseases
no information
- Control group (n = 20)
Mean age (years +- SD)
no information
Ratio of sex (malefemale) no information
Origins of liver diseases
no information
Interventions UDCA group
- Dose 600 mgday in two divided doses
- Route orally
- Duration immediately after intestinal transit recovery usually between postoperative
day five and day seven and continue for six months
Control group
- no treatment
Co-interventions all patients received standard immunosuppressive treatment (steroids
and cyclosporine)
Outcomes All cause mortality
Number of patients with acute cellular rejection
Notes Abstract
Letter was sent to the authors in September 2009 No reply was received
Risk of bias
Item Authorsrsquo judgement Description
Adequate sequence generation Unclear A randomisation list was performed before
patients were admitted to the trial (infor-
mation from principal author)
Allocation concealment Unclear No information provided
Blinding Unclear The principle author provided information
that the study was made according to a
single-blind randomised protocol The pri-
mary outcome was the occurrence of biopsy
proven rejection episodes The pathologists
were blind but the patients were not
29Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Sama 1991 (Continued)
Incomplete outcome data addressed
All outcomes
Unclear Five patients from the UDCA group and
six patients from the placebo group were
excluded Reasons for exclusion were not
fully stated
Free of selective reporting No Data about survival of patients were not
adequately reported
Sample size calculation No Not performed
Intention-to-treat analysis No Not stated and not used
Baseline imbalance Unclear Basic characteristics of patients not re-
ported
Early stopping of trial Unclear Not enough information provided
UDCA = ursodeoxycholic acid
TUDCA = tauroursodeoxycholic acid
PBC = primary biliary cirrhosis
PSC = primary sclerosing cholangitis
OKT3 = anti-CD3 monoclonal antibody
Characteristics of excluded studies [ordered by study ID]
Assy 2007 A randomised controlled trial that included only recipients of liver transplantation with stable graft function and
no episodes of rejection for at least 2 years that were then offered total immunosuppression withdrawal Fourteen
patients received UDCA (15 mgkg body weightday) and 12 received placebo Rejection occurred in 43 and
75 of patients respectively (no significant difference) None developed chronic rejection After follow-up two
patients were free of immunosuppression 80 were steroid free and 50 were able to reduce their dose of
cyclosporine
Clavien 1996 Case series Fifty consecutive liver-transplanted patients were treated with a standard cyclosporine immunosup-
pressive regimen Twenty three of the 43 survivors developed an episode of rejection and UDCA (10 mgkg
weightday) was initiated Only one patient had a second episode of rejection
Friman 1992 Observational study Thirty-three liver-transplanted patients received 10 mg UDCAkg body weightday for
median of 10 months (range four to 21 months) Eight historical liver-transplanted patients served as control
group The rejection incidence was significantly lower in the patients who received the treatment with UDCA
Biochemistry one month after transplantation demonstrated significantly lower average values of aminotrans-
ferases and alkaline phosphatases in patients treated with UDCA than in the control group
30Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
Heathcote 1999 Observational study From 1987 to 1996 37 UDCA treated and 53 placebo treated patients with primary biliary
cirrhosis were referred for transplantation Posttransplantation survival rates at one month were 939 in the
UDCA group and 884 in the placebo group and one year survival rates were 903 and 784 respectively
(no significant differences) However rejection (type not defined - a secondary outcome measure) occurred
significantly less often in the UDCA group (429) than in placebo group (688)
Henriksson 1991 Observational study All patients in this study were given sequential quadruple immunosuppression with anti-
lymphocyte globulin azathioprine steroids and cyclosporine All patients with primary graft function (n = 11)
were treated with 10 mg UDCAkg body weightday starting during the first postoperative week Patients who
received liver transplantation in the first 6 months of 1989 (n = 8) served as controls In the control group one
patient died after 9 months with chronic graft dysfunction and six patients had rejection episodes during the
first postoperative month All patients in the UDCA group were alive without rejection episodes
Persson 1990 Observational study All 11 adult patients transplanted between August 1989 and January 1990 with primary
graft function were treated with 10 mg UDCA kg body weightday Eight patients transplanted during the first
half of 1989 served as control UDCA was started during the first postoperative week and the treatment was
continued for six months All patients in the UDCA treated group survived with satisfactory graft function In
the control group six patients had at least one rejection episode needing treatment during the first postoperative
month
Rafael 1995 Observational study Seventeen patients who underwent liver transplantation between February 1990 and April
1993 and developed biliary complications after transplantation were retrospectively analysed regarding treatment
with UDCA UDCA was given in a dose of 500 to 1000 mgday Ten patients were treated for at least one year while
seven patients were treated for 14 to 250 days UDCA significantly improved gammaglutamyl transpeptidase in
liver graft recipients with biliary complications There was also a trend towards improvement in serum bilirubin
and alanine transaminase values
Sama 1998 Observational study Thirty-four patients who underwent liver transplantation between January 1995 and June
1996 were included in the study Seventeen were treated with UDCA 10 mgkg body weightday during 6
months while 17 served as controls on the basis of having undergone liver transplantation closest to UDCA
patients A significant decrease in serum bilirubin levels was observed in UDCA patients There was a significantly
higher incidence of recurrent hepatitis in the control group
UDCA ursodeoxycholic acid
31Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
D A T A A N D A N A L Y S E S
Comparison 1 Bile acids for liver-transplanted patients
Outcome or subgroup titleNo of
studies
No of
participants Statistical method Effect size
1 All-cause mortality at maximum
follow-up
5 257 Risk Ratio (M-H Fixed 95 CI) 085 [053 136]
11 UDCA versus placebo or
no treatment
4 224 Risk Ratio (M-H Fixed 95 CI) 080 [049 130]
12 TUDCA versus no
treatment
1 33 Risk Ratio (M-H Fixed 95 CI) 159 [030 833]
2 All-cause mortality worst-best
case and best-worst case
scenarios
5 Risk Ratio (M-H Fixed 95 CI) Subtotals only
21 Worst-best case scenario 5 257 Risk Ratio (M-H Fixed 95 CI) 130 [086 196]
22 Best-worst case scenario 5 257 Risk Ratio (M-H Fixed 95 CI) 058 [038 090]
3 Subgroup analyses all-cause
mortality at maximum
follow-up according to time of
start of bile acids
5 257 Risk Ratio (M-H Fixed 95 CI) 085 [053 136]
31 Less than three days after
transplantation
1 102 Risk Ratio (M-H Fixed 95 CI) 124 [061 254]
32 Three days or more after
transplantation
4 155 Risk Ratio (M-H Fixed 95 CI) 063 [033 120]
4 Subgroup analyses all cause
mortality at maximum
follow-up according to
treatment duration
5 257 Risk Ratio (M-H Fixed 95 CI) 085 [053 136]
41 Less than six months 3 184 Risk Ratio (M-H Fixed 95 CI) 078 [045 138]
42 Six months or more 2 73 Risk Ratio (M-H Fixed 95 CI) 102 [043 240]
5 Number of deaths related
to rejection at maximum
follow-up
1 102 Risk Ratio (M-H Fixed 95 CI) 030 [001 712]
51 UDCA versus placebo 1 102 Risk Ratio (M-H Fixed 95 CI) 030 [001 712]
6 Number of retransplantations at
maximum follow-up
2 132 Risk Ratio (M-H Fixed 95 CI) 076 [020 286]
7 Number of patients with acute
cellular rejection at maximum
follow-up
7 339 Risk Ratio (M-H Fixed 95 CI) 089 [074 106]
71 UDCA versus placebo or
no treatment
6 306 Risk Ratio (M-H Fixed 95 CI) 089 [074 108]
72 TUDCA versus no
treatment
1 33 Risk Ratio (M-H Fixed 95 CI) 085 [045 160]
8 Subgroup analysis number of
patients with acute cellular
rejection according to time of
start of bile acid
7 339 Risk Ratio (M-H Fixed 95 CI) 089 [074 106]
32Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
81 Less than three days after
transplantation
2 134 Risk Ratio (M-H Fixed 95 CI) 084 [063 111]
82 Three days or more after
liver transplantation
5 205 Risk Ratio (M-H Fixed 95 CI) 092 [072 117]
9 Subgroup analysis number
of patients with acute
cellular rejection according to
treatment duration
7 339 Risk Ratio (M-H Fixed 95 CI) 089 [074 106]
91 Less than six months 5 266 Risk Ratio (M-H Fixed 95 CI) 087 [071 107]
92 Six months or more 2 73 Risk Ratio (M-H Fixed 95 CI) 094 [065 136]
10 Number of patients with
chronic rejection at maximum
follow-up
3 184 Risk Ratio (M-H Fixed 95 CI) 028 [008 095]
11 Number of patients with
steroid-resistant rejection at
maximum follow-up
4 234 Risk Ratio (M-H Fixed 95 CI) 077 [047 127]
12 Serum bilirubin (mgdl) at the
end of treatment
1 30 Mean Difference (IV Fixed 95 CI) 26 [-096 616]
13 Number of days of
hospitalisation after liver
transplantation
1 52 Mean Difference (IV Fixed 95 CI) -85 [-1667 -033]
14 Adverse events 3 187 Risk Ratio (M-H Fixed 95 CI) 088 [030 260]
Analysis 11 Comparison 1 Bile acids for liver-transplanted patients Outcome 1 All-cause mortality at
maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 1 All-cause mortality at maximum follow-up
Study or subgroup Favours bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 UDCA versus placebo or no treatment
Barnes 1997 228 724 253 024 [ 006 107 ]
Fleckenstein 1998 214 416 125 057 [ 012 266 ]
Keiding 1997 1454 1048 355 124 [ 061 254 ]
Sama 1991 520 620 201 083 [ 030 229 ]
Subtotal (95 CI) 116 108 935 080 [ 049 130 ]
Total events 23 (Favours bile acids) 27 (Control)
Heterogeneity Chi2 = 416 df = 3 (P = 025) I2 =28
Test for overall effect Z = 091 (P = 036)
01 02 05 1 2 5 10
Favours bile acids Favours control
(Continued )
33Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Favours bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
2 TUDCA versus no treatment
Angelico 1999 316 217 65 159 [ 030 833 ]
Subtotal (95 CI) 16 17 65 159 [ 030 833 ]
Total events 3 (Favours bile acids) 2 (Control)
Heterogeneity not applicable
Test for overall effect Z = 055 (P = 058)
Total (95 CI) 132 125 1000 085 [ 053 136 ]
Total events 26 (Favours bile acids) 29 (Control)
Heterogeneity Chi2 = 466 df = 4 (P = 032) I2 =14
Test for overall effect Z = 069 (P = 049)
01 02 05 1 2 5 10
Favours bile acids Favours control
Analysis 12 Comparison 1 Bile acids for liver-transplanted patients Outcome 2 All-cause mortality worst-
best case and best-worst case scenarios
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 2 All-cause mortality worst-best case and best-worst case scenarios
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 Worst-best case scenario
Angelico 1999 516 217 65 266 [ 060 1180 ]
Barnes 1997 828 724 253 098 [ 042 230 ]
Fleckenstein 1998 314 416 125 086 [ 023 319 ]
Keiding 1997 1954 1048 355 169 [ 087 327 ]
Sama 1991 520 620 201 083 [ 030 229 ]
Subtotal (95 CI) 132 125 1000 130 [ 086 196 ]
Total events 40 (Bile acids) 29 (Control)
Heterogeneity Chi2 = 303 df = 4 (P = 055) I2 =00
Test for overall effect Z = 123 (P = 022)
2 Best-worst case scenario
005 02 1 5 20
Favours bile acids Favours control
(Continued )
34Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Angelico 1999 316 417 90 080 [ 021 302 ]
Barnes 1997 228 1124 274 016 [ 004 063 ]
Fleckenstein 1998 214 616 130 038 [ 009 159 ]
Keiding 1997 1454 1548 368 083 [ 045 154 ]
Sama 1991 520 620 139 083 [ 030 229 ]
Subtotal (95 CI) 132 125 1000 058 [ 038 090 ]
Total events 26 (Bile acids) 42 (Control)
Heterogeneity Chi2 = 567 df = 4 (P = 023) I2 =29
Test for overall effect Z = 247 (P = 0014)
005 02 1 5 20
Favours bile acids Favours control
Analysis 13 Comparison 1 Bile acids for liver-transplanted patients Outcome 3 Subgroup analyses all-
cause mortality at maximum follow-up according to time of start of bile acids
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 3 Subgroup analyses all-cause mortality at maximum follow-up according to time of start of bile acids
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 Less than three days after transplantation
Keiding 1997 1454 1048 355 124 [ 061 254 ]
Subtotal (95 CI) 54 48 355 124 [ 061 254 ]
Total events 14 (Bile acids) 10 (Control)
Heterogeneity not applicable
Test for overall effect Z = 060 (P = 055)
2 Three days or more after transplantation
Angelico 1999 316 217 65 159 [ 030 833 ]
Barnes 1997 228 724 253 024 [ 006 107 ]
Fleckenstein 1998 214 416 125 057 [ 012 266 ]
Sama 1991 520 620 201 083 [ 030 229 ]
005 02 1 5 20
Favours bile acids Favours control
(Continued )
35Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Subtotal (95 CI) 78 77 645 063 [ 033 120 ]
Total events 12 (Bile acids) 19 (Control)
Heterogeneity Chi2 = 310 df = 3 (P = 038) I2 =3
Test for overall effect Z = 141 (P = 016)
Total (95 CI) 132 125 1000 085 [ 053 136 ]
Total events 26 (Bile acids) 29 (Control)
Heterogeneity Chi2 = 466 df = 4 (P = 032) I2 =14
Test for overall effect Z = 069 (P = 049)
005 02 1 5 20
Favours bile acids Favours control
Analysis 14 Comparison 1 Bile acids for liver-transplanted patients Outcome 4 Subgroup analyses all
cause mortality at maximum follow-up according to treatment duration
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 4 Subgroup analyses all cause mortality at maximum follow-up according to treatment duration
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 Less than six months
Barnes 1997 228 724 253 024 [ 006 107 ]
Fleckenstein 1998 214 416 125 057 [ 012 266 ]
Keiding 1997 1454 1048 355 124 [ 061 254 ]
Subtotal (95 CI) 96 88 734 078 [ 045 138 ]
Total events 18 (Bile acids) 21 (Control)
Heterogeneity Chi2 = 417 df = 2 (P = 012) I2 =52
Test for overall effect Z = 084 (P = 040)
2 Six months or more
Angelico 1999 316 217 65 159 [ 030 833 ]
Sama 1991 520 620 201 083 [ 030 229 ]
Subtotal (95 CI) 36 37 266 102 [ 043 240 ]
Total events 8 (Bile acids) 8 (Control)
Heterogeneity Chi2 = 043 df = 1 (P = 051) I2 =00
005 02 1 5 20
Favours bile acids Favours control
(Continued )
36Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Test for overall effect Z = 004 (P = 097)
Total (95 CI) 132 125 1000 085 [ 053 136 ]
Total events 26 (Bile acids) 29 (Control)
Heterogeneity Chi2 = 466 df = 4 (P = 032) I2 =14
Test for overall effect Z = 069 (P = 049)
005 02 1 5 20
Favours bile acids Favours control
Analysis 15 Comparison 1 Bile acids for liver-transplanted patients Outcome 5 Number of deaths related
to rejection at maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 5 Number of deaths related to rejection at maximum follow-up
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 UDCA versus placebo
Keiding 1997 054 148 1000 030 [ 001 712 ]
Total (95 CI) 54 48 1000 030 [ 001 712 ]
Total events 0 (Bile acids) 1 (Control)
Heterogeneity not applicable
Test for overall effect Z = 075 (P = 045)
0001 001 01 1 10 100 1000
Favours bile acids Favours control
37Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 16 Comparison 1 Bile acids for liver-transplanted patients Outcome 6 Number of
retransplantations at maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 6 Number of retransplantations at maximum follow-up
Study or subgroup Bile acids Placebo Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Fleckenstein 1998 214 016 100 567 [ 029 10891 ]
Keiding 1997 154 448 900 022 [ 003 192 ]
Total (95 CI) 68 64 1000 076 [ 020 286 ]
Total events 3 (Bile acids) 4 (Placebo)
Heterogeneity Chi2 = 303 df = 1 (P = 008) I2 =67
Test for overall effect Z = 040 (P = 069)
0001 001 01 1 10 100 1000
Favours bile acids Favours placebo
Analysis 17 Comparison 1 Bile acids for liver-transplanted patients Outcome 7 Number of patients with
acute cellular rejection at maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 7 Number of patients with acute cellular rejection at maximum follow-up
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 UDCA versus placebo or no treatment
Barnes 1997 1728 1724 180 086 [ 058 127 ]
Fleckenstein 1998 814 916 83 102 [ 054 190 ]
Keiding 1997 3554 3248 333 097 [ 073 129 ]
Koneru 1993 316 916 89 033 [ 011 101 ]
Pageaux 1995 926 924 92 092 [ 044 193 ]
Sama 1991 1320 1320 128 100 [ 063 158 ]
Subtotal (95 CI) 158 148 905 089 [ 074 108 ]
01 02 05 1 2 5 10
Favours bile acids Favours control
(Continued )
38Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Total events 85 (Bile acids) 89 (Control)
Heterogeneity Chi2 = 387 df = 5 (P = 057) I2 =00
Test for overall effect Z = 120 (P = 023)
2 TUDCA versus no treatment
Angelico 1999 816 1017 95 085 [ 045 160 ]
Subtotal (95 CI) 16 17 95 085 [ 045 160 ]
Total events 8 (Bile acids) 10 (Control)
Heterogeneity not applicable
Test for overall effect Z = 050 (P = 061)
Total (95 CI) 174 165 1000 089 [ 074 106 ]
Total events 93 (Bile acids) 99 (Control)
Heterogeneity Chi2 = 392 df = 6 (P = 069) I2 =00
Test for overall effect Z = 130 (P = 019)
01 02 05 1 2 5 10
Favours bile acids Favours control
Analysis 18 Comparison 1 Bile acids for liver-transplanted patients Outcome 8 Subgroup analysis
number of patients with acute cellular rejection according to time of start of bile acid
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 8 Subgroup analysis number of patients with acute cellular rejection according to time of start of bile acid
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 Less than three days after transplantation
Keiding 1997 3554 3248 333 097 [ 073 129 ]
Koneru 1993 316 916 89 033 [ 011 101 ]
Subtotal (95 CI) 70 64 422 084 [ 063 111 ]
Total events 38 (Bile acids) 41 (Control)
Heterogeneity Chi2 = 374 df = 1 (P = 005) I2 =73
Test for overall effect Z = 124 (P = 022)
2 Three days or more after liver transplantation
Angelico 1999 816 1017 95 085 [ 045 160 ]
01 02 05 1 2 5 10
Favours bile acids Favours control
(Continued )
39Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Barnes 1997 1728 1724 180 086 [ 058 127 ]
Fleckenstein 1998 814 916 83 102 [ 054 190 ]
Pageaux 1995 926 924 92 092 [ 044 193 ]
Sama 1991 1320 1320 128 100 [ 063 158 ]
Subtotal (95 CI) 104 101 578 092 [ 072 117 ]
Total events 55 (Bile acids) 58 (Control)
Heterogeneity Chi2 = 041 df = 4 (P = 098) I2 =00
Test for overall effect Z = 067 (P = 050)
Total (95 CI) 174 165 1000 089 [ 074 106 ]
Total events 93 (Bile acids) 99 (Control)
Heterogeneity Chi2 = 392 df = 6 (P = 069) I2 =00
Test for overall effect Z = 130 (P = 019)
01 02 05 1 2 5 10
Favours bile acids Favours control
40Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 19 Comparison 1 Bile acids for liver-transplanted patients Outcome 9 Subgroup analysis
number of patients with acute cellular rejection according to treatment duration
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 9 Subgroup analysis number of patients with acute cellular rejection according to treatment duration
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 Less than six months
Barnes 1997 1728 1724 180 086 [ 058 127 ]
Fleckenstein 1998 814 916 83 102 [ 054 190 ]
Keiding 1997 3554 3248 333 097 [ 073 129 ]
Koneru 1993 316 916 89 033 [ 011 101 ]
Pageaux 1995 926 924 92 092 [ 044 193 ]
Subtotal (95 CI) 138 128 777 087 [ 071 107 ]
Total events 72 (Bile acids) 76 (Control)
Heterogeneity Chi2 = 374 df = 4 (P = 044) I2 =00
Test for overall effect Z = 129 (P = 020)
2 Six months or more
Angelico 1999 816 1017 95 085 [ 045 160 ]
Sama 1991 1320 1320 128 100 [ 063 158 ]
Subtotal (95 CI) 36 37 223 094 [ 065 136 ]
Total events 21 (Bile acids) 23 (Control)
Heterogeneity Chi2 = 017 df = 1 (P = 068) I2 =00
Test for overall effect Z = 035 (P = 073)
Total (95 CI) 174 165 1000 089 [ 074 106 ]
Total events 93 (Bile acids) 99 (Control)
Heterogeneity Chi2 = 392 df = 6 (P = 069) I2 =00
Test for overall effect Z = 130 (P = 019)
01 02 05 1 2 5 10
Favours bile acids Favours control
41Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 110 Comparison 1 Bile acids for liver-transplanted patients Outcome 10 Number of patients
with chronic rejection at maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 10 Number of patients with chronic rejection at maximum follow-up
Study or subgroup Bile acids Placebo Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Barnes 1997 128 624 611 014 [ 002 110 ]
Fleckenstein 1998 114 116 88 114 [ 008 1663 ]
Keiding 1997 154 348 300 030 [ 003 275 ]
Total (95 CI) 96 88 1000 028 [ 008 095 ]
Total events 3 (Bile acids) 10 (Placebo)
Heterogeneity Chi2 = 148 df = 2 (P = 048) I2 =00
Test for overall effect Z = 204 (P = 0041)
0001 001 01 1 10 100 1000
Favours bile acids Favours placebo
Analysis 111 Comparison 1 Bile acids for liver-transplanted patients Outcome 11 Number of patients
with steroid-resistant rejection at maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 11 Number of patients with steroid-resistant rejection at maximum follow-up
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Barnes 1997 328 724 277 037 [ 011 127 ]
Fleckenstein 1998 314 316 103 114 [ 027 478 ]
Keiding 1997 1454 1548 583 083 [ 045 154 ]
Pageaux 1995 226 124 38 185 [ 018 1908 ]
Total (95 CI) 122 112 1000 077 [ 047 127 ]
Total events 22 (Bile acids) 26 (Control)
Heterogeneity Chi2 = 226 df = 3 (P = 052) I2 =00
Test for overall effect Z = 102 (P = 031)
001 01 1 10 100
Favours bile acids Favours placebo
42Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 112 Comparison 1 Bile acids for liver-transplanted patients Outcome 12 Serum bilirubin (mgdl)
at the end of treatment
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 12 Serum bilirubin (mgdl) at the end of treatment
Study or subgroup Bile acids Placebo Mean Difference Weight Mean Difference
N Mean(SD) N Mean(SD) IVFixed95 CI IVFixed95 CI
Fleckenstein 1998 14 319 (68) 16 059 (022) 1000 260 [ -096 616 ]
Total (95 CI) 14 16 1000 260 [ -096 616 ]
Heterogeneity not applicable
Test for overall effect Z = 143 (P = 015)
-10 -5 0 5 10
Favours bile acids Favours placebo
Analysis 113 Comparison 1 Bile acids for liver-transplanted patients Outcome 13 Number of days of
hospitalisation after liver transplantation
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 13 Number of days of hospitalisation after liver transplantation
Study or subgroup Bile acids Placebo Mean Difference Weight Mean Difference
N Mean(SD) N Mean(SD) IVFixed95 CI IVFixed95 CI
Barnes 1997 28 25 (17) 24 335 (13) 1000 -850 [ -1667 -033 ]
Total (95 CI) 28 24 1000 -850 [ -1667 -033 ]
Heterogeneity not applicable
Test for overall effect Z = 204 (P = 0041)
-100 -50 0 50 100
Favours bile acids Favours placebo
43Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 114 Comparison 1 Bile acids for liver-transplanted patients Outcome 14 Adverse events
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 14 Adverse events
Study or subgroup Bile acids Placebo Risk Ratio Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Angelico 1999 016 017 00 [ 00 00 ]
Barnes 1997 128 124 086 [ 006 1298 ]
Keiding 1997 554 548 089 [ 027 288 ]
Total (95 CI) 98 89 088 [ 030 260 ]
Total events 6 (Bile acids) 6 (Placebo)
Heterogeneity Chi2 = 000 df = 1 (P = 098) I2 =00
Test for overall effect Z = 022 (P = 082)
001 01 1 10 100
Favours bile acids Favours placebo
A P P E N D I C E S
Appendix 1 Search strategies
Data Base Date of Search Search Strategy
The Cochrane Hepato-Biliary Group Con-
trolled Trials Register
September 2009 1 rsquoliver transplantationrsquo and rsquochenodeoxy-
cholicrsquo
2 rsquoliver transplantationrsquo and rsquocholicrsquo
3 rsquoliver transplantationrsquo and rsquodeoxycholicrsquo
4 rsquoliver transplantationrsquo and rsquoglycochen-
odeoxycholicrsquo
5 rsquoliver transplantationrsquo and rsquoglycocholicrsquo
6 rsquoliver transplantationrsquo and rsquoglycodeoxy-
cholicrsquo
7 rsquoliver transplantationrsquo and rsquoglycolitho-
cholicrsquo
8 rsquoliver transplantationrsquo and rsquohyodeoxy-
cholicrsquo
9 rsquoliver transplantationrsquo and rsquolithocholicrsquo
10 rsquoliver transplantationrsquo and rsquotaurochen-
odeoxycholicrsquo
44Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
11 rsquoliver transplantationrsquo and rsquotauro-
cholicrsquo
12 rsquoliver transplantationrsquo and rsquotaurodehy-
drocholicrsquo
13 rsquoliver transplantationrsquo and rsquotau-
rodeoxycholicrsquo
14 rsquoliver transplantationrsquo and rsquotauroglyco-
cholicrsquo
15 rsquoliver transplantationrsquo and rsquotaurolitho-
cholicrsquo
16 rsquoliver transplantationrsquo and rsquotaurosel-
cholicrsquo
17 rsquoliver transplantationrsquo and rsquotaurourso-
cholicrsquo
18 rsquoliver transplantationrsquo and rsquotaurour-
sodeoxycholicrsquo
19 rsquoliver transplantationrsquo and rsquoursocholicrsquo
20 rsquoliver transplantationrsquo and rsquoursodeoxy-
cholicrsquo
The Cochrane Central Register of Con-
trolled Trials in The Cochrane Library
Issue 3 2009 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
6 3 or 4
7 5 and 6
MEDLINE September 2009 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
45Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
6 3 or 4
7 5 and 6
8 RANDOMIZED-CONTROLLED-
TRIAL ME
9 RANDOM
10 8 or 9
11 7 and 10
EMBASE September 2009 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
6 3 or 4
7 5 and 6
8 RANDOMIZED-CONTROLLED-
TRIAL ME
9 RANDOM
10 8 or 9
11 7 and 10
46Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
Science Citation Index Expanded September 2009 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
6 3 or 4
7 5 and 6
8 RANDOMIZED-CONTROLLED-
TRIAL ME
9 RANDOM
10 8 or 9
11 7 and 10
The Chinese Biomedical Database Searched from January 1980 to April 2002 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
47Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
6 3 or 4
7 5 and 6
8 RANDOMIZED-CONTROLLED-
TRIAL ME
9 RANDOM
10 8 or 9
11 7 and 10
W H A T rsquo S N E W
Last assessed as up-to-date 8 February 2010
18 September 2009 New citation required but conclusions have not
changed
This review is an updated version of a review that was
published for the first time in Issue 3 2005 of TheCochrane Library by Chen 2003b
18 September 2009 New search has been performed No new studies fulfilled the inclusion criteria
H I S T O R Y
Protocol first published Issue 3 2003
Review first published Issue 3 2005
C O N T R I B U T I O N S O F A U T H O R S
GP and VG independently performed searches of relevant databases GP validated the search selected trials for inclusion contacted
the authors of the trials performed data extraction and data analysis and drafted the systematic review VG revised the review update
CG and DS revised the review update solved discrepancies of data extraction validated data analyses and provided consultation
D E C L A R A T I O N S O F I N T E R E S T
None known
48Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
S O U R C E S O F S U P P O R T
Internal sources
bull Copenhagen Trial Unit Denmark
External sources
bull Danish Medical Research Councilrsquos Grant on Getting Research into Practice (GRIP) Denmark
D I F F E R E N C E S B E T W E E N P R O T O C O L A N D R E V I E W
We assessed the risk of bias in the included studies for another four domains that were added to the review protocol (incomplete
outcome data selective outcome reporting baseline imbalance and early stopping of trial) In general the text of the risk of bias
domains were updated following Higgins 2008 Trials were considered at low risk of bias when judged as adequate in all domains
Quasi-randomised studies observational and case-control studies were included for the report of adverse events
We performed trial sequential analysis for outcomes demonstrating a statistically significant result
I N D E X T E R M S
Medical Subject Headings (MeSH)
lowastLiver Transplantation Cholagogues and Choleretics [lowasttherapeutic use] Graft Rejection [lowastprevention amp control] Randomized Con-
trolled Trials as Topic Taurochenodeoxycholic Acid [lowasttherapeutic use] Ursodeoxycholic Acid [lowasttherapeutic use]
MeSH check words
Humans
49Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Figure 2 Methodological quality summary review authorsrsquo judgements about each methodological quality
item for each included study
9Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Following the assessment of risk of bias domains none of the seven
trials were considered to have low risk of bias that is having all
the nine domains for risk of bias assessed as adequate
Effects of interventions
We were able to include seven randomised clinical trials in this
review Six trials with 306 liver-transplanted patients compared
ursodeoxycholic acid (UDCA) with placebo or no intervention
and one trial with 29 liver-transplanted patients compared tauro-
UDCA (TUDCA) with no intervention
All-cause mortality
Five trials including 257 liver-transplanted patients reported on
all-cause mortality at the end of treatment or at maximum follow-
up Bile acids did not significantly reduce all-cause mortality (RR
085 95 CI 053 to 136) there were 26 deaths among 132
patients treated with bile acids (197) versus 29 deaths among
125 patients in the control groups (232) (Analysis 11) There
was no statistically significant heterogeneity (I2 = 141)
Four trials (Sama 1991 Barnes 1997 Keiding 1997 Fleckenstein
1998) showed that UDCA did not significantly reduce all-cause
mortality (RR 080 95 CI 049 to 130) 23 deaths among 116
patients treated with UCDA (198) versus 27 deaths among
108 patients in the control groups (250) The Angelico 1999
trial demonstrated that TUDCA was not able to reduce all-cause
mortality (RR 159 95 CI 030 to 833) there were 3 deaths
among 16 patients (188) versus 2 deaths among 17 patients
(118)
The Fleckenstein 1998 trial and the Sama 1991 trial did not report
the causes of deaths In the three other trials the deaths were
considered to be caused by infections (n = 11) hepatic failure (n =
7) abdominal bleeding (n = 3) renal failure (n = 2) multiple organ
failure (n = 2) hepatitis B virus fibrosis (n = 2) acute rejection
(n = 1) hepatic artery thrombosis (n = 1) encephalitis (n = 1)
lymphoproliferative disorder (n = 1) cerebral haemorrhage (n =
1) or other reasons (n = 6)
Worst-best case and best-worst case scenario analyses
In the worst-best case scenario analysis bile acids did not signif-
icantly reduce all-cause mortality when compared with placebo
or no intervention (RR 130 95 CI 086 to 196) 40 deaths
among 132 patients on bile acids (303) versus 29 deaths among
125 patients in the control groups (232) However all-cause
mortality was significantly reduced by bile acids in the best-worst
case scenario analysis (RR 058 95 CI 038 to 090) 26 deaths
among 132 patients (197) versus 42 deaths among 125 patients
in the control groups (336) (Analysis 12)
Subgroup analyses
We performed subgroup analyses regarding the time that bile acid
intake was started The Keiding 1997 trial started bile acid intake
less than three days after liver transplantation and demonstrated
no significant effect of UDCA on all-cause mortality (RR 124
95 CI 061 to 254) 14 deaths out of 54 patients (259)
versus 10 out of 48 control patients (208) The same effect
was noticed in the four other trials (Sama 1991 Barnes 1997
Fleckenstein 1998 Angelico 1999) which started bile acids three
days or more after liver transplantation (RR 063 95 CI 033
to 120) 12 deaths among 78 patients (154) versus 9 deaths
among 77 control patients (247) (Analysis 13) There were no
statistically significant differences between the two estimates
We also performed subgroup analyses regarding the duration of
bile acid treatment Bile acids were administrated for less than six
months in three trials (Barnes 1997 Keiding 1997 Fleckenstein
1998) and were not able to significantly decrease all-cause mor-
tality (RR 078 95 CI 045 to 138) 18 deaths in a group of
96 treated patients (188) versus 21 deaths among 88 control
patients (239) In the other two trials (Sama 1991 Angelico
1999) patients were treated with bile acids for six months or more
The treatment did not show statistically significant decrease in all-
cause mortality (RR 102 95 CI 043 to 24) 8 deaths in a
group of 36 treated patients (222) versus 8 deaths in a group
of 37 control patients (216) (Analysis 14) There were no sta-
tistically significant differences between the two estimates
Mortality related to allograft rejection
We did not find statistically significant reduction in mortality re-
lated to allograft rejection at maximum follow-up in the three tri-
als reporting cause of death (Barnes 1997 Keiding 1997 Angelico
1999) (RR 030 95 CI 001 to 712) 098 (0) versus 189
(11)) (Analysis 15) The only death due to acute rejection was
found in the placebo group of the Keiding 1997 trial
Number of liver retransplantations
Two trials (Fleckenstein 1998 Keiding 1997) including 132 liver-
transplanted patients reported the number of liver retransplan-
tations UDCA did not significantly reduce the risk of liver re-
transplantation at maximum follow-up (RR 076 95 CI 020
to 286) 368 (44) versus 464 (63)) (Analysis 16) In the
Keiding 1997 trial one patient in the UDCA group was retrans-
planted due to chronic rejection and four patients in the placebo
group were retransplanted either due to chronic rejection (three
cases) or acute rejection (one case) In the Fleckenstein 1998 trial
two patients in the UDCA group were retransplanted due to acute
rejection (one case) and chronic rejection (one case) respectively
Number of patients with acute cellular rejection
Seven trials reported the number of patients who had acute cellu-
lar rejection after liver transplantation Bile acids did not signifi-
cantly reduce the number of patients who experienced acute cel-
lular rejection (RR 089 95 CI 074 to 106) 93174(535)
versus 99165 (600)) There was no significant heterogeneity
(I2 = 0)
Six trials (Sama 1991 Koneru 1993 Pageaux 1995 Barnes 1997
10Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Keiding 1997 Fleckenstein 1998) compared UDCA with placebo
or no intervention and demonstrated that UDCA did not signifi-
cantly reduce the number of patients with acute cellular rejection
after liver transplantation (RR 089 95 CI 074 to 108 85
158 (538) versus 89148 (601)) Neither did the Angelico
1999 trial demonstrate significant reduction of the number of pa-
tients with acute cellular rejection with TUDCA (RR 085 95
CI 045 to 160) 816 (500) versus 1017 (588) (Analysis
17)
Subgroup analyses
Two trials (Koneru 1993 Keiding 1997) in which the patients
started bile acids intake less than three days after liver transplan-
tation did not demonstrate any significant reduction of the risk
of acute cellular rejection by bile acids (RR 084 95 CI 063 to
111) 3870 (543) versus 4164 (641) The other five tri-
als (Sama 1991 Pageaux 1995 Barnes 1997 Fleckenstein 1998
Angelico 1999) in which the patients were started on bile acid
intake three days or more after liver transplantation did not find
a significant reduction of the risk of acute cellular rejection by bile
acids (RR 092 95 CI 072 to 117) 55104 (529) versus 58
101 (574) (Analysis 18) There was no significant difference
between the two estimates
Bile acids did not significantly reduce the risk of acute cellular
rejection in the five trials (Koneru 1993 Pageaux 1995 Barnes
1997 Keiding 1997 Fleckenstein 1998) in which the patients
received treatment with bile acids less than six months (RR 087
95 CI 071 to 107) 72138 (522) versus 76128 (594)
Neither did bile acids in the two other trials (Sama 1991 Angelico
1999) in which the patients received bile acids for more than six
months (RR 094 95 CI 065 to 136) 2136 (583) versus
2337 (622) (Analysis 19) There were no significant difference
between the two estimates
Number of patients with chronic rejection
Three trials comparing UDCA versus placebo (Barnes 1997
Keiding 1997 Fleckenstein 1998) reported the number of patients
with chronic rejection after liver transplantation UDCA signifi-
cantly reduced the number of patients with chronic rejection in
the fixed-effect model analysis (RR 028 95 CI 008 to 095)
396 (31) versus 1088 (114) (Analysis 110) but not in the
random-effects model analysis (RR 030 95 CI 008 to 113) 3
96 (31) versus 1088 (114) There was no statistically signifi-
cant heterogeneity (I2 0) We performed trial sequential analysis
for the available data from three trials (Figure 3) with heterogene-
ity corrected required information size based on proportion of this
outcome of 12 in the control group a relative risk reduction of
50 in the intervention group at a type I error of 5 and a type
II error of 10 We obtained a required information size of 957
patients UDCA was not able to reach or break the trial sequential
monitoring boundary and only 183 out of 957 (19) patients
were randomised regarding this outcome
11Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Figure 3 Trial sequential analysis for the number of patients with chronic rejection at maximum follow-up
We calculated the heterogeneity-corrected required information size (HCRIS) based on a proportion of 12 of
the patients in the placebo group with chronic rejection at maximum follow-up a 50 risk ratio reduction in
the bile acid group an alpha of 5 a beta of 10 and a heterogeneity of 0 Only 184 patients have been
randomised reporting this outcome which is only 19 of the HCRIS of 957 patients The cumulative Z-score
crosses the conventional boundaries for P 005 but not the monitoring boundaries
Number of patients with steroid-resistant rejection
Four trials (Pageaux 1995 Barnes 1997 Keiding 1997
Fleckenstein 1998) reported the number of patients with steroid-
resistant rejection These trials demonstrated that UDCA did not
significantly reduce the number of patients with steroid-resistant
rejection when compared with placebo (22122 (18) versus 26
112 (232) (RR 077 95 CI 047 to 127) (Analysis 111)
There was no significant heterogeneity (I2 0)
Liver biochemistry
The Fleckenstein 1998 trial reported serum bilirubin levels after
a three-month-treatment period in 30 liver-transplanted patients
There was no statistically significant difference in serum bilirubin
levels between the UDCA group and the placebo group (MD 260
mgdl 95 CI -096 to 616 mgdl) (Analysis 112)
No data were available for other liver biochemical variables
Cost-effectiveness
One trial (Barnes 1997) with 52 liver-transplanted patients re-
ported the days of hospitalisation after liver transplantation
UDCA significantly decreased the number of days of hospitali-
sation when compared with placebo (MD -850 days 95 CI -
1667 to -033 days) (Analysis 113) We were not able to extract
other medical cost from the trials
Adverse events
Among all the included and excluded trials only four reported on
adverse events however adverse events only occurred in two of
the included trials (Barnes 1997 Keiding 1997) There were no
significant differences regarding adverse events (RR 088 95 CI
030 to 260) 6112 (54) versus 6105 (57) (Analysis 114)
In the Barnes 1997 trial diarrhoea was reported by two patients
(one in the UDCA group and one in the placebo group) In the
Keiding 1997 trial five UDCA patients and five placebo patients
stopped intake of the trial medicine because of diarrhoea or dif-
ficulties in swallowing the capsules The remaining included trial
by Angelico 1999 stated that no adverse events occurred during
the study period The excluded trial by Assy 2007 was the only
one reporting on a case of mild diarrhoea in one patient in the
12Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
intervention group No other excluded studies reported on adverse
events (see Table 1)
Quality of life
None of the included studies assessed quality of life as an outcome
Other subgroup analyses
We planned to perform subgroup analyses regarding the risk of
bias of trials the dosage of bile acid and any co-intervention
However none of the trials were considered to be of low risk of
bias they all used a similar dosage of bile acid and patients in all
trials received similar immunosuppressive treatment as co-inter-
ventions (steroids azathioprine and cyclosporine or tacrolimus)
after liver transplantation Therefore we were not able to perform
the planned subgroup analyses
Funnel plot asymmetry
We did not draw a funnel plot analysis due to the limited number
of trials included in the present review
D I S C U S S I O N
In the update of this review we included no new trials assessing
the use of bile acids for liver-transplanted patients The analyses
of the seven previously included trials showed that bile acids did
not significantly affect mortality acute cellular rejection steroid-
resistant rejection retransplantation or serum bilirubin Bile acids
might significantly decrease the length of hospital stay and the
number of patients with chronic rejection included in these tri-
als but more supportive evidence is needed The number of pa-
tients with chronic rejection was not significantly influenced by
bile acids when a random-effects model was used and length of
stay was assessed in one single trial Furthermore none of the trials
were considered to be of low risk of bias and few patients were en-
rolled Therefore our positive findings may be due to bias (Schulz
1995 Moher 1998 Kjaergard 2001 Wood 2008) or random er-
rors (Wetterslev 2008 Brok 2009 Thorlund 2009) On the other
hand we are not able to exclude type II errors (that is finding
no significant differences when in fact they exist) due to the low
number of participants Therefore this topic could be of potential
interest in future large randomised trials with adequate control of
bias
All-cause mortality at one year after liver transplantation is re-
ported to be about 20 (Thuluvath 2003) which we also ob-
served for the patients included in the present review According to
our subgroup analyses neither UDCA nor TUDCA significantly
decreased all-cause mortality We also performed a subgroup anal-
ysis regarding treatment duration but we were not able to find any
difference between short (less than six months) and long treatment
duration (six months or more) Thus bile acids do not seem to
have statistically significant effects in reducing all-cause mortal-
ity after liver transplantation We performed both worst-best-case
scenario and best-worst-case scenario analyses In the worst-best-
case scenario bile acids did not differ significantly from placebo or
no intervention regarding all-cause mortality However bile acids
significantly decreased all-cause mortality in the best-worst-case
scenario analysis However such an analysis is very extreme and
may not be realistic We have also found that UDCA may be able
to decrease the risk of chronic rejection in liver-transplanted pa-
tients but trial sequential analysis could not confirm this result
Due to a limited number of patients (Ioannidis 2001) we are not
able to exclude the possibility that it may be relevant to perform
placebo-controlled trials with low risk of bias on the use of bile
acids for liver-transplanted patients
We looked into the causes of deaths that were reported by the trials
and only one trial reported one death related to rejection At the
same time the number of retransplantations was 3 among 68 liver-
transplanted patients who received treatment with UDCA and 4
among 64 liver-transplanted patients who received treatment with
placebo We noticed that all patients in the included trials received
co-interventions of standard triple-drug regimens (steroids aza-
thioprine and cyclosporine or tacrolimus) which were able to
control the possible acute or chronic rejection and prevent deaths
due to allograft rejection (FK506 1994)
The assumption that UDCA might reduce the incidence of acute
graft rejection came from the findings that UDCA could regulate
major histocompatibility complex antigen expression in bile ducts
and liver endothelia and inhibit lymphocyte activity (Calmus
1990 Terasaki 1991 Perez 2009) However in the present review
bile acids did not significantly reduce the risk of acute cellular re-
jection in liver-transplanted patients Considering that acute cellu-
lar rejection is commonly found within a few days after liver trans-
plantation (Vierling 1992) some might argue that the adminis-
tration of bile acids was started too late to prevent acute cellular
rejection We performed subgroup analyses regarding the time bile
acids were started and no statistically significant difference was
found Furthermore bile acids were not able to decrease the risk
of steroid-resistant rejection Therefore the lack of effects of bile
acids does not seem to be due to a delayed start to bile acid ad-
ministration after liver transplantation However it is a possibility
that one should start bile acids intake before liver transplantation
A retrospective study found that rejection rates differed signifi-
cantly between patients with primary biliary cirrhosis treated with
or without UDCA before liver transplantation (Heathcote 1999)
One could argue whether UDCA-induced delay in transplantation
has an adverse effect on post-transplantation outcome Since we
did not find any prospective randomised clinical trials addressing
this issue further research might be needed Furthermore some
studies may provide an explanation why UDCA was not able to
prevent acute cellular rejection These studies found that UDCA
did not appear to change the expression of major histocompatibil-
ity complex class II antigens but rather major histocompatibility
complex class I antigens (Calmus 1990) The initial mechanism
of acute rejection is thought to be recognition of MHC class II
13Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
antigens by CD4+ T cells (Vierling 1992) Moreover the inhibi-
tion of the production of interleukin-2 by peripheral blood lym-
phocytes with UDCA (Heuman 1993) might be negated by the
immunosuppressive treatment after liver transplantation (van den
Berg 1998) so that UDCA is unable to demonstrate effects on
graft rejection In a recent study by Assy 2007 a significant re-
duction in the mean dose of immunosuppressive medications was
achieved in stable liver graft recipients treated with UDCA indi-
cating a possible influence of UDCA on rejection mechanisms
In accordance with previous systematic reviews (Chen 2003a
Chen 2007 Gong 2008) bile acids were not associated with the
occurrence of serious adverse events or any major occurrence of
adverse events
In summary our results do not support or refute the use of bile
acids (UDCA and TUDCA) additional to standard immunosup-
pressive treatment in liver-transplanted patients
A U T H O R S rsquo C O N C L U S I O N SImplications for practice
There seems to be no evidence to support or refute the use of bile
acids for liver-transplanted patients receiving standard immuno-
suppressive treatment
Implications for research
We need more randomised placebo-controlled clinical trials with
enough statistical power and low risk of bias to explore the poten-
tial effects of bile acids on chronic rejection and mortality in liver-
transplanted patients Such trials should also consider evaluation
of quality of life and length of hospitalisation Such trials may
consider starting bile acid and placebo interventions before liver
transplantation we were not able to identify any randomised trials
addressing this regimen Such trials ought to be reported accord-
ing to the CONSORT statement (wwwconsort-statementorg)
However before embarking on such trials the effects of bile acids
in other patient groups should be scrutinised as they may have
small or negative effects
A C K N O W L E D G E M E N T S
We thank all the patients and investigators who were involved in
the clinical trials mentioned in this review We thank Wendong
Chen for his work and contribution on the previous version of this
review We thank the staff of The Cochrane Hepato-Biliary Group
Editorial Team especially Dimitrinka Nikolova and Sarah Louise
Klingenberg for excellent collaboration and assistance during the
update of this review
Peer Reviewers Carlo Merkel Italy M Tomikawa Japan
Contact Editor Bodil Als-Nielsen Denmark
R E F E R E N C E S
References to studies included in this review
Angelico 1999 published data only
Angelico M Tisone G Baiocchi L Palmieri G Pisani F Negrini S
et alOne-year pilot study on tauroursodeoxycholic acid as an
adjuvant treatment after liver transplantation Italian Journal of
Gastroenterology and Hepatology 199931(6)462ndash8 [MEDLINE
10575563]
Barnes 1997 published data onlylowast Barnes D Talenti D Cammell G Goormastic M Farquhar L
Henderson M et alA randomized clinical trial of ursodeoxycholic
acid as adjuvant treatment to prevent liver transplant rejection
Hepatology 199726(4)853ndash7 [MEDLINE 9328304]
Barnes D Talenti D Goormastic M Farquhar L Cammell G
Henderson M et alUrsodeoxycholic acid (UDCA) reduces hepatic
allograft rejection after orthotopic liver transplantation (OLT) - a
prospective randomized placebo-controlled double-blind trial
Hepatology 199522149A
Fleckenstein 1998 published data only
Fleckenstein JF Paredes M Thuluvath PJ A prospective
randomized double-blind trial evaluating the efficacy of
ursodeoxycholic acid in prevention of liver transplant rejection
Liver Transplantation and Surgery 19984(4)276ndash9 [MEDLINE
9649640]
Keiding 1997 published data only
Keiding S Hockerstedt K Bjoro K Bondesen S Hjortrup A
Isoniemi H et alThe Nordic multicenter double-blind randomized
controlled trial of prophylactic ursodeoxycholic acid in liver
transplant patients Transplantation 199763(11)1591ndash4
[MEDLINE 9197351]
Koneru 1993 published data only
Koneru B Tint GS Wilson DJ Leevy CB Salen F Randomised
prospective trial of ursodeoxycholic acid in liver transplant
recipients Hepatology 199318336A
Pageaux 1995 published data only
Pageaux GP Blanc P Perrigault PF Navarro F Fabre JM Souche B
et alFailure of ursodeoxycholic acid to prevent acute cellular
rejection after liver transplantation Journal of Hepatology 199523
(2)119ndash22 [MEDLINE 7499781]
Sama 1991 published data only
Sama C Mazziotti A Grigioni W Morselli AM Chianura A
Stefanini GF et alUrsodeoxycholic acid administration does not
14Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
prevent rejection after OLT Journal of Hepatology 199113(Suppl
2)68
References to studies excluded from this review
Assy 2007 published data only
Assy N Adams PC Myers P Simon V Minuk GY Wall W et
alRandomized controlled trial of total immunosuppression
withdrawal in liver transplant recipients role of ursodeoxycholic
acid Transplantation 200783(12)1571ndash6 [MEDLINE
17589339]
Clavien 1996 published data only
Clavien PA Sharara AI Camargo CA Jr Harland RC Fitz JG
Evidence that ursodeoxycholic acid prevents steroid-resistant
rejection in adult liver transplantation Clinical Transplantation
199610(6 Pt 2)658ndash62 [MEDLINE 8996761]
Friman 1992 published data only
Friman S Persson H Schersten T Svanvik J Karlberg I Adjuvant
treatment with ursodeoxycholic acid reduces acute rejection after
liver transplantation Transplantation Proceedings 199224(1)
389ndash90 [MEDLINE 1539328]
Heathcote 1999 published data onlylowast Heathcote EJ Stone J Cauch-Dudek K Poupon R Chazouilleres
O Lindor KD et alEffect of pretransplantation ursodeoxycholic
acid therapy on the outcome of liver transplantation in patients
with primary biliary cirrhosis Liver Transplantation and Surgery
19995(4)269ndash74 [MEDLINE 10388499]
Henriksson 1991 published data only
Henriksson BA Persson H Friman S Wangberg B Svanvik J
Karlberg I Adjuvant ursodeoxycholic acid prevents acute rejection
in liver transplant recipients Transplantation Proceedings 199123
(3)1971 [MEDLINE 2063453]
Persson 1990 published data only
Persson H Friman S Schersten T Svanvik J Karlberg I
Ursodeoxycholic acid for prevention of acute rejection in liver
transplant recipients Lancet 1990336(8706)52ndash3 [MEDLINE
1973232]
Rafael 1995 published data only
Rafael E Duraj F Rudstrom H Wilczek H Ericzon B Effect of
ursodeoxycholic acid treatment for cholestasis in liver transplant
recipients Transplantation Proceedings 199527(6)3501ndash2
[MEDLINE 8540069]
Sama 1998 published data only
Sama C Morselli-Labate AM Grazi GL Mastroianni A Danesi G
Pianta P et alUrsodeoxycholic acid in liver transplantation effect
on cholestasis and rejection Gastroenterology 1998114(4 Suppl)
A1332
Additional references
Adams 1990
Adams DH Neuberger JM Patterns of graft rejection following
liver transplantation Journal of Hepatology 199010(1)113ndash9
[MEDLINE 2407770]
Al-Quaiz 1994
Al-Quaiz M OrsquoGrady J Tredger J Williams R Variable effect of
ursodeoxycholic acid on cyclosporin absorption after orthotopic
liver transplantation Transplant International 19947(3)190ndash4
[MEDLINE 8060468]
Armstrong 1982
Armstrong MJ Carey MC The hydrophobic-hydrophilic balance
of bile salt Inverse correlation between reverse phase high
performance liquid chromatographic mobilities and micellar
cholesterol-solubilizing capacities Journal of Lipid Research 1982
23(1)70ndash80 [MEDLINE 7057113]
Ascher 1988
Ascher NL Stock PG Baumgardner GL Payne WD Najarian JS
Infection and rejection of primary hepatic transplant in 93
consecutive patients treated with triple immunosuppressive therapy
Surgery Gynecology amp Obstetrics 1988167(6)474ndash84
[MEDLINE 3055368]
Brok 2008
Brok J Thorlund K Gluud C Wetterslev J Trial sequential
analysis reveals insufficient information size and potentially false
positive results in many meta-analyses Journal of Clinical
Epidemiology 200861(8)763ndash9 [MEDLINE 18411040]
Brok 2009
Brok J Thorlund K Wetterslev J Gluud C Apparently conclusive
meta-analysis may be inconclusive - Trial sequential analysis
adjustment of random error risk due to repetitive testing of
accumulating data in apparently conclusive neonatal meta-analysis
International Journal of Epidemiology 200938(1)298ndash303
[MEDLINE 18824466]
Calmus 1990
Calmus Y Gane P Rouger P Poupon R Hepatic expression of class
I and class II major histocompatibility complex molecules in
primary biliary cirrhosis effect of ursodeoxycholic acid Hepatology
199011(1)12ndash5 [MEDLINE 2403961]
Calmus 1992
Calmus Y Arvieux C Gane P Boucher E Nordlinger B Rouger P
et alCholestasis induces major histocompatibility complex class I
expression in hepatocytes Gastroenterology 1992102(4 Pt 1)
1371ndash7 [MEDLINE 1551542]
Chen 2003a
Chen W Gluud C Bile acids for primary sclerosing cholangitis
Cochrane Database of Systematic Reviews 2003 Issue 2 [DOI
10100214651858CD003626]
Chen 2007
Chen W Liu J Gluud C Bile acids for viral hepatitis Cochrane
Database of Systematic Reviews 2007 Issue 4 [DOI 101002
14651858CD003181pub2]
Cheng 2002
Cheng K Ashby D Smyth R Ursodeoxycholic acid for cystic
fibrosis-related liver disease Cochrane Database of Systematic
Reviews 2002 Issue 2 [DOI 10100214651858CD000222]
Corbani 2008
Corbani A Burroughs AK Intrahepatic cholestasis after liver
transplantation Clinics in Liver Disease 200812(1)111ndash29
[MEDLINE 18242500]
DeMets 1987
DeMets DL Methods for combining randomised clinical trials
strengths and limitations Statistics in Medicine 19876(3)341ndash50
[MEDLINE 3616287]
15Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
DerSimonian 1986
DerSimonian R Laird N Meta-analysis in clinical trials Controlled
Clinical Trials 19867(3)177ndash88 [MEDLINE 3802833]
Egger 1997
Egger M Davey Smith G Schneider M Minder C Bias in meta-
analysis detected by a simple graphical test BMJ (Clinical Research
Ed) 1997315(7109)629ndash34 [MEDLINE 9310563]
Ericzon 1990
Ericzon BG Eusufzai S Kubota K Einarsson K Angelin B
Characteristics of biliary lipid metabolism after liver
transplantation Hepatology 199012(5)1222ndash8 [MEDLINE
2227822]
FK506 1994
The US Multicenter FK506 Liver Study Group A comparison of
tacrolimus (FK506) and cyclosporine for immunosuppression in
liver transplantation New England Journal of Medicine 1994331
(17)1110ndash5 [MEDLINE 7523946]
Friman 1994
Friman S Svanvik J A possible role of ursodeoxycholic acid in liver
transplantation Scandinavian Journal of Gastroenterology 1994204
62ndash4 [MEDLINE 7824880]
Fuchs 1999
Fuchs M Stange EF Metabolism of bile acids In Johannes
Bircher Jean-Pierre Benhamou Neil McIntyre Mario Rizzetto
Juan Rodes editor(s) Oxford Textbook of Clinical Hepatology 2
Vol 1 Oxford Oxford University Press 1999223ndash56
Fusai 2006
Fusai G Dhaliwal P Rolando N Sabin CA Patch D Davidson BR
et alIncidence and risk factors for the development of prolonged
and severe intrahepatic cholestasis after liver transplantation Liver
Transplantation 200612(11)1626ndash33 [DOI 101002lt20870]
Gluud 2001
Gluud C Alcoholic hepatitis no glucocorticosteroids In
Leuschner U James OFW Dancygier H editor(s) Steatohepatitis
(NASH and ASH) Falk Symposium 121 Lancaster Kluwer
Academic Publisher 2001322ndash42
Gluud 2010
Gluud C Nikolova D Klingenberg SL Alexakis N Als-Nielsen B
Colli A et alCochrane Hepato-Biliary Group About The
Cochrane Collaboration (Cochrane Review Groups (CRGs))
2010 Issue 1 Art No LIVER
Gong 2008
Gong Y Huang ZB Christiansen E Gluud C Ursodeoxycholic
acid for primary biliary cirrhosis Cochrane Database of Systematic
Reviews 2008 Issue 3 [DOI 101002
14651858CD000551pub2]
Haddad 2006
Haddad EM McAlister VC Renouf E Malthaner R Kjaer MS
Gluud LL Cyclosporin versus tacrolimus for liver transplanted
patients Cochrane Database of Systematic Reviews 2006 Issue 4
[DOI 10100214651858CD005161pub2]
Heuman 1993
Heuman DM Hepatoprotective properties of ursodeoxycholic acid
Gastroenterology 1993104(6)1865ndash9 [MEDLINE 8500748]
Higgins 2008
Higgins PTJ Green S editors Cochrane Handbook for Systematic
Reviews of Interventions West Sussex England Wiley-Blackwell
2008
Hirschfield 2009
Hirschfield GM Gibbs P Griffiths WJH Adult liver
transplantation what non-specialists need to know BMJ (Clinical
Research Ed) 2009338(b1670)1321ndash7 [DOI 101136
bmjb1670]
Hussain 2002
Hussain HK Nghiem HV Imaging of hepatic transplantation
Clinics in Liver Disease 20026(1)247ndash70 [MEDLINE
11933592]
ICH-GCP 1997
International Conference on Harmonisation Expert Working
Group Code of Federal Regulations amp International Conference on
Harmonization Guidelines Media Parexel Barnett 1997
Ioannidis 2001
Ioannidis JPA Lau J Evolution of treatment effects over time
Empirical insight from recursive cumulative meta analyses
Proceedings of the National Academy of Sciences 200198(3)831ndash6
IWP 1995
International Working Party Terminology for hepatic allograft
rejection Hepatology 199522(2)648ndash54 [MEDLINE 7635435]
Kjaergard 2001
Kjaergard LL Villumsen J Gluud C Reported methodological
quality and discrepancies between large and small randomised trials
in meta-analyses Annals of Internal Medicine 2001135(11)982ndash9
[MEDLINE 11730399]
Klintmalm 1989
Klintmalm GB Nery JR Husberg BS Gonwa TA Tillery GW
Rejection in liver transplantation Hepatology 198910(6)978ndash85
[MEDLINE 2583691]
Knechtle 2009
Knechtle SJ Kwun J Unique aspects of rejection and tolerance in
liver transplantation Seminars in Liver Disease 200929(1)91ndash101
[MEDLINE 19235662]
Krams 1993
Krams SM Ascher NL Martinez OM New immunologic insights
into mechanisms of allograft rejection Gastroenterology Clinics of
North America 199318(2)374ndash7 [MEDLINE 8509176]
Lan 1983
Lan KKG DeMets DL Discrete sequential boundaries for clinical
trials Biometrika 198370659ndash63
Merion 1989
Merion RM Gorski DH Burtch GD Turcotte JG Colletti LM
Campbell DA Jr Bile refeeding after liver transplantation and
avoidance of intravenous cyclosporine Surgery 1989106(4)
604ndash9 [MEDLINE 2799635]
Moher 1998
Moher D Pham B Jones A Cook DJ Jadad AR Moher M et
alDoes quality of reports of randomised trials affect estimates of
intervention efficacy reported in meta-analyses Lancet 1998352
(9128)609ndash13 [MEDLINE 9746022]
16Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Neuberger 1999
Neuberger J Incidence timing and risk factors for acute and
chronic rejection Liver Transplantation and Surgery 19995(4 Suppl
1)S30ndashS36 [MEDLINE 10431015]
Okolicsanyi 1986
Okolicsanyi L Lirussi F Strazzabosco M Jemmolo RM Orlando R
Nassuato G et alThe effect of drugs on bile flow and composition
An overview Drugs 198631(5)430ndash48 [MEDLINE 2872047]
Palmer 1972
Palmer RH Bile acids liver injury and liver disease Archives of
Internal Medicine 1972130(4)606ndash17 [MEDLINE 4627840]
Perez 2009
Perez MJ Briz O Bile-acid-induced cell injury and protection
World Journal of Gastroenterology 200915(14)1677ndash89
[MEDLINE 19360911]
Pogue 1997
Pogue JM Yusuf S Cumulating evidence from randomized trials
Utilizing sequential monitoring boundaries for cumulative meta-
analysis Controlled Clinical Trials 199718(6)580ndash93
[MEDLINE 9408720]
Pogue 1998
Pogue J Yusuf S Overcoming the limitations of current meta-
analysis of randomised controlled trials Lancet 1998351(9095)
45ndash52 [MEDLINE 9433436]
RevMan 2008
The Nordic Cochrane Centre The Cochrane Collaboration
Review Manager (RevMan) 50 Copenhagen The Nordic
Cochrane Centre The Cochrane Collaboration 2008
Royle 2003
Royle P Milne R Literature searching for randomized controlled
trials used in Cochrane reviews rapid versus exhaustive searches
International Journal of Technology Assessment in Health Care 2003
19(4)591ndash603
Schulz 1995
Schulz KF Chalmers I Hayer R Altman D Empirical evidence of
bias JAMA 1995273(5)408ndash12 [MEDLINE 7823387]
Sharara 1995
Sharara AI Camargo CA Clavien PA Ursodeoxycholic acid
prevents steroid resistant rejection in liver transplant recipients
Gastroenterology 1995108A1168
Sholmerich 1984
Sholmerich J Becher MS Schmidt KH Schubert R Kremer B
Felhaus S et alInfluence of hydroxylation and conjugation of bile
salts on their membrane damaging properties Hepatology 19844
(4)661ndash7 [MEDLINE 6745854]
Soderdahl 1998
Soderdahl G Nowak G Duraj F Wang FH Einarsson C Ericzon
BG Ursodeoxycholic acid increased bile flow and affects bile
composition in the early postoperative phase following liver
transplantation Transplantation International 199811(Suppl 1)
S231ndashS238 [MEDLINE 9664985]
Terasaki 1991
Terasaki S Nakanuma Y Ogino H Unoura M Kobayashi K
Hepatocellular and biliary expression of HLA antigens in primary
biliary cirrhosis before and after ursodeoxycholic acid therapy
American Journal of Gastroenterology 199186(9)1194ndash9
[MEDLINE 1882800]
Thalheimer 2002
Thalheimer U Capra F Liver transplantation making the best out
of what we have Digestive Diseases and Sciences 200247(5)
945ndash53 [MEDLINE 12018919]
Thorlund 2009
Thorlund K Devereaux PJ Wetterslev J Guyatt G Ioannidis JP
Thabane L et alCan trial sequential monitoring boundaries reduce
spurious inferences from meta-analyses International Journal of
Epidemiology 200938(1)276ndash86 [MEDLINE 18824467]
Thuluvath 2003
Thuluvath PJ Yoo HY Thompson RE A model to predict survival
at one month one year and five years after liver transplantation
based on pretransplant clinical characteristics Liver Transplantation
20039(5)527ndash32 [MEDLINE 12740799]
van den Berg 1998
van den Berg AP Twilhaar WN Mesander G van Son WJ van der
Bij W Klompmaker IJ et alQuantitation of immunosuppression
by flow cytometric measurement of the capacity of T cells for
interleukin-2 production Transplantation 199865(8)1066ndash71
[MEDLINE 9583867]
Vierling 1992
Vierling J Immunologic mechanisms of hepatic allograft rejection
Seminars in Liver Disease 199212(1)16ndash27 [MEDLINE
1570548]
Wetterslev 2008
Wetterslev J Thorlund K Brok J Gluud C Trial sequential
analysis may establish when firm evidence is reached in cumulative
meta-analysis Journal of Clinical Epidemiology 200861(1)64ndash75
[MEDLINE 18083463]
Wiesner 1992
Wiesner RH Acute cellular rejection following liver
transplantation incidence risk factors and outcome in the
NIDDK Liver Transplant Database (LTD) study Gastroenterology
1992102A910
Wood 2008
Wood L Egger M Gluud LL Schulz KF Juni P Altman DG et
alEmpirical evidence of bias in treatment effect estimates in
controlled trials with different interventions and outcomes meta-
epidemiological study BMJ (Clinical Research Ed) 2008336
(7644)601ndash5 [MEDLINE 18316340]
Yoshikawa 1998
Yoshikawa M Matsui Y Kawamoto H Toyohara M Matsumura
K Yamao J et alIntragastric administration of ursodeoxycholic
acid suppresses immunoglobulin secretion by lymphocytes from
liver but not from peripheral blood spleen or Peyerrsquos patches in
mice International Journal of Immunopharmacology 199820(1-3)
29ndash38 [MEDLINE 9717080]
References to other published versions of this review
17Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Chen 2003b
Chen W Gluud C Bile acids for liver transplanted patients
Cochrane Database of Systematic Reviews 2005 Issue 3 [DOI
10100214651858CD005442]lowast Indicates the major publication for the study
18Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
C H A R A C T E R I S T I C S O F S T U D I E S
Characteristics of included studies [ordered by study ID]
Angelico 1999
Methods Study design open-label randomised one-year pilot study
Participants Country Italy
Publication language English
Inclusion criteria
- patients who underwent liver transplantation from April 1994 to December 1994
Exclusion criteria
- not mentioned
Participants
Two patients in TUDCA group and two patients in control group were excluded from
the basic information of participants by the study due to withdrawal
- TUDCA group (n = 14)
Mean age (years +- SD)
467 +- 84
Ratio of sex (malefemale) 122
Origins of liver diseases
hepatitis C cirrhosis (9) hepatitis B cirrhosis (2) hepatitis B and C cirrhosis (1) cryp-
togenic cirrhosis (2) alcoholic cirrhosis (0) Wilson cirrhosis (0)
- Control group (n = 15)
Mean age (years +- SD)
474 +- 74
Ratio of sex (malefemale) 123
Origins of liver diseases
hepatitis C cirrhosis (7) hepatitis B cirrhosis (2) hepatitis B and C cirrhosis (2) cryp-
togenic cirrhosis (2) alcoholic cirrhosis (1) Wilson cirrhosis (1)
Interventions TUDCA group
- Dose 500 mgday in two divided doses
- Route orally
- Duration the treatment was started on day 5 after transplantation and continued for
one year
Control group
- no treatment
Co-interventions all patients received standard triple-drug regimens (steroids azathio-
prine and cyclosporine or tacrolimus)
Outcomes All cause mortality
Number of patients with rejection after liver transplantation
Notes Letter was sent to the authors in September 2009 A reply with additional information
was received shortly after
Risk of bias
19Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Angelico 1999 (Continued)
Item Authorsrsquo judgement Description
Adequate sequence generation Yes Computer generated table
Allocation concealment Unclear No information provided
Blinding No Not performed
Incomplete outcome data addressed
All outcomes
Yes Withdrawal two patients from the
TUDCA group and two patients from the
placebo group Three of them died due to
transplant non-function in the first postop-
erative week and one patient was regrafted
due to thrombosis of hepatic artery
Free of selective reporting Unclear Post-transplant cholestasis and liver bio-
chemistry specified as outcomes Differ-
ence reported as not significant but no ac-
tual data given
Sample size calculation No Not reported
Intention-to-treat analysis No Not stated and not used
Baseline imbalance Unclear Not enough information provided
Early stopping of trial Unclear Not enough information provided
Barnes 1997
Methods Study design randomised placebo-controlled double-blind trial
Participants Country United States
Publication language English
Inclusion criteria
- patients aged 18 years or older who underwent liver transplantation at the Cleveland
Clinic Foundation from April 1992 through June of 1994
Exclusion criteria
- patients who were found to have cancer at surgically resected margins of the biliary
tree
- patents who underwent retransplantation
Participants
- UDCA group (n = 28)
Mean age (years +- SD)
505 +- 116
Ratio of sex (malefemale) 1810
Child class A 7
20Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Barnes 1997 (Continued)
B 13
and C 8
Origins of liver diseases Laennecrsquos cirrhosis 4
PBC 3
cryptogenic cirrhosis 6
hepatitis Ccirrhosis 4
hepatitis Bcirrhosis 3
autoimmune hepatitis with cirrhosis 3
PSC 2
other 3
- Placebo group (n = 24)
Mean age (years +- SD)
507 +- 93
Ratio of sex (malefemale) 159
Child class A 6
B 14
and C 4
Origins of liver diseases Laennecrsquos cirrhosis 9
PBC 5
cryptogenic cirrhosis 1
hepatitis Ccirrhosis 1
hepatitis Bcirrhosis 1
autoimmune hepatitis with cirrhosis 1
PSC 2
other 4
Interventions UDCA group
- Dose 10-15 mgkg body weightday in divided doses
- Route orally
- Duration immediately after intestinal transit recovery usually between postoperative
days three and five and continue for three months
Placebo group
- identical-appearing capsules administered in the same quantity and manner
Co-interventions all patients received standard triple-drug regimens (steroids azathio-
prine and cyclosporine or tacrolimus)
Outcomes All cause mortality
Number of patients with acute cellular rejection
Number of patients with chronic rejection
Number of patients with steroid-resistant rejection
Number of days of hospitalisation
Adverse events
Notes Letter was sent to the authors in September 2009 A reply with additional information
was received shortly after
Risk of bias
Item Authorsrsquo judgement Description
21Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Barnes 1997 (Continued)
Adequate sequence generation Yes Computer generated table
Allocation concealment Unclear No information provided
Blinding Yes Quote ldquorandomised to receive either
UDCA or an identical placebo capsulerdquo
Incomplete outcome data addressed
All outcomes
Yes Mean follow-up time 18 months Ten pa-
tients withdrawn from study 6 in UDCA
group and 4 in placebo group Reasons
for withdrawal were reported Four patients
died in the placebo group
Free of selective reporting Yes All expected outcomes reported
Sample size calculation Unclear The trial reported the method of sample
size calculation but the actual number of
patients needed was not reported
Intention-to-treat analysis Yes Stated and used
Baseline imbalance Unclear Not enough information provided
Early stopping of trial Unclear The number of patients needed to gain the
actual power was not reported Whether
the trial was terminated early is not clear
Fleckenstein 1998
Methods Study design prospective randomised double-blind trial
Participants Country United States
Publication language English
Inclusion criteria
- patients who underwent liver transplantation at the Johns Hopkins Hospital
Exclusion criteria
- patients who were under 18 years old undergoing repeat transplantation had primary
graft nonfunction or refused consent
Participants
- UDCA group (n = 14)
Mean age (years +- SD)
443 +- 127
Ratio of sex (malefemale) 68
Origins of liver diseases hepatitis C 6
alcohol 2
autoimmune 1
PBC 2
22Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Fleckenstein 1998 (Continued)
PSC 1
autoimmune cholangiopathy 1
hepatitis B 1
- Placebo group (n = 16)
Mean age (years +- SD)
496 +- 109
Ratio of sex (malefemale) 124
Origins of liver diseases hepatitis C 3
alcohol 3
autoimmune 3
PBC 1
PSC 2
cryptogenic 2
hepatitis B 1
alpha1-antitrypsin deficiency 1
Interventions UDCA group
- Dose 15 mgkg body weightday in divided doses
- Route orally
- Duration immediately after intestinal transit recovery usually between postoperative
days three and five and continue for three months
Placebo group
- Identical-appearing capsules administered in the same quantity and manner
Co-interventions all patients received standard triple-drug regimens (steroids azathio-
prine and cyclosporine or tacrolimus)
Outcomes All cause mortality
Number with retransplantation
Number of patients with acute cellular rejection
Number of patients with chronic rejection
Serum bilirubin levels at the end of treatment
Notes Follow-up time nine months
Letter was sent to the authors in September 2009 No reply was received
Risk of bias
Item Authorsrsquo judgement Description
Adequate sequence generation Unclear No information provided
Allocation concealment Unclear No information provided
Blinding Yes Method of blinding not described but
probably adequate
Incomplete outcome data addressed
All outcomes
Yes Withdrawal one patient from the UDCA
group and two patients from the placebo
group because of capsule size
23Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Fleckenstein 1998 (Continued)
Free of selective reporting Unclear Outcomes were not completely described
Sample size calculation No Not reported
Intention-to-treat analysis Yes Quote ldquoThree patients withdrew after in-
clusionThey were included in the statis-
tical analysisrdquo
Baseline imbalance Unclear Not enough information provided
Early stopping of trial Unclear Not enough information provided
Keiding 1997
Methods Study design prospective randomised placebo-controlled multicenter study
Participants Country Denmark Finland Norway and Sweden
Publication language English
Inclusion criteria
- patients who underwent liver transplantation in Denmark Finland Norway and Swe-
den from September 1 1992 to May 31 1994
Exclusion criteria
- patients with malignant diseases
Participants
The age of the children ranged from 0 to 13 years (median 15) and the age of adults
ranged from 14 to 59 years old (median 44) MaleFemale ratio was 96 for children and
4344 for adults
- UDCA group (n = 54)
Origins of liver diseases
paracetamol intoxication 1 hepatitis B 1 autoimmune hepatitis 0 biliary atresia 2
metabolic diseases 7 neonatal hepatitis 2 PBC 13 post hepatitis cirrhosis 8 PSC 3
cryptogenic cirrhosis 7 alcoholic cirrhosis 2 other reasons 8
- Placebo group (n = 48)
Origins of liver diseases paracetamol intoxication 1 hepatitis B 0 autoimmune hepatitis
1 biliary atresia 3 metabolic diseases 11 neonatal hepatitis 0 PBC 7 post hepatitis
cirrhosis 5 PSC 7 cryptogenic cirrhosis 2 alcoholic cirrhosis 6 other reasons 5
Interventions UDCA group
- Dose 15 mgkg body weightday in two or three divided doses
- Route orally
- Duration immediately after intestinal transit recovery usually between postoperative
days three and five and continue for three months
Placebo group
- Identical-appearing capsules administered in the same quantity and manner
Co-interventions all patients received standard triple-drug regimens (steroids azathio-
prine and cyclosporine or tacrolimus)
24Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Keiding 1997 (Continued)
Outcomes All cause mortality
Number of deaths related to rejection
Number of patients with acute cellular rejection
Number of patients with chronic rejection
Number of patients with steroid-resistant rejection
Adverse events
Notes Letter was sent to the authors in September 2009 No reply was received
Risk of bias
Item Authorsrsquo judgement Description
Adequate sequence generation Unclear Patients were randomised at a ratio of 11
Allocation concealment Yes Quote ldquo The allocation was performed in
blocks of 10 patients using the sealed serial
envelope methodrdquo
Blinding Yes Quote ldquoThe UDCA and the placebo cap-
sules had identical appearance and tasterdquo
Incomplete outcome data addressed
All outcomes
Yes Follow-up time 12 months Five UDCA
patients and five placebo patients withdrew
from study Reasons were reported
Free of selective reporting Unclear Insufficient information
Sample size calculation Yes Performed and allowed for a difference in
the incidence of at least one episode of
acute rejection of 50 between the treat-
ment and placebo groups with 90 statisti-
cal power and a significance level of P value
less than 005 The calculated sample size
was 80 patients
Intention-to-treat analysis Yes Stated and used
Baseline imbalance Yes The study seems to be free of baseline im-
balance
Early stopping of trial Yes Study attained the pre-specified sample
size
25Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Koneru 1993
Methods Study design randomised controlled trial
Participants Country United States
Publication language English
Inclusion criteria
- patients who underwent liver transplantation
Exclusion criteria
- not mentioned
Participants
- UDCA group (n = 16)
Mean age (years +- SD)
no information
Ratio of sex (malefemale) no information
Origins of liver diseases
no information
- Control group (n = 16)
Mean age (years +- SD)
no information
Ratio of sex (malefemale) no information
Origins of liver diseases
no information
Interventions UDCA group
- Dose 900 mgday
- Route orally
- Duration immediately after intestinal transit recovery usually between postoperative
days three and five and continue for three months
Control group
- no treatment
Co-interventions all patients received standard triple-drug regimens (steroids azathio-
prine and cyclosporine)
Outcomes Number of patients with retransplantation due to rejection
Number of patients with rejection episodes
Notes Abstract
Letter was sent to the authors in September 2009 No reply was received
Risk of bias
Item Authorsrsquo judgement Description
Adequate sequence generation Unclear No information provided
Allocation concealment Unclear No information provided
Blinding No Not performed
26Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Koneru 1993 (Continued)
Incomplete outcome data addressed
All outcomes
Unclear The study gives the impression that there
were no withdrawals but this was not ex-
plicitly stated
Free of selective reporting Unclear Insufficient information provided
Sample size calculation No Not performed
Intention-to-treat analysis Unclear No information provided
Baseline imbalance Unclear Not enough information provided
Early stopping of trial Unclear Not enough information provided
Pageaux 1995
Methods Study design double-blind randomised study
Participants Country France
Publication language English
Inclusion criteria
- patients who underwent liver transplantation
Exclusion criteria
- not mentioned
Participants
- UDCA group (n=26)
Mean age (years +- SD)
47 +- 10
Ratio of sex (malefemale) 179
Origins of liver diseases alcoholic cirrhosis 14
post-hepatic B cirrhosis 2
post-hepatitis C cirrhosis 4
PBC 2
liver cancer 2
fulminant hepatitis 1
miscellaneous 1
- Placebo group (n = 24)
Mean age (years +- SD)
51+- 9
Ratio of sex (malefemale) 159
Origins of liver diseases alcoholic cirrhosis 10
post-hepatic B cirrhosis 0
post-hepatic C cirrhosis 6
PBC 3
liver cancer 4
fulminant hepatitis 0
miscellaneous 1
27Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Pageaux 1995 (Continued)
Interventions UDCA group
- Dose 600 mgday in three divided doses
- Route orally
- Duration immediately after intestinal transit recovery usually between postoperative
days three and five and continue for two months
Placebo group
- identical-appearing capsules administered in the same quantity and manner
Co-interventions all patients received standard triple-drug regimens (steroids azathio-
prine and cyclosporine or tacrolimus)
Outcomes Number of patients with acute cellular rejection
Number of patients with steroid-resistant rejection
Notes Letter was sent to the authors in September 2009 No reply was received
Risk of bias
Item Authorsrsquo judgement Description
Adequate sequence generation Unclear No information provided
Allocation concealment Unclear No information provided
Blinding Unclear Method of blinding not described
Incomplete outcome data addressed
All outcomes
Yes Five patients died from non-immunologi-
cal causes before the end of the first month
and were excluded from the study Reasons
were reported
Free of selective reporting Unclear Not enough information provided
Sample size calculation No Not performed
Intention-to-treat analysis No Not stated and not used
Baseline imbalance Unclear Not enough information provided
Early stopping of trial Unclear Not enough information provided
Sama 1991
Methods Study design randomised controlled trial
Participants Country Italy
Publication language English
Inclusion criteria
28Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Sama 1991 (Continued)
- patients who underwent liver transplantation
Exclusion criteria
- not mentioned
Participants
- UDCA group (n = 20)
Mean age (years +- SD)
no information
Ratio of sex (malefemale) no information
Origins of liver diseases
no information
- Control group (n = 20)
Mean age (years +- SD)
no information
Ratio of sex (malefemale) no information
Origins of liver diseases
no information
Interventions UDCA group
- Dose 600 mgday in two divided doses
- Route orally
- Duration immediately after intestinal transit recovery usually between postoperative
day five and day seven and continue for six months
Control group
- no treatment
Co-interventions all patients received standard immunosuppressive treatment (steroids
and cyclosporine)
Outcomes All cause mortality
Number of patients with acute cellular rejection
Notes Abstract
Letter was sent to the authors in September 2009 No reply was received
Risk of bias
Item Authorsrsquo judgement Description
Adequate sequence generation Unclear A randomisation list was performed before
patients were admitted to the trial (infor-
mation from principal author)
Allocation concealment Unclear No information provided
Blinding Unclear The principle author provided information
that the study was made according to a
single-blind randomised protocol The pri-
mary outcome was the occurrence of biopsy
proven rejection episodes The pathologists
were blind but the patients were not
29Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Sama 1991 (Continued)
Incomplete outcome data addressed
All outcomes
Unclear Five patients from the UDCA group and
six patients from the placebo group were
excluded Reasons for exclusion were not
fully stated
Free of selective reporting No Data about survival of patients were not
adequately reported
Sample size calculation No Not performed
Intention-to-treat analysis No Not stated and not used
Baseline imbalance Unclear Basic characteristics of patients not re-
ported
Early stopping of trial Unclear Not enough information provided
UDCA = ursodeoxycholic acid
TUDCA = tauroursodeoxycholic acid
PBC = primary biliary cirrhosis
PSC = primary sclerosing cholangitis
OKT3 = anti-CD3 monoclonal antibody
Characteristics of excluded studies [ordered by study ID]
Assy 2007 A randomised controlled trial that included only recipients of liver transplantation with stable graft function and
no episodes of rejection for at least 2 years that were then offered total immunosuppression withdrawal Fourteen
patients received UDCA (15 mgkg body weightday) and 12 received placebo Rejection occurred in 43 and
75 of patients respectively (no significant difference) None developed chronic rejection After follow-up two
patients were free of immunosuppression 80 were steroid free and 50 were able to reduce their dose of
cyclosporine
Clavien 1996 Case series Fifty consecutive liver-transplanted patients were treated with a standard cyclosporine immunosup-
pressive regimen Twenty three of the 43 survivors developed an episode of rejection and UDCA (10 mgkg
weightday) was initiated Only one patient had a second episode of rejection
Friman 1992 Observational study Thirty-three liver-transplanted patients received 10 mg UDCAkg body weightday for
median of 10 months (range four to 21 months) Eight historical liver-transplanted patients served as control
group The rejection incidence was significantly lower in the patients who received the treatment with UDCA
Biochemistry one month after transplantation demonstrated significantly lower average values of aminotrans-
ferases and alkaline phosphatases in patients treated with UDCA than in the control group
30Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
Heathcote 1999 Observational study From 1987 to 1996 37 UDCA treated and 53 placebo treated patients with primary biliary
cirrhosis were referred for transplantation Posttransplantation survival rates at one month were 939 in the
UDCA group and 884 in the placebo group and one year survival rates were 903 and 784 respectively
(no significant differences) However rejection (type not defined - a secondary outcome measure) occurred
significantly less often in the UDCA group (429) than in placebo group (688)
Henriksson 1991 Observational study All patients in this study were given sequential quadruple immunosuppression with anti-
lymphocyte globulin azathioprine steroids and cyclosporine All patients with primary graft function (n = 11)
were treated with 10 mg UDCAkg body weightday starting during the first postoperative week Patients who
received liver transplantation in the first 6 months of 1989 (n = 8) served as controls In the control group one
patient died after 9 months with chronic graft dysfunction and six patients had rejection episodes during the
first postoperative month All patients in the UDCA group were alive without rejection episodes
Persson 1990 Observational study All 11 adult patients transplanted between August 1989 and January 1990 with primary
graft function were treated with 10 mg UDCA kg body weightday Eight patients transplanted during the first
half of 1989 served as control UDCA was started during the first postoperative week and the treatment was
continued for six months All patients in the UDCA treated group survived with satisfactory graft function In
the control group six patients had at least one rejection episode needing treatment during the first postoperative
month
Rafael 1995 Observational study Seventeen patients who underwent liver transplantation between February 1990 and April
1993 and developed biliary complications after transplantation were retrospectively analysed regarding treatment
with UDCA UDCA was given in a dose of 500 to 1000 mgday Ten patients were treated for at least one year while
seven patients were treated for 14 to 250 days UDCA significantly improved gammaglutamyl transpeptidase in
liver graft recipients with biliary complications There was also a trend towards improvement in serum bilirubin
and alanine transaminase values
Sama 1998 Observational study Thirty-four patients who underwent liver transplantation between January 1995 and June
1996 were included in the study Seventeen were treated with UDCA 10 mgkg body weightday during 6
months while 17 served as controls on the basis of having undergone liver transplantation closest to UDCA
patients A significant decrease in serum bilirubin levels was observed in UDCA patients There was a significantly
higher incidence of recurrent hepatitis in the control group
UDCA ursodeoxycholic acid
31Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
D A T A A N D A N A L Y S E S
Comparison 1 Bile acids for liver-transplanted patients
Outcome or subgroup titleNo of
studies
No of
participants Statistical method Effect size
1 All-cause mortality at maximum
follow-up
5 257 Risk Ratio (M-H Fixed 95 CI) 085 [053 136]
11 UDCA versus placebo or
no treatment
4 224 Risk Ratio (M-H Fixed 95 CI) 080 [049 130]
12 TUDCA versus no
treatment
1 33 Risk Ratio (M-H Fixed 95 CI) 159 [030 833]
2 All-cause mortality worst-best
case and best-worst case
scenarios
5 Risk Ratio (M-H Fixed 95 CI) Subtotals only
21 Worst-best case scenario 5 257 Risk Ratio (M-H Fixed 95 CI) 130 [086 196]
22 Best-worst case scenario 5 257 Risk Ratio (M-H Fixed 95 CI) 058 [038 090]
3 Subgroup analyses all-cause
mortality at maximum
follow-up according to time of
start of bile acids
5 257 Risk Ratio (M-H Fixed 95 CI) 085 [053 136]
31 Less than three days after
transplantation
1 102 Risk Ratio (M-H Fixed 95 CI) 124 [061 254]
32 Three days or more after
transplantation
4 155 Risk Ratio (M-H Fixed 95 CI) 063 [033 120]
4 Subgroup analyses all cause
mortality at maximum
follow-up according to
treatment duration
5 257 Risk Ratio (M-H Fixed 95 CI) 085 [053 136]
41 Less than six months 3 184 Risk Ratio (M-H Fixed 95 CI) 078 [045 138]
42 Six months or more 2 73 Risk Ratio (M-H Fixed 95 CI) 102 [043 240]
5 Number of deaths related
to rejection at maximum
follow-up
1 102 Risk Ratio (M-H Fixed 95 CI) 030 [001 712]
51 UDCA versus placebo 1 102 Risk Ratio (M-H Fixed 95 CI) 030 [001 712]
6 Number of retransplantations at
maximum follow-up
2 132 Risk Ratio (M-H Fixed 95 CI) 076 [020 286]
7 Number of patients with acute
cellular rejection at maximum
follow-up
7 339 Risk Ratio (M-H Fixed 95 CI) 089 [074 106]
71 UDCA versus placebo or
no treatment
6 306 Risk Ratio (M-H Fixed 95 CI) 089 [074 108]
72 TUDCA versus no
treatment
1 33 Risk Ratio (M-H Fixed 95 CI) 085 [045 160]
8 Subgroup analysis number of
patients with acute cellular
rejection according to time of
start of bile acid
7 339 Risk Ratio (M-H Fixed 95 CI) 089 [074 106]
32Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
81 Less than three days after
transplantation
2 134 Risk Ratio (M-H Fixed 95 CI) 084 [063 111]
82 Three days or more after
liver transplantation
5 205 Risk Ratio (M-H Fixed 95 CI) 092 [072 117]
9 Subgroup analysis number
of patients with acute
cellular rejection according to
treatment duration
7 339 Risk Ratio (M-H Fixed 95 CI) 089 [074 106]
91 Less than six months 5 266 Risk Ratio (M-H Fixed 95 CI) 087 [071 107]
92 Six months or more 2 73 Risk Ratio (M-H Fixed 95 CI) 094 [065 136]
10 Number of patients with
chronic rejection at maximum
follow-up
3 184 Risk Ratio (M-H Fixed 95 CI) 028 [008 095]
11 Number of patients with
steroid-resistant rejection at
maximum follow-up
4 234 Risk Ratio (M-H Fixed 95 CI) 077 [047 127]
12 Serum bilirubin (mgdl) at the
end of treatment
1 30 Mean Difference (IV Fixed 95 CI) 26 [-096 616]
13 Number of days of
hospitalisation after liver
transplantation
1 52 Mean Difference (IV Fixed 95 CI) -85 [-1667 -033]
14 Adverse events 3 187 Risk Ratio (M-H Fixed 95 CI) 088 [030 260]
Analysis 11 Comparison 1 Bile acids for liver-transplanted patients Outcome 1 All-cause mortality at
maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 1 All-cause mortality at maximum follow-up
Study or subgroup Favours bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 UDCA versus placebo or no treatment
Barnes 1997 228 724 253 024 [ 006 107 ]
Fleckenstein 1998 214 416 125 057 [ 012 266 ]
Keiding 1997 1454 1048 355 124 [ 061 254 ]
Sama 1991 520 620 201 083 [ 030 229 ]
Subtotal (95 CI) 116 108 935 080 [ 049 130 ]
Total events 23 (Favours bile acids) 27 (Control)
Heterogeneity Chi2 = 416 df = 3 (P = 025) I2 =28
Test for overall effect Z = 091 (P = 036)
01 02 05 1 2 5 10
Favours bile acids Favours control
(Continued )
33Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Favours bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
2 TUDCA versus no treatment
Angelico 1999 316 217 65 159 [ 030 833 ]
Subtotal (95 CI) 16 17 65 159 [ 030 833 ]
Total events 3 (Favours bile acids) 2 (Control)
Heterogeneity not applicable
Test for overall effect Z = 055 (P = 058)
Total (95 CI) 132 125 1000 085 [ 053 136 ]
Total events 26 (Favours bile acids) 29 (Control)
Heterogeneity Chi2 = 466 df = 4 (P = 032) I2 =14
Test for overall effect Z = 069 (P = 049)
01 02 05 1 2 5 10
Favours bile acids Favours control
Analysis 12 Comparison 1 Bile acids for liver-transplanted patients Outcome 2 All-cause mortality worst-
best case and best-worst case scenarios
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 2 All-cause mortality worst-best case and best-worst case scenarios
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 Worst-best case scenario
Angelico 1999 516 217 65 266 [ 060 1180 ]
Barnes 1997 828 724 253 098 [ 042 230 ]
Fleckenstein 1998 314 416 125 086 [ 023 319 ]
Keiding 1997 1954 1048 355 169 [ 087 327 ]
Sama 1991 520 620 201 083 [ 030 229 ]
Subtotal (95 CI) 132 125 1000 130 [ 086 196 ]
Total events 40 (Bile acids) 29 (Control)
Heterogeneity Chi2 = 303 df = 4 (P = 055) I2 =00
Test for overall effect Z = 123 (P = 022)
2 Best-worst case scenario
005 02 1 5 20
Favours bile acids Favours control
(Continued )
34Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Angelico 1999 316 417 90 080 [ 021 302 ]
Barnes 1997 228 1124 274 016 [ 004 063 ]
Fleckenstein 1998 214 616 130 038 [ 009 159 ]
Keiding 1997 1454 1548 368 083 [ 045 154 ]
Sama 1991 520 620 139 083 [ 030 229 ]
Subtotal (95 CI) 132 125 1000 058 [ 038 090 ]
Total events 26 (Bile acids) 42 (Control)
Heterogeneity Chi2 = 567 df = 4 (P = 023) I2 =29
Test for overall effect Z = 247 (P = 0014)
005 02 1 5 20
Favours bile acids Favours control
Analysis 13 Comparison 1 Bile acids for liver-transplanted patients Outcome 3 Subgroup analyses all-
cause mortality at maximum follow-up according to time of start of bile acids
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 3 Subgroup analyses all-cause mortality at maximum follow-up according to time of start of bile acids
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 Less than three days after transplantation
Keiding 1997 1454 1048 355 124 [ 061 254 ]
Subtotal (95 CI) 54 48 355 124 [ 061 254 ]
Total events 14 (Bile acids) 10 (Control)
Heterogeneity not applicable
Test for overall effect Z = 060 (P = 055)
2 Three days or more after transplantation
Angelico 1999 316 217 65 159 [ 030 833 ]
Barnes 1997 228 724 253 024 [ 006 107 ]
Fleckenstein 1998 214 416 125 057 [ 012 266 ]
Sama 1991 520 620 201 083 [ 030 229 ]
005 02 1 5 20
Favours bile acids Favours control
(Continued )
35Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Subtotal (95 CI) 78 77 645 063 [ 033 120 ]
Total events 12 (Bile acids) 19 (Control)
Heterogeneity Chi2 = 310 df = 3 (P = 038) I2 =3
Test for overall effect Z = 141 (P = 016)
Total (95 CI) 132 125 1000 085 [ 053 136 ]
Total events 26 (Bile acids) 29 (Control)
Heterogeneity Chi2 = 466 df = 4 (P = 032) I2 =14
Test for overall effect Z = 069 (P = 049)
005 02 1 5 20
Favours bile acids Favours control
Analysis 14 Comparison 1 Bile acids for liver-transplanted patients Outcome 4 Subgroup analyses all
cause mortality at maximum follow-up according to treatment duration
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 4 Subgroup analyses all cause mortality at maximum follow-up according to treatment duration
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 Less than six months
Barnes 1997 228 724 253 024 [ 006 107 ]
Fleckenstein 1998 214 416 125 057 [ 012 266 ]
Keiding 1997 1454 1048 355 124 [ 061 254 ]
Subtotal (95 CI) 96 88 734 078 [ 045 138 ]
Total events 18 (Bile acids) 21 (Control)
Heterogeneity Chi2 = 417 df = 2 (P = 012) I2 =52
Test for overall effect Z = 084 (P = 040)
2 Six months or more
Angelico 1999 316 217 65 159 [ 030 833 ]
Sama 1991 520 620 201 083 [ 030 229 ]
Subtotal (95 CI) 36 37 266 102 [ 043 240 ]
Total events 8 (Bile acids) 8 (Control)
Heterogeneity Chi2 = 043 df = 1 (P = 051) I2 =00
005 02 1 5 20
Favours bile acids Favours control
(Continued )
36Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Test for overall effect Z = 004 (P = 097)
Total (95 CI) 132 125 1000 085 [ 053 136 ]
Total events 26 (Bile acids) 29 (Control)
Heterogeneity Chi2 = 466 df = 4 (P = 032) I2 =14
Test for overall effect Z = 069 (P = 049)
005 02 1 5 20
Favours bile acids Favours control
Analysis 15 Comparison 1 Bile acids for liver-transplanted patients Outcome 5 Number of deaths related
to rejection at maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 5 Number of deaths related to rejection at maximum follow-up
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 UDCA versus placebo
Keiding 1997 054 148 1000 030 [ 001 712 ]
Total (95 CI) 54 48 1000 030 [ 001 712 ]
Total events 0 (Bile acids) 1 (Control)
Heterogeneity not applicable
Test for overall effect Z = 075 (P = 045)
0001 001 01 1 10 100 1000
Favours bile acids Favours control
37Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 16 Comparison 1 Bile acids for liver-transplanted patients Outcome 6 Number of
retransplantations at maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 6 Number of retransplantations at maximum follow-up
Study or subgroup Bile acids Placebo Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Fleckenstein 1998 214 016 100 567 [ 029 10891 ]
Keiding 1997 154 448 900 022 [ 003 192 ]
Total (95 CI) 68 64 1000 076 [ 020 286 ]
Total events 3 (Bile acids) 4 (Placebo)
Heterogeneity Chi2 = 303 df = 1 (P = 008) I2 =67
Test for overall effect Z = 040 (P = 069)
0001 001 01 1 10 100 1000
Favours bile acids Favours placebo
Analysis 17 Comparison 1 Bile acids for liver-transplanted patients Outcome 7 Number of patients with
acute cellular rejection at maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 7 Number of patients with acute cellular rejection at maximum follow-up
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 UDCA versus placebo or no treatment
Barnes 1997 1728 1724 180 086 [ 058 127 ]
Fleckenstein 1998 814 916 83 102 [ 054 190 ]
Keiding 1997 3554 3248 333 097 [ 073 129 ]
Koneru 1993 316 916 89 033 [ 011 101 ]
Pageaux 1995 926 924 92 092 [ 044 193 ]
Sama 1991 1320 1320 128 100 [ 063 158 ]
Subtotal (95 CI) 158 148 905 089 [ 074 108 ]
01 02 05 1 2 5 10
Favours bile acids Favours control
(Continued )
38Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Total events 85 (Bile acids) 89 (Control)
Heterogeneity Chi2 = 387 df = 5 (P = 057) I2 =00
Test for overall effect Z = 120 (P = 023)
2 TUDCA versus no treatment
Angelico 1999 816 1017 95 085 [ 045 160 ]
Subtotal (95 CI) 16 17 95 085 [ 045 160 ]
Total events 8 (Bile acids) 10 (Control)
Heterogeneity not applicable
Test for overall effect Z = 050 (P = 061)
Total (95 CI) 174 165 1000 089 [ 074 106 ]
Total events 93 (Bile acids) 99 (Control)
Heterogeneity Chi2 = 392 df = 6 (P = 069) I2 =00
Test for overall effect Z = 130 (P = 019)
01 02 05 1 2 5 10
Favours bile acids Favours control
Analysis 18 Comparison 1 Bile acids for liver-transplanted patients Outcome 8 Subgroup analysis
number of patients with acute cellular rejection according to time of start of bile acid
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 8 Subgroup analysis number of patients with acute cellular rejection according to time of start of bile acid
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 Less than three days after transplantation
Keiding 1997 3554 3248 333 097 [ 073 129 ]
Koneru 1993 316 916 89 033 [ 011 101 ]
Subtotal (95 CI) 70 64 422 084 [ 063 111 ]
Total events 38 (Bile acids) 41 (Control)
Heterogeneity Chi2 = 374 df = 1 (P = 005) I2 =73
Test for overall effect Z = 124 (P = 022)
2 Three days or more after liver transplantation
Angelico 1999 816 1017 95 085 [ 045 160 ]
01 02 05 1 2 5 10
Favours bile acids Favours control
(Continued )
39Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Barnes 1997 1728 1724 180 086 [ 058 127 ]
Fleckenstein 1998 814 916 83 102 [ 054 190 ]
Pageaux 1995 926 924 92 092 [ 044 193 ]
Sama 1991 1320 1320 128 100 [ 063 158 ]
Subtotal (95 CI) 104 101 578 092 [ 072 117 ]
Total events 55 (Bile acids) 58 (Control)
Heterogeneity Chi2 = 041 df = 4 (P = 098) I2 =00
Test for overall effect Z = 067 (P = 050)
Total (95 CI) 174 165 1000 089 [ 074 106 ]
Total events 93 (Bile acids) 99 (Control)
Heterogeneity Chi2 = 392 df = 6 (P = 069) I2 =00
Test for overall effect Z = 130 (P = 019)
01 02 05 1 2 5 10
Favours bile acids Favours control
40Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 19 Comparison 1 Bile acids for liver-transplanted patients Outcome 9 Subgroup analysis
number of patients with acute cellular rejection according to treatment duration
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 9 Subgroup analysis number of patients with acute cellular rejection according to treatment duration
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 Less than six months
Barnes 1997 1728 1724 180 086 [ 058 127 ]
Fleckenstein 1998 814 916 83 102 [ 054 190 ]
Keiding 1997 3554 3248 333 097 [ 073 129 ]
Koneru 1993 316 916 89 033 [ 011 101 ]
Pageaux 1995 926 924 92 092 [ 044 193 ]
Subtotal (95 CI) 138 128 777 087 [ 071 107 ]
Total events 72 (Bile acids) 76 (Control)
Heterogeneity Chi2 = 374 df = 4 (P = 044) I2 =00
Test for overall effect Z = 129 (P = 020)
2 Six months or more
Angelico 1999 816 1017 95 085 [ 045 160 ]
Sama 1991 1320 1320 128 100 [ 063 158 ]
Subtotal (95 CI) 36 37 223 094 [ 065 136 ]
Total events 21 (Bile acids) 23 (Control)
Heterogeneity Chi2 = 017 df = 1 (P = 068) I2 =00
Test for overall effect Z = 035 (P = 073)
Total (95 CI) 174 165 1000 089 [ 074 106 ]
Total events 93 (Bile acids) 99 (Control)
Heterogeneity Chi2 = 392 df = 6 (P = 069) I2 =00
Test for overall effect Z = 130 (P = 019)
01 02 05 1 2 5 10
Favours bile acids Favours control
41Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 110 Comparison 1 Bile acids for liver-transplanted patients Outcome 10 Number of patients
with chronic rejection at maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 10 Number of patients with chronic rejection at maximum follow-up
Study or subgroup Bile acids Placebo Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Barnes 1997 128 624 611 014 [ 002 110 ]
Fleckenstein 1998 114 116 88 114 [ 008 1663 ]
Keiding 1997 154 348 300 030 [ 003 275 ]
Total (95 CI) 96 88 1000 028 [ 008 095 ]
Total events 3 (Bile acids) 10 (Placebo)
Heterogeneity Chi2 = 148 df = 2 (P = 048) I2 =00
Test for overall effect Z = 204 (P = 0041)
0001 001 01 1 10 100 1000
Favours bile acids Favours placebo
Analysis 111 Comparison 1 Bile acids for liver-transplanted patients Outcome 11 Number of patients
with steroid-resistant rejection at maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 11 Number of patients with steroid-resistant rejection at maximum follow-up
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Barnes 1997 328 724 277 037 [ 011 127 ]
Fleckenstein 1998 314 316 103 114 [ 027 478 ]
Keiding 1997 1454 1548 583 083 [ 045 154 ]
Pageaux 1995 226 124 38 185 [ 018 1908 ]
Total (95 CI) 122 112 1000 077 [ 047 127 ]
Total events 22 (Bile acids) 26 (Control)
Heterogeneity Chi2 = 226 df = 3 (P = 052) I2 =00
Test for overall effect Z = 102 (P = 031)
001 01 1 10 100
Favours bile acids Favours placebo
42Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 112 Comparison 1 Bile acids for liver-transplanted patients Outcome 12 Serum bilirubin (mgdl)
at the end of treatment
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 12 Serum bilirubin (mgdl) at the end of treatment
Study or subgroup Bile acids Placebo Mean Difference Weight Mean Difference
N Mean(SD) N Mean(SD) IVFixed95 CI IVFixed95 CI
Fleckenstein 1998 14 319 (68) 16 059 (022) 1000 260 [ -096 616 ]
Total (95 CI) 14 16 1000 260 [ -096 616 ]
Heterogeneity not applicable
Test for overall effect Z = 143 (P = 015)
-10 -5 0 5 10
Favours bile acids Favours placebo
Analysis 113 Comparison 1 Bile acids for liver-transplanted patients Outcome 13 Number of days of
hospitalisation after liver transplantation
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 13 Number of days of hospitalisation after liver transplantation
Study or subgroup Bile acids Placebo Mean Difference Weight Mean Difference
N Mean(SD) N Mean(SD) IVFixed95 CI IVFixed95 CI
Barnes 1997 28 25 (17) 24 335 (13) 1000 -850 [ -1667 -033 ]
Total (95 CI) 28 24 1000 -850 [ -1667 -033 ]
Heterogeneity not applicable
Test for overall effect Z = 204 (P = 0041)
-100 -50 0 50 100
Favours bile acids Favours placebo
43Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 114 Comparison 1 Bile acids for liver-transplanted patients Outcome 14 Adverse events
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 14 Adverse events
Study or subgroup Bile acids Placebo Risk Ratio Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Angelico 1999 016 017 00 [ 00 00 ]
Barnes 1997 128 124 086 [ 006 1298 ]
Keiding 1997 554 548 089 [ 027 288 ]
Total (95 CI) 98 89 088 [ 030 260 ]
Total events 6 (Bile acids) 6 (Placebo)
Heterogeneity Chi2 = 000 df = 1 (P = 098) I2 =00
Test for overall effect Z = 022 (P = 082)
001 01 1 10 100
Favours bile acids Favours placebo
A P P E N D I C E S
Appendix 1 Search strategies
Data Base Date of Search Search Strategy
The Cochrane Hepato-Biliary Group Con-
trolled Trials Register
September 2009 1 rsquoliver transplantationrsquo and rsquochenodeoxy-
cholicrsquo
2 rsquoliver transplantationrsquo and rsquocholicrsquo
3 rsquoliver transplantationrsquo and rsquodeoxycholicrsquo
4 rsquoliver transplantationrsquo and rsquoglycochen-
odeoxycholicrsquo
5 rsquoliver transplantationrsquo and rsquoglycocholicrsquo
6 rsquoliver transplantationrsquo and rsquoglycodeoxy-
cholicrsquo
7 rsquoliver transplantationrsquo and rsquoglycolitho-
cholicrsquo
8 rsquoliver transplantationrsquo and rsquohyodeoxy-
cholicrsquo
9 rsquoliver transplantationrsquo and rsquolithocholicrsquo
10 rsquoliver transplantationrsquo and rsquotaurochen-
odeoxycholicrsquo
44Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
11 rsquoliver transplantationrsquo and rsquotauro-
cholicrsquo
12 rsquoliver transplantationrsquo and rsquotaurodehy-
drocholicrsquo
13 rsquoliver transplantationrsquo and rsquotau-
rodeoxycholicrsquo
14 rsquoliver transplantationrsquo and rsquotauroglyco-
cholicrsquo
15 rsquoliver transplantationrsquo and rsquotaurolitho-
cholicrsquo
16 rsquoliver transplantationrsquo and rsquotaurosel-
cholicrsquo
17 rsquoliver transplantationrsquo and rsquotaurourso-
cholicrsquo
18 rsquoliver transplantationrsquo and rsquotaurour-
sodeoxycholicrsquo
19 rsquoliver transplantationrsquo and rsquoursocholicrsquo
20 rsquoliver transplantationrsquo and rsquoursodeoxy-
cholicrsquo
The Cochrane Central Register of Con-
trolled Trials in The Cochrane Library
Issue 3 2009 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
6 3 or 4
7 5 and 6
MEDLINE September 2009 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
45Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
6 3 or 4
7 5 and 6
8 RANDOMIZED-CONTROLLED-
TRIAL ME
9 RANDOM
10 8 or 9
11 7 and 10
EMBASE September 2009 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
6 3 or 4
7 5 and 6
8 RANDOMIZED-CONTROLLED-
TRIAL ME
9 RANDOM
10 8 or 9
11 7 and 10
46Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
Science Citation Index Expanded September 2009 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
6 3 or 4
7 5 and 6
8 RANDOMIZED-CONTROLLED-
TRIAL ME
9 RANDOM
10 8 or 9
11 7 and 10
The Chinese Biomedical Database Searched from January 1980 to April 2002 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
47Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
6 3 or 4
7 5 and 6
8 RANDOMIZED-CONTROLLED-
TRIAL ME
9 RANDOM
10 8 or 9
11 7 and 10
W H A T rsquo S N E W
Last assessed as up-to-date 8 February 2010
18 September 2009 New citation required but conclusions have not
changed
This review is an updated version of a review that was
published for the first time in Issue 3 2005 of TheCochrane Library by Chen 2003b
18 September 2009 New search has been performed No new studies fulfilled the inclusion criteria
H I S T O R Y
Protocol first published Issue 3 2003
Review first published Issue 3 2005
C O N T R I B U T I O N S O F A U T H O R S
GP and VG independently performed searches of relevant databases GP validated the search selected trials for inclusion contacted
the authors of the trials performed data extraction and data analysis and drafted the systematic review VG revised the review update
CG and DS revised the review update solved discrepancies of data extraction validated data analyses and provided consultation
D E C L A R A T I O N S O F I N T E R E S T
None known
48Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
S O U R C E S O F S U P P O R T
Internal sources
bull Copenhagen Trial Unit Denmark
External sources
bull Danish Medical Research Councilrsquos Grant on Getting Research into Practice (GRIP) Denmark
D I F F E R E N C E S B E T W E E N P R O T O C O L A N D R E V I E W
We assessed the risk of bias in the included studies for another four domains that were added to the review protocol (incomplete
outcome data selective outcome reporting baseline imbalance and early stopping of trial) In general the text of the risk of bias
domains were updated following Higgins 2008 Trials were considered at low risk of bias when judged as adequate in all domains
Quasi-randomised studies observational and case-control studies were included for the report of adverse events
We performed trial sequential analysis for outcomes demonstrating a statistically significant result
I N D E X T E R M S
Medical Subject Headings (MeSH)
lowastLiver Transplantation Cholagogues and Choleretics [lowasttherapeutic use] Graft Rejection [lowastprevention amp control] Randomized Con-
trolled Trials as Topic Taurochenodeoxycholic Acid [lowasttherapeutic use] Ursodeoxycholic Acid [lowasttherapeutic use]
MeSH check words
Humans
49Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Following the assessment of risk of bias domains none of the seven
trials were considered to have low risk of bias that is having all
the nine domains for risk of bias assessed as adequate
Effects of interventions
We were able to include seven randomised clinical trials in this
review Six trials with 306 liver-transplanted patients compared
ursodeoxycholic acid (UDCA) with placebo or no intervention
and one trial with 29 liver-transplanted patients compared tauro-
UDCA (TUDCA) with no intervention
All-cause mortality
Five trials including 257 liver-transplanted patients reported on
all-cause mortality at the end of treatment or at maximum follow-
up Bile acids did not significantly reduce all-cause mortality (RR
085 95 CI 053 to 136) there were 26 deaths among 132
patients treated with bile acids (197) versus 29 deaths among
125 patients in the control groups (232) (Analysis 11) There
was no statistically significant heterogeneity (I2 = 141)
Four trials (Sama 1991 Barnes 1997 Keiding 1997 Fleckenstein
1998) showed that UDCA did not significantly reduce all-cause
mortality (RR 080 95 CI 049 to 130) 23 deaths among 116
patients treated with UCDA (198) versus 27 deaths among
108 patients in the control groups (250) The Angelico 1999
trial demonstrated that TUDCA was not able to reduce all-cause
mortality (RR 159 95 CI 030 to 833) there were 3 deaths
among 16 patients (188) versus 2 deaths among 17 patients
(118)
The Fleckenstein 1998 trial and the Sama 1991 trial did not report
the causes of deaths In the three other trials the deaths were
considered to be caused by infections (n = 11) hepatic failure (n =
7) abdominal bleeding (n = 3) renal failure (n = 2) multiple organ
failure (n = 2) hepatitis B virus fibrosis (n = 2) acute rejection
(n = 1) hepatic artery thrombosis (n = 1) encephalitis (n = 1)
lymphoproliferative disorder (n = 1) cerebral haemorrhage (n =
1) or other reasons (n = 6)
Worst-best case and best-worst case scenario analyses
In the worst-best case scenario analysis bile acids did not signif-
icantly reduce all-cause mortality when compared with placebo
or no intervention (RR 130 95 CI 086 to 196) 40 deaths
among 132 patients on bile acids (303) versus 29 deaths among
125 patients in the control groups (232) However all-cause
mortality was significantly reduced by bile acids in the best-worst
case scenario analysis (RR 058 95 CI 038 to 090) 26 deaths
among 132 patients (197) versus 42 deaths among 125 patients
in the control groups (336) (Analysis 12)
Subgroup analyses
We performed subgroup analyses regarding the time that bile acid
intake was started The Keiding 1997 trial started bile acid intake
less than three days after liver transplantation and demonstrated
no significant effect of UDCA on all-cause mortality (RR 124
95 CI 061 to 254) 14 deaths out of 54 patients (259)
versus 10 out of 48 control patients (208) The same effect
was noticed in the four other trials (Sama 1991 Barnes 1997
Fleckenstein 1998 Angelico 1999) which started bile acids three
days or more after liver transplantation (RR 063 95 CI 033
to 120) 12 deaths among 78 patients (154) versus 9 deaths
among 77 control patients (247) (Analysis 13) There were no
statistically significant differences between the two estimates
We also performed subgroup analyses regarding the duration of
bile acid treatment Bile acids were administrated for less than six
months in three trials (Barnes 1997 Keiding 1997 Fleckenstein
1998) and were not able to significantly decrease all-cause mor-
tality (RR 078 95 CI 045 to 138) 18 deaths in a group of
96 treated patients (188) versus 21 deaths among 88 control
patients (239) In the other two trials (Sama 1991 Angelico
1999) patients were treated with bile acids for six months or more
The treatment did not show statistically significant decrease in all-
cause mortality (RR 102 95 CI 043 to 24) 8 deaths in a
group of 36 treated patients (222) versus 8 deaths in a group
of 37 control patients (216) (Analysis 14) There were no sta-
tistically significant differences between the two estimates
Mortality related to allograft rejection
We did not find statistically significant reduction in mortality re-
lated to allograft rejection at maximum follow-up in the three tri-
als reporting cause of death (Barnes 1997 Keiding 1997 Angelico
1999) (RR 030 95 CI 001 to 712) 098 (0) versus 189
(11)) (Analysis 15) The only death due to acute rejection was
found in the placebo group of the Keiding 1997 trial
Number of liver retransplantations
Two trials (Fleckenstein 1998 Keiding 1997) including 132 liver-
transplanted patients reported the number of liver retransplan-
tations UDCA did not significantly reduce the risk of liver re-
transplantation at maximum follow-up (RR 076 95 CI 020
to 286) 368 (44) versus 464 (63)) (Analysis 16) In the
Keiding 1997 trial one patient in the UDCA group was retrans-
planted due to chronic rejection and four patients in the placebo
group were retransplanted either due to chronic rejection (three
cases) or acute rejection (one case) In the Fleckenstein 1998 trial
two patients in the UDCA group were retransplanted due to acute
rejection (one case) and chronic rejection (one case) respectively
Number of patients with acute cellular rejection
Seven trials reported the number of patients who had acute cellu-
lar rejection after liver transplantation Bile acids did not signifi-
cantly reduce the number of patients who experienced acute cel-
lular rejection (RR 089 95 CI 074 to 106) 93174(535)
versus 99165 (600)) There was no significant heterogeneity
(I2 = 0)
Six trials (Sama 1991 Koneru 1993 Pageaux 1995 Barnes 1997
10Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Keiding 1997 Fleckenstein 1998) compared UDCA with placebo
or no intervention and demonstrated that UDCA did not signifi-
cantly reduce the number of patients with acute cellular rejection
after liver transplantation (RR 089 95 CI 074 to 108 85
158 (538) versus 89148 (601)) Neither did the Angelico
1999 trial demonstrate significant reduction of the number of pa-
tients with acute cellular rejection with TUDCA (RR 085 95
CI 045 to 160) 816 (500) versus 1017 (588) (Analysis
17)
Subgroup analyses
Two trials (Koneru 1993 Keiding 1997) in which the patients
started bile acids intake less than three days after liver transplan-
tation did not demonstrate any significant reduction of the risk
of acute cellular rejection by bile acids (RR 084 95 CI 063 to
111) 3870 (543) versus 4164 (641) The other five tri-
als (Sama 1991 Pageaux 1995 Barnes 1997 Fleckenstein 1998
Angelico 1999) in which the patients were started on bile acid
intake three days or more after liver transplantation did not find
a significant reduction of the risk of acute cellular rejection by bile
acids (RR 092 95 CI 072 to 117) 55104 (529) versus 58
101 (574) (Analysis 18) There was no significant difference
between the two estimates
Bile acids did not significantly reduce the risk of acute cellular
rejection in the five trials (Koneru 1993 Pageaux 1995 Barnes
1997 Keiding 1997 Fleckenstein 1998) in which the patients
received treatment with bile acids less than six months (RR 087
95 CI 071 to 107) 72138 (522) versus 76128 (594)
Neither did bile acids in the two other trials (Sama 1991 Angelico
1999) in which the patients received bile acids for more than six
months (RR 094 95 CI 065 to 136) 2136 (583) versus
2337 (622) (Analysis 19) There were no significant difference
between the two estimates
Number of patients with chronic rejection
Three trials comparing UDCA versus placebo (Barnes 1997
Keiding 1997 Fleckenstein 1998) reported the number of patients
with chronic rejection after liver transplantation UDCA signifi-
cantly reduced the number of patients with chronic rejection in
the fixed-effect model analysis (RR 028 95 CI 008 to 095)
396 (31) versus 1088 (114) (Analysis 110) but not in the
random-effects model analysis (RR 030 95 CI 008 to 113) 3
96 (31) versus 1088 (114) There was no statistically signifi-
cant heterogeneity (I2 0) We performed trial sequential analysis
for the available data from three trials (Figure 3) with heterogene-
ity corrected required information size based on proportion of this
outcome of 12 in the control group a relative risk reduction of
50 in the intervention group at a type I error of 5 and a type
II error of 10 We obtained a required information size of 957
patients UDCA was not able to reach or break the trial sequential
monitoring boundary and only 183 out of 957 (19) patients
were randomised regarding this outcome
11Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Figure 3 Trial sequential analysis for the number of patients with chronic rejection at maximum follow-up
We calculated the heterogeneity-corrected required information size (HCRIS) based on a proportion of 12 of
the patients in the placebo group with chronic rejection at maximum follow-up a 50 risk ratio reduction in
the bile acid group an alpha of 5 a beta of 10 and a heterogeneity of 0 Only 184 patients have been
randomised reporting this outcome which is only 19 of the HCRIS of 957 patients The cumulative Z-score
crosses the conventional boundaries for P 005 but not the monitoring boundaries
Number of patients with steroid-resistant rejection
Four trials (Pageaux 1995 Barnes 1997 Keiding 1997
Fleckenstein 1998) reported the number of patients with steroid-
resistant rejection These trials demonstrated that UDCA did not
significantly reduce the number of patients with steroid-resistant
rejection when compared with placebo (22122 (18) versus 26
112 (232) (RR 077 95 CI 047 to 127) (Analysis 111)
There was no significant heterogeneity (I2 0)
Liver biochemistry
The Fleckenstein 1998 trial reported serum bilirubin levels after
a three-month-treatment period in 30 liver-transplanted patients
There was no statistically significant difference in serum bilirubin
levels between the UDCA group and the placebo group (MD 260
mgdl 95 CI -096 to 616 mgdl) (Analysis 112)
No data were available for other liver biochemical variables
Cost-effectiveness
One trial (Barnes 1997) with 52 liver-transplanted patients re-
ported the days of hospitalisation after liver transplantation
UDCA significantly decreased the number of days of hospitali-
sation when compared with placebo (MD -850 days 95 CI -
1667 to -033 days) (Analysis 113) We were not able to extract
other medical cost from the trials
Adverse events
Among all the included and excluded trials only four reported on
adverse events however adverse events only occurred in two of
the included trials (Barnes 1997 Keiding 1997) There were no
significant differences regarding adverse events (RR 088 95 CI
030 to 260) 6112 (54) versus 6105 (57) (Analysis 114)
In the Barnes 1997 trial diarrhoea was reported by two patients
(one in the UDCA group and one in the placebo group) In the
Keiding 1997 trial five UDCA patients and five placebo patients
stopped intake of the trial medicine because of diarrhoea or dif-
ficulties in swallowing the capsules The remaining included trial
by Angelico 1999 stated that no adverse events occurred during
the study period The excluded trial by Assy 2007 was the only
one reporting on a case of mild diarrhoea in one patient in the
12Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
intervention group No other excluded studies reported on adverse
events (see Table 1)
Quality of life
None of the included studies assessed quality of life as an outcome
Other subgroup analyses
We planned to perform subgroup analyses regarding the risk of
bias of trials the dosage of bile acid and any co-intervention
However none of the trials were considered to be of low risk of
bias they all used a similar dosage of bile acid and patients in all
trials received similar immunosuppressive treatment as co-inter-
ventions (steroids azathioprine and cyclosporine or tacrolimus)
after liver transplantation Therefore we were not able to perform
the planned subgroup analyses
Funnel plot asymmetry
We did not draw a funnel plot analysis due to the limited number
of trials included in the present review
D I S C U S S I O N
In the update of this review we included no new trials assessing
the use of bile acids for liver-transplanted patients The analyses
of the seven previously included trials showed that bile acids did
not significantly affect mortality acute cellular rejection steroid-
resistant rejection retransplantation or serum bilirubin Bile acids
might significantly decrease the length of hospital stay and the
number of patients with chronic rejection included in these tri-
als but more supportive evidence is needed The number of pa-
tients with chronic rejection was not significantly influenced by
bile acids when a random-effects model was used and length of
stay was assessed in one single trial Furthermore none of the trials
were considered to be of low risk of bias and few patients were en-
rolled Therefore our positive findings may be due to bias (Schulz
1995 Moher 1998 Kjaergard 2001 Wood 2008) or random er-
rors (Wetterslev 2008 Brok 2009 Thorlund 2009) On the other
hand we are not able to exclude type II errors (that is finding
no significant differences when in fact they exist) due to the low
number of participants Therefore this topic could be of potential
interest in future large randomised trials with adequate control of
bias
All-cause mortality at one year after liver transplantation is re-
ported to be about 20 (Thuluvath 2003) which we also ob-
served for the patients included in the present review According to
our subgroup analyses neither UDCA nor TUDCA significantly
decreased all-cause mortality We also performed a subgroup anal-
ysis regarding treatment duration but we were not able to find any
difference between short (less than six months) and long treatment
duration (six months or more) Thus bile acids do not seem to
have statistically significant effects in reducing all-cause mortal-
ity after liver transplantation We performed both worst-best-case
scenario and best-worst-case scenario analyses In the worst-best-
case scenario bile acids did not differ significantly from placebo or
no intervention regarding all-cause mortality However bile acids
significantly decreased all-cause mortality in the best-worst-case
scenario analysis However such an analysis is very extreme and
may not be realistic We have also found that UDCA may be able
to decrease the risk of chronic rejection in liver-transplanted pa-
tients but trial sequential analysis could not confirm this result
Due to a limited number of patients (Ioannidis 2001) we are not
able to exclude the possibility that it may be relevant to perform
placebo-controlled trials with low risk of bias on the use of bile
acids for liver-transplanted patients
We looked into the causes of deaths that were reported by the trials
and only one trial reported one death related to rejection At the
same time the number of retransplantations was 3 among 68 liver-
transplanted patients who received treatment with UDCA and 4
among 64 liver-transplanted patients who received treatment with
placebo We noticed that all patients in the included trials received
co-interventions of standard triple-drug regimens (steroids aza-
thioprine and cyclosporine or tacrolimus) which were able to
control the possible acute or chronic rejection and prevent deaths
due to allograft rejection (FK506 1994)
The assumption that UDCA might reduce the incidence of acute
graft rejection came from the findings that UDCA could regulate
major histocompatibility complex antigen expression in bile ducts
and liver endothelia and inhibit lymphocyte activity (Calmus
1990 Terasaki 1991 Perez 2009) However in the present review
bile acids did not significantly reduce the risk of acute cellular re-
jection in liver-transplanted patients Considering that acute cellu-
lar rejection is commonly found within a few days after liver trans-
plantation (Vierling 1992) some might argue that the adminis-
tration of bile acids was started too late to prevent acute cellular
rejection We performed subgroup analyses regarding the time bile
acids were started and no statistically significant difference was
found Furthermore bile acids were not able to decrease the risk
of steroid-resistant rejection Therefore the lack of effects of bile
acids does not seem to be due to a delayed start to bile acid ad-
ministration after liver transplantation However it is a possibility
that one should start bile acids intake before liver transplantation
A retrospective study found that rejection rates differed signifi-
cantly between patients with primary biliary cirrhosis treated with
or without UDCA before liver transplantation (Heathcote 1999)
One could argue whether UDCA-induced delay in transplantation
has an adverse effect on post-transplantation outcome Since we
did not find any prospective randomised clinical trials addressing
this issue further research might be needed Furthermore some
studies may provide an explanation why UDCA was not able to
prevent acute cellular rejection These studies found that UDCA
did not appear to change the expression of major histocompatibil-
ity complex class II antigens but rather major histocompatibility
complex class I antigens (Calmus 1990) The initial mechanism
of acute rejection is thought to be recognition of MHC class II
13Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
antigens by CD4+ T cells (Vierling 1992) Moreover the inhibi-
tion of the production of interleukin-2 by peripheral blood lym-
phocytes with UDCA (Heuman 1993) might be negated by the
immunosuppressive treatment after liver transplantation (van den
Berg 1998) so that UDCA is unable to demonstrate effects on
graft rejection In a recent study by Assy 2007 a significant re-
duction in the mean dose of immunosuppressive medications was
achieved in stable liver graft recipients treated with UDCA indi-
cating a possible influence of UDCA on rejection mechanisms
In accordance with previous systematic reviews (Chen 2003a
Chen 2007 Gong 2008) bile acids were not associated with the
occurrence of serious adverse events or any major occurrence of
adverse events
In summary our results do not support or refute the use of bile
acids (UDCA and TUDCA) additional to standard immunosup-
pressive treatment in liver-transplanted patients
A U T H O R S rsquo C O N C L U S I O N SImplications for practice
There seems to be no evidence to support or refute the use of bile
acids for liver-transplanted patients receiving standard immuno-
suppressive treatment
Implications for research
We need more randomised placebo-controlled clinical trials with
enough statistical power and low risk of bias to explore the poten-
tial effects of bile acids on chronic rejection and mortality in liver-
transplanted patients Such trials should also consider evaluation
of quality of life and length of hospitalisation Such trials may
consider starting bile acid and placebo interventions before liver
transplantation we were not able to identify any randomised trials
addressing this regimen Such trials ought to be reported accord-
ing to the CONSORT statement (wwwconsort-statementorg)
However before embarking on such trials the effects of bile acids
in other patient groups should be scrutinised as they may have
small or negative effects
A C K N O W L E D G E M E N T S
We thank all the patients and investigators who were involved in
the clinical trials mentioned in this review We thank Wendong
Chen for his work and contribution on the previous version of this
review We thank the staff of The Cochrane Hepato-Biliary Group
Editorial Team especially Dimitrinka Nikolova and Sarah Louise
Klingenberg for excellent collaboration and assistance during the
update of this review
Peer Reviewers Carlo Merkel Italy M Tomikawa Japan
Contact Editor Bodil Als-Nielsen Denmark
R E F E R E N C E S
References to studies included in this review
Angelico 1999 published data only
Angelico M Tisone G Baiocchi L Palmieri G Pisani F Negrini S
et alOne-year pilot study on tauroursodeoxycholic acid as an
adjuvant treatment after liver transplantation Italian Journal of
Gastroenterology and Hepatology 199931(6)462ndash8 [MEDLINE
10575563]
Barnes 1997 published data onlylowast Barnes D Talenti D Cammell G Goormastic M Farquhar L
Henderson M et alA randomized clinical trial of ursodeoxycholic
acid as adjuvant treatment to prevent liver transplant rejection
Hepatology 199726(4)853ndash7 [MEDLINE 9328304]
Barnes D Talenti D Goormastic M Farquhar L Cammell G
Henderson M et alUrsodeoxycholic acid (UDCA) reduces hepatic
allograft rejection after orthotopic liver transplantation (OLT) - a
prospective randomized placebo-controlled double-blind trial
Hepatology 199522149A
Fleckenstein 1998 published data only
Fleckenstein JF Paredes M Thuluvath PJ A prospective
randomized double-blind trial evaluating the efficacy of
ursodeoxycholic acid in prevention of liver transplant rejection
Liver Transplantation and Surgery 19984(4)276ndash9 [MEDLINE
9649640]
Keiding 1997 published data only
Keiding S Hockerstedt K Bjoro K Bondesen S Hjortrup A
Isoniemi H et alThe Nordic multicenter double-blind randomized
controlled trial of prophylactic ursodeoxycholic acid in liver
transplant patients Transplantation 199763(11)1591ndash4
[MEDLINE 9197351]
Koneru 1993 published data only
Koneru B Tint GS Wilson DJ Leevy CB Salen F Randomised
prospective trial of ursodeoxycholic acid in liver transplant
recipients Hepatology 199318336A
Pageaux 1995 published data only
Pageaux GP Blanc P Perrigault PF Navarro F Fabre JM Souche B
et alFailure of ursodeoxycholic acid to prevent acute cellular
rejection after liver transplantation Journal of Hepatology 199523
(2)119ndash22 [MEDLINE 7499781]
Sama 1991 published data only
Sama C Mazziotti A Grigioni W Morselli AM Chianura A
Stefanini GF et alUrsodeoxycholic acid administration does not
14Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
prevent rejection after OLT Journal of Hepatology 199113(Suppl
2)68
References to studies excluded from this review
Assy 2007 published data only
Assy N Adams PC Myers P Simon V Minuk GY Wall W et
alRandomized controlled trial of total immunosuppression
withdrawal in liver transplant recipients role of ursodeoxycholic
acid Transplantation 200783(12)1571ndash6 [MEDLINE
17589339]
Clavien 1996 published data only
Clavien PA Sharara AI Camargo CA Jr Harland RC Fitz JG
Evidence that ursodeoxycholic acid prevents steroid-resistant
rejection in adult liver transplantation Clinical Transplantation
199610(6 Pt 2)658ndash62 [MEDLINE 8996761]
Friman 1992 published data only
Friman S Persson H Schersten T Svanvik J Karlberg I Adjuvant
treatment with ursodeoxycholic acid reduces acute rejection after
liver transplantation Transplantation Proceedings 199224(1)
389ndash90 [MEDLINE 1539328]
Heathcote 1999 published data onlylowast Heathcote EJ Stone J Cauch-Dudek K Poupon R Chazouilleres
O Lindor KD et alEffect of pretransplantation ursodeoxycholic
acid therapy on the outcome of liver transplantation in patients
with primary biliary cirrhosis Liver Transplantation and Surgery
19995(4)269ndash74 [MEDLINE 10388499]
Henriksson 1991 published data only
Henriksson BA Persson H Friman S Wangberg B Svanvik J
Karlberg I Adjuvant ursodeoxycholic acid prevents acute rejection
in liver transplant recipients Transplantation Proceedings 199123
(3)1971 [MEDLINE 2063453]
Persson 1990 published data only
Persson H Friman S Schersten T Svanvik J Karlberg I
Ursodeoxycholic acid for prevention of acute rejection in liver
transplant recipients Lancet 1990336(8706)52ndash3 [MEDLINE
1973232]
Rafael 1995 published data only
Rafael E Duraj F Rudstrom H Wilczek H Ericzon B Effect of
ursodeoxycholic acid treatment for cholestasis in liver transplant
recipients Transplantation Proceedings 199527(6)3501ndash2
[MEDLINE 8540069]
Sama 1998 published data only
Sama C Morselli-Labate AM Grazi GL Mastroianni A Danesi G
Pianta P et alUrsodeoxycholic acid in liver transplantation effect
on cholestasis and rejection Gastroenterology 1998114(4 Suppl)
A1332
Additional references
Adams 1990
Adams DH Neuberger JM Patterns of graft rejection following
liver transplantation Journal of Hepatology 199010(1)113ndash9
[MEDLINE 2407770]
Al-Quaiz 1994
Al-Quaiz M OrsquoGrady J Tredger J Williams R Variable effect of
ursodeoxycholic acid on cyclosporin absorption after orthotopic
liver transplantation Transplant International 19947(3)190ndash4
[MEDLINE 8060468]
Armstrong 1982
Armstrong MJ Carey MC The hydrophobic-hydrophilic balance
of bile salt Inverse correlation between reverse phase high
performance liquid chromatographic mobilities and micellar
cholesterol-solubilizing capacities Journal of Lipid Research 1982
23(1)70ndash80 [MEDLINE 7057113]
Ascher 1988
Ascher NL Stock PG Baumgardner GL Payne WD Najarian JS
Infection and rejection of primary hepatic transplant in 93
consecutive patients treated with triple immunosuppressive therapy
Surgery Gynecology amp Obstetrics 1988167(6)474ndash84
[MEDLINE 3055368]
Brok 2008
Brok J Thorlund K Gluud C Wetterslev J Trial sequential
analysis reveals insufficient information size and potentially false
positive results in many meta-analyses Journal of Clinical
Epidemiology 200861(8)763ndash9 [MEDLINE 18411040]
Brok 2009
Brok J Thorlund K Wetterslev J Gluud C Apparently conclusive
meta-analysis may be inconclusive - Trial sequential analysis
adjustment of random error risk due to repetitive testing of
accumulating data in apparently conclusive neonatal meta-analysis
International Journal of Epidemiology 200938(1)298ndash303
[MEDLINE 18824466]
Calmus 1990
Calmus Y Gane P Rouger P Poupon R Hepatic expression of class
I and class II major histocompatibility complex molecules in
primary biliary cirrhosis effect of ursodeoxycholic acid Hepatology
199011(1)12ndash5 [MEDLINE 2403961]
Calmus 1992
Calmus Y Arvieux C Gane P Boucher E Nordlinger B Rouger P
et alCholestasis induces major histocompatibility complex class I
expression in hepatocytes Gastroenterology 1992102(4 Pt 1)
1371ndash7 [MEDLINE 1551542]
Chen 2003a
Chen W Gluud C Bile acids for primary sclerosing cholangitis
Cochrane Database of Systematic Reviews 2003 Issue 2 [DOI
10100214651858CD003626]
Chen 2007
Chen W Liu J Gluud C Bile acids for viral hepatitis Cochrane
Database of Systematic Reviews 2007 Issue 4 [DOI 101002
14651858CD003181pub2]
Cheng 2002
Cheng K Ashby D Smyth R Ursodeoxycholic acid for cystic
fibrosis-related liver disease Cochrane Database of Systematic
Reviews 2002 Issue 2 [DOI 10100214651858CD000222]
Corbani 2008
Corbani A Burroughs AK Intrahepatic cholestasis after liver
transplantation Clinics in Liver Disease 200812(1)111ndash29
[MEDLINE 18242500]
DeMets 1987
DeMets DL Methods for combining randomised clinical trials
strengths and limitations Statistics in Medicine 19876(3)341ndash50
[MEDLINE 3616287]
15Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
DerSimonian 1986
DerSimonian R Laird N Meta-analysis in clinical trials Controlled
Clinical Trials 19867(3)177ndash88 [MEDLINE 3802833]
Egger 1997
Egger M Davey Smith G Schneider M Minder C Bias in meta-
analysis detected by a simple graphical test BMJ (Clinical Research
Ed) 1997315(7109)629ndash34 [MEDLINE 9310563]
Ericzon 1990
Ericzon BG Eusufzai S Kubota K Einarsson K Angelin B
Characteristics of biliary lipid metabolism after liver
transplantation Hepatology 199012(5)1222ndash8 [MEDLINE
2227822]
FK506 1994
The US Multicenter FK506 Liver Study Group A comparison of
tacrolimus (FK506) and cyclosporine for immunosuppression in
liver transplantation New England Journal of Medicine 1994331
(17)1110ndash5 [MEDLINE 7523946]
Friman 1994
Friman S Svanvik J A possible role of ursodeoxycholic acid in liver
transplantation Scandinavian Journal of Gastroenterology 1994204
62ndash4 [MEDLINE 7824880]
Fuchs 1999
Fuchs M Stange EF Metabolism of bile acids In Johannes
Bircher Jean-Pierre Benhamou Neil McIntyre Mario Rizzetto
Juan Rodes editor(s) Oxford Textbook of Clinical Hepatology 2
Vol 1 Oxford Oxford University Press 1999223ndash56
Fusai 2006
Fusai G Dhaliwal P Rolando N Sabin CA Patch D Davidson BR
et alIncidence and risk factors for the development of prolonged
and severe intrahepatic cholestasis after liver transplantation Liver
Transplantation 200612(11)1626ndash33 [DOI 101002lt20870]
Gluud 2001
Gluud C Alcoholic hepatitis no glucocorticosteroids In
Leuschner U James OFW Dancygier H editor(s) Steatohepatitis
(NASH and ASH) Falk Symposium 121 Lancaster Kluwer
Academic Publisher 2001322ndash42
Gluud 2010
Gluud C Nikolova D Klingenberg SL Alexakis N Als-Nielsen B
Colli A et alCochrane Hepato-Biliary Group About The
Cochrane Collaboration (Cochrane Review Groups (CRGs))
2010 Issue 1 Art No LIVER
Gong 2008
Gong Y Huang ZB Christiansen E Gluud C Ursodeoxycholic
acid for primary biliary cirrhosis Cochrane Database of Systematic
Reviews 2008 Issue 3 [DOI 101002
14651858CD000551pub2]
Haddad 2006
Haddad EM McAlister VC Renouf E Malthaner R Kjaer MS
Gluud LL Cyclosporin versus tacrolimus for liver transplanted
patients Cochrane Database of Systematic Reviews 2006 Issue 4
[DOI 10100214651858CD005161pub2]
Heuman 1993
Heuman DM Hepatoprotective properties of ursodeoxycholic acid
Gastroenterology 1993104(6)1865ndash9 [MEDLINE 8500748]
Higgins 2008
Higgins PTJ Green S editors Cochrane Handbook for Systematic
Reviews of Interventions West Sussex England Wiley-Blackwell
2008
Hirschfield 2009
Hirschfield GM Gibbs P Griffiths WJH Adult liver
transplantation what non-specialists need to know BMJ (Clinical
Research Ed) 2009338(b1670)1321ndash7 [DOI 101136
bmjb1670]
Hussain 2002
Hussain HK Nghiem HV Imaging of hepatic transplantation
Clinics in Liver Disease 20026(1)247ndash70 [MEDLINE
11933592]
ICH-GCP 1997
International Conference on Harmonisation Expert Working
Group Code of Federal Regulations amp International Conference on
Harmonization Guidelines Media Parexel Barnett 1997
Ioannidis 2001
Ioannidis JPA Lau J Evolution of treatment effects over time
Empirical insight from recursive cumulative meta analyses
Proceedings of the National Academy of Sciences 200198(3)831ndash6
IWP 1995
International Working Party Terminology for hepatic allograft
rejection Hepatology 199522(2)648ndash54 [MEDLINE 7635435]
Kjaergard 2001
Kjaergard LL Villumsen J Gluud C Reported methodological
quality and discrepancies between large and small randomised trials
in meta-analyses Annals of Internal Medicine 2001135(11)982ndash9
[MEDLINE 11730399]
Klintmalm 1989
Klintmalm GB Nery JR Husberg BS Gonwa TA Tillery GW
Rejection in liver transplantation Hepatology 198910(6)978ndash85
[MEDLINE 2583691]
Knechtle 2009
Knechtle SJ Kwun J Unique aspects of rejection and tolerance in
liver transplantation Seminars in Liver Disease 200929(1)91ndash101
[MEDLINE 19235662]
Krams 1993
Krams SM Ascher NL Martinez OM New immunologic insights
into mechanisms of allograft rejection Gastroenterology Clinics of
North America 199318(2)374ndash7 [MEDLINE 8509176]
Lan 1983
Lan KKG DeMets DL Discrete sequential boundaries for clinical
trials Biometrika 198370659ndash63
Merion 1989
Merion RM Gorski DH Burtch GD Turcotte JG Colletti LM
Campbell DA Jr Bile refeeding after liver transplantation and
avoidance of intravenous cyclosporine Surgery 1989106(4)
604ndash9 [MEDLINE 2799635]
Moher 1998
Moher D Pham B Jones A Cook DJ Jadad AR Moher M et
alDoes quality of reports of randomised trials affect estimates of
intervention efficacy reported in meta-analyses Lancet 1998352
(9128)609ndash13 [MEDLINE 9746022]
16Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Neuberger 1999
Neuberger J Incidence timing and risk factors for acute and
chronic rejection Liver Transplantation and Surgery 19995(4 Suppl
1)S30ndashS36 [MEDLINE 10431015]
Okolicsanyi 1986
Okolicsanyi L Lirussi F Strazzabosco M Jemmolo RM Orlando R
Nassuato G et alThe effect of drugs on bile flow and composition
An overview Drugs 198631(5)430ndash48 [MEDLINE 2872047]
Palmer 1972
Palmer RH Bile acids liver injury and liver disease Archives of
Internal Medicine 1972130(4)606ndash17 [MEDLINE 4627840]
Perez 2009
Perez MJ Briz O Bile-acid-induced cell injury and protection
World Journal of Gastroenterology 200915(14)1677ndash89
[MEDLINE 19360911]
Pogue 1997
Pogue JM Yusuf S Cumulating evidence from randomized trials
Utilizing sequential monitoring boundaries for cumulative meta-
analysis Controlled Clinical Trials 199718(6)580ndash93
[MEDLINE 9408720]
Pogue 1998
Pogue J Yusuf S Overcoming the limitations of current meta-
analysis of randomised controlled trials Lancet 1998351(9095)
45ndash52 [MEDLINE 9433436]
RevMan 2008
The Nordic Cochrane Centre The Cochrane Collaboration
Review Manager (RevMan) 50 Copenhagen The Nordic
Cochrane Centre The Cochrane Collaboration 2008
Royle 2003
Royle P Milne R Literature searching for randomized controlled
trials used in Cochrane reviews rapid versus exhaustive searches
International Journal of Technology Assessment in Health Care 2003
19(4)591ndash603
Schulz 1995
Schulz KF Chalmers I Hayer R Altman D Empirical evidence of
bias JAMA 1995273(5)408ndash12 [MEDLINE 7823387]
Sharara 1995
Sharara AI Camargo CA Clavien PA Ursodeoxycholic acid
prevents steroid resistant rejection in liver transplant recipients
Gastroenterology 1995108A1168
Sholmerich 1984
Sholmerich J Becher MS Schmidt KH Schubert R Kremer B
Felhaus S et alInfluence of hydroxylation and conjugation of bile
salts on their membrane damaging properties Hepatology 19844
(4)661ndash7 [MEDLINE 6745854]
Soderdahl 1998
Soderdahl G Nowak G Duraj F Wang FH Einarsson C Ericzon
BG Ursodeoxycholic acid increased bile flow and affects bile
composition in the early postoperative phase following liver
transplantation Transplantation International 199811(Suppl 1)
S231ndashS238 [MEDLINE 9664985]
Terasaki 1991
Terasaki S Nakanuma Y Ogino H Unoura M Kobayashi K
Hepatocellular and biliary expression of HLA antigens in primary
biliary cirrhosis before and after ursodeoxycholic acid therapy
American Journal of Gastroenterology 199186(9)1194ndash9
[MEDLINE 1882800]
Thalheimer 2002
Thalheimer U Capra F Liver transplantation making the best out
of what we have Digestive Diseases and Sciences 200247(5)
945ndash53 [MEDLINE 12018919]
Thorlund 2009
Thorlund K Devereaux PJ Wetterslev J Guyatt G Ioannidis JP
Thabane L et alCan trial sequential monitoring boundaries reduce
spurious inferences from meta-analyses International Journal of
Epidemiology 200938(1)276ndash86 [MEDLINE 18824467]
Thuluvath 2003
Thuluvath PJ Yoo HY Thompson RE A model to predict survival
at one month one year and five years after liver transplantation
based on pretransplant clinical characteristics Liver Transplantation
20039(5)527ndash32 [MEDLINE 12740799]
van den Berg 1998
van den Berg AP Twilhaar WN Mesander G van Son WJ van der
Bij W Klompmaker IJ et alQuantitation of immunosuppression
by flow cytometric measurement of the capacity of T cells for
interleukin-2 production Transplantation 199865(8)1066ndash71
[MEDLINE 9583867]
Vierling 1992
Vierling J Immunologic mechanisms of hepatic allograft rejection
Seminars in Liver Disease 199212(1)16ndash27 [MEDLINE
1570548]
Wetterslev 2008
Wetterslev J Thorlund K Brok J Gluud C Trial sequential
analysis may establish when firm evidence is reached in cumulative
meta-analysis Journal of Clinical Epidemiology 200861(1)64ndash75
[MEDLINE 18083463]
Wiesner 1992
Wiesner RH Acute cellular rejection following liver
transplantation incidence risk factors and outcome in the
NIDDK Liver Transplant Database (LTD) study Gastroenterology
1992102A910
Wood 2008
Wood L Egger M Gluud LL Schulz KF Juni P Altman DG et
alEmpirical evidence of bias in treatment effect estimates in
controlled trials with different interventions and outcomes meta-
epidemiological study BMJ (Clinical Research Ed) 2008336
(7644)601ndash5 [MEDLINE 18316340]
Yoshikawa 1998
Yoshikawa M Matsui Y Kawamoto H Toyohara M Matsumura
K Yamao J et alIntragastric administration of ursodeoxycholic
acid suppresses immunoglobulin secretion by lymphocytes from
liver but not from peripheral blood spleen or Peyerrsquos patches in
mice International Journal of Immunopharmacology 199820(1-3)
29ndash38 [MEDLINE 9717080]
References to other published versions of this review
17Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Chen 2003b
Chen W Gluud C Bile acids for liver transplanted patients
Cochrane Database of Systematic Reviews 2005 Issue 3 [DOI
10100214651858CD005442]lowast Indicates the major publication for the study
18Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
C H A R A C T E R I S T I C S O F S T U D I E S
Characteristics of included studies [ordered by study ID]
Angelico 1999
Methods Study design open-label randomised one-year pilot study
Participants Country Italy
Publication language English
Inclusion criteria
- patients who underwent liver transplantation from April 1994 to December 1994
Exclusion criteria
- not mentioned
Participants
Two patients in TUDCA group and two patients in control group were excluded from
the basic information of participants by the study due to withdrawal
- TUDCA group (n = 14)
Mean age (years +- SD)
467 +- 84
Ratio of sex (malefemale) 122
Origins of liver diseases
hepatitis C cirrhosis (9) hepatitis B cirrhosis (2) hepatitis B and C cirrhosis (1) cryp-
togenic cirrhosis (2) alcoholic cirrhosis (0) Wilson cirrhosis (0)
- Control group (n = 15)
Mean age (years +- SD)
474 +- 74
Ratio of sex (malefemale) 123
Origins of liver diseases
hepatitis C cirrhosis (7) hepatitis B cirrhosis (2) hepatitis B and C cirrhosis (2) cryp-
togenic cirrhosis (2) alcoholic cirrhosis (1) Wilson cirrhosis (1)
Interventions TUDCA group
- Dose 500 mgday in two divided doses
- Route orally
- Duration the treatment was started on day 5 after transplantation and continued for
one year
Control group
- no treatment
Co-interventions all patients received standard triple-drug regimens (steroids azathio-
prine and cyclosporine or tacrolimus)
Outcomes All cause mortality
Number of patients with rejection after liver transplantation
Notes Letter was sent to the authors in September 2009 A reply with additional information
was received shortly after
Risk of bias
19Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Angelico 1999 (Continued)
Item Authorsrsquo judgement Description
Adequate sequence generation Yes Computer generated table
Allocation concealment Unclear No information provided
Blinding No Not performed
Incomplete outcome data addressed
All outcomes
Yes Withdrawal two patients from the
TUDCA group and two patients from the
placebo group Three of them died due to
transplant non-function in the first postop-
erative week and one patient was regrafted
due to thrombosis of hepatic artery
Free of selective reporting Unclear Post-transplant cholestasis and liver bio-
chemistry specified as outcomes Differ-
ence reported as not significant but no ac-
tual data given
Sample size calculation No Not reported
Intention-to-treat analysis No Not stated and not used
Baseline imbalance Unclear Not enough information provided
Early stopping of trial Unclear Not enough information provided
Barnes 1997
Methods Study design randomised placebo-controlled double-blind trial
Participants Country United States
Publication language English
Inclusion criteria
- patients aged 18 years or older who underwent liver transplantation at the Cleveland
Clinic Foundation from April 1992 through June of 1994
Exclusion criteria
- patients who were found to have cancer at surgically resected margins of the biliary
tree
- patents who underwent retransplantation
Participants
- UDCA group (n = 28)
Mean age (years +- SD)
505 +- 116
Ratio of sex (malefemale) 1810
Child class A 7
20Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Barnes 1997 (Continued)
B 13
and C 8
Origins of liver diseases Laennecrsquos cirrhosis 4
PBC 3
cryptogenic cirrhosis 6
hepatitis Ccirrhosis 4
hepatitis Bcirrhosis 3
autoimmune hepatitis with cirrhosis 3
PSC 2
other 3
- Placebo group (n = 24)
Mean age (years +- SD)
507 +- 93
Ratio of sex (malefemale) 159
Child class A 6
B 14
and C 4
Origins of liver diseases Laennecrsquos cirrhosis 9
PBC 5
cryptogenic cirrhosis 1
hepatitis Ccirrhosis 1
hepatitis Bcirrhosis 1
autoimmune hepatitis with cirrhosis 1
PSC 2
other 4
Interventions UDCA group
- Dose 10-15 mgkg body weightday in divided doses
- Route orally
- Duration immediately after intestinal transit recovery usually between postoperative
days three and five and continue for three months
Placebo group
- identical-appearing capsules administered in the same quantity and manner
Co-interventions all patients received standard triple-drug regimens (steroids azathio-
prine and cyclosporine or tacrolimus)
Outcomes All cause mortality
Number of patients with acute cellular rejection
Number of patients with chronic rejection
Number of patients with steroid-resistant rejection
Number of days of hospitalisation
Adverse events
Notes Letter was sent to the authors in September 2009 A reply with additional information
was received shortly after
Risk of bias
Item Authorsrsquo judgement Description
21Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Barnes 1997 (Continued)
Adequate sequence generation Yes Computer generated table
Allocation concealment Unclear No information provided
Blinding Yes Quote ldquorandomised to receive either
UDCA or an identical placebo capsulerdquo
Incomplete outcome data addressed
All outcomes
Yes Mean follow-up time 18 months Ten pa-
tients withdrawn from study 6 in UDCA
group and 4 in placebo group Reasons
for withdrawal were reported Four patients
died in the placebo group
Free of selective reporting Yes All expected outcomes reported
Sample size calculation Unclear The trial reported the method of sample
size calculation but the actual number of
patients needed was not reported
Intention-to-treat analysis Yes Stated and used
Baseline imbalance Unclear Not enough information provided
Early stopping of trial Unclear The number of patients needed to gain the
actual power was not reported Whether
the trial was terminated early is not clear
Fleckenstein 1998
Methods Study design prospective randomised double-blind trial
Participants Country United States
Publication language English
Inclusion criteria
- patients who underwent liver transplantation at the Johns Hopkins Hospital
Exclusion criteria
- patients who were under 18 years old undergoing repeat transplantation had primary
graft nonfunction or refused consent
Participants
- UDCA group (n = 14)
Mean age (years +- SD)
443 +- 127
Ratio of sex (malefemale) 68
Origins of liver diseases hepatitis C 6
alcohol 2
autoimmune 1
PBC 2
22Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Fleckenstein 1998 (Continued)
PSC 1
autoimmune cholangiopathy 1
hepatitis B 1
- Placebo group (n = 16)
Mean age (years +- SD)
496 +- 109
Ratio of sex (malefemale) 124
Origins of liver diseases hepatitis C 3
alcohol 3
autoimmune 3
PBC 1
PSC 2
cryptogenic 2
hepatitis B 1
alpha1-antitrypsin deficiency 1
Interventions UDCA group
- Dose 15 mgkg body weightday in divided doses
- Route orally
- Duration immediately after intestinal transit recovery usually between postoperative
days three and five and continue for three months
Placebo group
- Identical-appearing capsules administered in the same quantity and manner
Co-interventions all patients received standard triple-drug regimens (steroids azathio-
prine and cyclosporine or tacrolimus)
Outcomes All cause mortality
Number with retransplantation
Number of patients with acute cellular rejection
Number of patients with chronic rejection
Serum bilirubin levels at the end of treatment
Notes Follow-up time nine months
Letter was sent to the authors in September 2009 No reply was received
Risk of bias
Item Authorsrsquo judgement Description
Adequate sequence generation Unclear No information provided
Allocation concealment Unclear No information provided
Blinding Yes Method of blinding not described but
probably adequate
Incomplete outcome data addressed
All outcomes
Yes Withdrawal one patient from the UDCA
group and two patients from the placebo
group because of capsule size
23Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Fleckenstein 1998 (Continued)
Free of selective reporting Unclear Outcomes were not completely described
Sample size calculation No Not reported
Intention-to-treat analysis Yes Quote ldquoThree patients withdrew after in-
clusionThey were included in the statis-
tical analysisrdquo
Baseline imbalance Unclear Not enough information provided
Early stopping of trial Unclear Not enough information provided
Keiding 1997
Methods Study design prospective randomised placebo-controlled multicenter study
Participants Country Denmark Finland Norway and Sweden
Publication language English
Inclusion criteria
- patients who underwent liver transplantation in Denmark Finland Norway and Swe-
den from September 1 1992 to May 31 1994
Exclusion criteria
- patients with malignant diseases
Participants
The age of the children ranged from 0 to 13 years (median 15) and the age of adults
ranged from 14 to 59 years old (median 44) MaleFemale ratio was 96 for children and
4344 for adults
- UDCA group (n = 54)
Origins of liver diseases
paracetamol intoxication 1 hepatitis B 1 autoimmune hepatitis 0 biliary atresia 2
metabolic diseases 7 neonatal hepatitis 2 PBC 13 post hepatitis cirrhosis 8 PSC 3
cryptogenic cirrhosis 7 alcoholic cirrhosis 2 other reasons 8
- Placebo group (n = 48)
Origins of liver diseases paracetamol intoxication 1 hepatitis B 0 autoimmune hepatitis
1 biliary atresia 3 metabolic diseases 11 neonatal hepatitis 0 PBC 7 post hepatitis
cirrhosis 5 PSC 7 cryptogenic cirrhosis 2 alcoholic cirrhosis 6 other reasons 5
Interventions UDCA group
- Dose 15 mgkg body weightday in two or three divided doses
- Route orally
- Duration immediately after intestinal transit recovery usually between postoperative
days three and five and continue for three months
Placebo group
- Identical-appearing capsules administered in the same quantity and manner
Co-interventions all patients received standard triple-drug regimens (steroids azathio-
prine and cyclosporine or tacrolimus)
24Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Keiding 1997 (Continued)
Outcomes All cause mortality
Number of deaths related to rejection
Number of patients with acute cellular rejection
Number of patients with chronic rejection
Number of patients with steroid-resistant rejection
Adverse events
Notes Letter was sent to the authors in September 2009 No reply was received
Risk of bias
Item Authorsrsquo judgement Description
Adequate sequence generation Unclear Patients were randomised at a ratio of 11
Allocation concealment Yes Quote ldquo The allocation was performed in
blocks of 10 patients using the sealed serial
envelope methodrdquo
Blinding Yes Quote ldquoThe UDCA and the placebo cap-
sules had identical appearance and tasterdquo
Incomplete outcome data addressed
All outcomes
Yes Follow-up time 12 months Five UDCA
patients and five placebo patients withdrew
from study Reasons were reported
Free of selective reporting Unclear Insufficient information
Sample size calculation Yes Performed and allowed for a difference in
the incidence of at least one episode of
acute rejection of 50 between the treat-
ment and placebo groups with 90 statisti-
cal power and a significance level of P value
less than 005 The calculated sample size
was 80 patients
Intention-to-treat analysis Yes Stated and used
Baseline imbalance Yes The study seems to be free of baseline im-
balance
Early stopping of trial Yes Study attained the pre-specified sample
size
25Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Koneru 1993
Methods Study design randomised controlled trial
Participants Country United States
Publication language English
Inclusion criteria
- patients who underwent liver transplantation
Exclusion criteria
- not mentioned
Participants
- UDCA group (n = 16)
Mean age (years +- SD)
no information
Ratio of sex (malefemale) no information
Origins of liver diseases
no information
- Control group (n = 16)
Mean age (years +- SD)
no information
Ratio of sex (malefemale) no information
Origins of liver diseases
no information
Interventions UDCA group
- Dose 900 mgday
- Route orally
- Duration immediately after intestinal transit recovery usually between postoperative
days three and five and continue for three months
Control group
- no treatment
Co-interventions all patients received standard triple-drug regimens (steroids azathio-
prine and cyclosporine)
Outcomes Number of patients with retransplantation due to rejection
Number of patients with rejection episodes
Notes Abstract
Letter was sent to the authors in September 2009 No reply was received
Risk of bias
Item Authorsrsquo judgement Description
Adequate sequence generation Unclear No information provided
Allocation concealment Unclear No information provided
Blinding No Not performed
26Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Koneru 1993 (Continued)
Incomplete outcome data addressed
All outcomes
Unclear The study gives the impression that there
were no withdrawals but this was not ex-
plicitly stated
Free of selective reporting Unclear Insufficient information provided
Sample size calculation No Not performed
Intention-to-treat analysis Unclear No information provided
Baseline imbalance Unclear Not enough information provided
Early stopping of trial Unclear Not enough information provided
Pageaux 1995
Methods Study design double-blind randomised study
Participants Country France
Publication language English
Inclusion criteria
- patients who underwent liver transplantation
Exclusion criteria
- not mentioned
Participants
- UDCA group (n=26)
Mean age (years +- SD)
47 +- 10
Ratio of sex (malefemale) 179
Origins of liver diseases alcoholic cirrhosis 14
post-hepatic B cirrhosis 2
post-hepatitis C cirrhosis 4
PBC 2
liver cancer 2
fulminant hepatitis 1
miscellaneous 1
- Placebo group (n = 24)
Mean age (years +- SD)
51+- 9
Ratio of sex (malefemale) 159
Origins of liver diseases alcoholic cirrhosis 10
post-hepatic B cirrhosis 0
post-hepatic C cirrhosis 6
PBC 3
liver cancer 4
fulminant hepatitis 0
miscellaneous 1
27Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Pageaux 1995 (Continued)
Interventions UDCA group
- Dose 600 mgday in three divided doses
- Route orally
- Duration immediately after intestinal transit recovery usually between postoperative
days three and five and continue for two months
Placebo group
- identical-appearing capsules administered in the same quantity and manner
Co-interventions all patients received standard triple-drug regimens (steroids azathio-
prine and cyclosporine or tacrolimus)
Outcomes Number of patients with acute cellular rejection
Number of patients with steroid-resistant rejection
Notes Letter was sent to the authors in September 2009 No reply was received
Risk of bias
Item Authorsrsquo judgement Description
Adequate sequence generation Unclear No information provided
Allocation concealment Unclear No information provided
Blinding Unclear Method of blinding not described
Incomplete outcome data addressed
All outcomes
Yes Five patients died from non-immunologi-
cal causes before the end of the first month
and were excluded from the study Reasons
were reported
Free of selective reporting Unclear Not enough information provided
Sample size calculation No Not performed
Intention-to-treat analysis No Not stated and not used
Baseline imbalance Unclear Not enough information provided
Early stopping of trial Unclear Not enough information provided
Sama 1991
Methods Study design randomised controlled trial
Participants Country Italy
Publication language English
Inclusion criteria
28Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Sama 1991 (Continued)
- patients who underwent liver transplantation
Exclusion criteria
- not mentioned
Participants
- UDCA group (n = 20)
Mean age (years +- SD)
no information
Ratio of sex (malefemale) no information
Origins of liver diseases
no information
- Control group (n = 20)
Mean age (years +- SD)
no information
Ratio of sex (malefemale) no information
Origins of liver diseases
no information
Interventions UDCA group
- Dose 600 mgday in two divided doses
- Route orally
- Duration immediately after intestinal transit recovery usually between postoperative
day five and day seven and continue for six months
Control group
- no treatment
Co-interventions all patients received standard immunosuppressive treatment (steroids
and cyclosporine)
Outcomes All cause mortality
Number of patients with acute cellular rejection
Notes Abstract
Letter was sent to the authors in September 2009 No reply was received
Risk of bias
Item Authorsrsquo judgement Description
Adequate sequence generation Unclear A randomisation list was performed before
patients were admitted to the trial (infor-
mation from principal author)
Allocation concealment Unclear No information provided
Blinding Unclear The principle author provided information
that the study was made according to a
single-blind randomised protocol The pri-
mary outcome was the occurrence of biopsy
proven rejection episodes The pathologists
were blind but the patients were not
29Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Sama 1991 (Continued)
Incomplete outcome data addressed
All outcomes
Unclear Five patients from the UDCA group and
six patients from the placebo group were
excluded Reasons for exclusion were not
fully stated
Free of selective reporting No Data about survival of patients were not
adequately reported
Sample size calculation No Not performed
Intention-to-treat analysis No Not stated and not used
Baseline imbalance Unclear Basic characteristics of patients not re-
ported
Early stopping of trial Unclear Not enough information provided
UDCA = ursodeoxycholic acid
TUDCA = tauroursodeoxycholic acid
PBC = primary biliary cirrhosis
PSC = primary sclerosing cholangitis
OKT3 = anti-CD3 monoclonal antibody
Characteristics of excluded studies [ordered by study ID]
Assy 2007 A randomised controlled trial that included only recipients of liver transplantation with stable graft function and
no episodes of rejection for at least 2 years that were then offered total immunosuppression withdrawal Fourteen
patients received UDCA (15 mgkg body weightday) and 12 received placebo Rejection occurred in 43 and
75 of patients respectively (no significant difference) None developed chronic rejection After follow-up two
patients were free of immunosuppression 80 were steroid free and 50 were able to reduce their dose of
cyclosporine
Clavien 1996 Case series Fifty consecutive liver-transplanted patients were treated with a standard cyclosporine immunosup-
pressive regimen Twenty three of the 43 survivors developed an episode of rejection and UDCA (10 mgkg
weightday) was initiated Only one patient had a second episode of rejection
Friman 1992 Observational study Thirty-three liver-transplanted patients received 10 mg UDCAkg body weightday for
median of 10 months (range four to 21 months) Eight historical liver-transplanted patients served as control
group The rejection incidence was significantly lower in the patients who received the treatment with UDCA
Biochemistry one month after transplantation demonstrated significantly lower average values of aminotrans-
ferases and alkaline phosphatases in patients treated with UDCA than in the control group
30Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
Heathcote 1999 Observational study From 1987 to 1996 37 UDCA treated and 53 placebo treated patients with primary biliary
cirrhosis were referred for transplantation Posttransplantation survival rates at one month were 939 in the
UDCA group and 884 in the placebo group and one year survival rates were 903 and 784 respectively
(no significant differences) However rejection (type not defined - a secondary outcome measure) occurred
significantly less often in the UDCA group (429) than in placebo group (688)
Henriksson 1991 Observational study All patients in this study were given sequential quadruple immunosuppression with anti-
lymphocyte globulin azathioprine steroids and cyclosporine All patients with primary graft function (n = 11)
were treated with 10 mg UDCAkg body weightday starting during the first postoperative week Patients who
received liver transplantation in the first 6 months of 1989 (n = 8) served as controls In the control group one
patient died after 9 months with chronic graft dysfunction and six patients had rejection episodes during the
first postoperative month All patients in the UDCA group were alive without rejection episodes
Persson 1990 Observational study All 11 adult patients transplanted between August 1989 and January 1990 with primary
graft function were treated with 10 mg UDCA kg body weightday Eight patients transplanted during the first
half of 1989 served as control UDCA was started during the first postoperative week and the treatment was
continued for six months All patients in the UDCA treated group survived with satisfactory graft function In
the control group six patients had at least one rejection episode needing treatment during the first postoperative
month
Rafael 1995 Observational study Seventeen patients who underwent liver transplantation between February 1990 and April
1993 and developed biliary complications after transplantation were retrospectively analysed regarding treatment
with UDCA UDCA was given in a dose of 500 to 1000 mgday Ten patients were treated for at least one year while
seven patients were treated for 14 to 250 days UDCA significantly improved gammaglutamyl transpeptidase in
liver graft recipients with biliary complications There was also a trend towards improvement in serum bilirubin
and alanine transaminase values
Sama 1998 Observational study Thirty-four patients who underwent liver transplantation between January 1995 and June
1996 were included in the study Seventeen were treated with UDCA 10 mgkg body weightday during 6
months while 17 served as controls on the basis of having undergone liver transplantation closest to UDCA
patients A significant decrease in serum bilirubin levels was observed in UDCA patients There was a significantly
higher incidence of recurrent hepatitis in the control group
UDCA ursodeoxycholic acid
31Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
D A T A A N D A N A L Y S E S
Comparison 1 Bile acids for liver-transplanted patients
Outcome or subgroup titleNo of
studies
No of
participants Statistical method Effect size
1 All-cause mortality at maximum
follow-up
5 257 Risk Ratio (M-H Fixed 95 CI) 085 [053 136]
11 UDCA versus placebo or
no treatment
4 224 Risk Ratio (M-H Fixed 95 CI) 080 [049 130]
12 TUDCA versus no
treatment
1 33 Risk Ratio (M-H Fixed 95 CI) 159 [030 833]
2 All-cause mortality worst-best
case and best-worst case
scenarios
5 Risk Ratio (M-H Fixed 95 CI) Subtotals only
21 Worst-best case scenario 5 257 Risk Ratio (M-H Fixed 95 CI) 130 [086 196]
22 Best-worst case scenario 5 257 Risk Ratio (M-H Fixed 95 CI) 058 [038 090]
3 Subgroup analyses all-cause
mortality at maximum
follow-up according to time of
start of bile acids
5 257 Risk Ratio (M-H Fixed 95 CI) 085 [053 136]
31 Less than three days after
transplantation
1 102 Risk Ratio (M-H Fixed 95 CI) 124 [061 254]
32 Three days or more after
transplantation
4 155 Risk Ratio (M-H Fixed 95 CI) 063 [033 120]
4 Subgroup analyses all cause
mortality at maximum
follow-up according to
treatment duration
5 257 Risk Ratio (M-H Fixed 95 CI) 085 [053 136]
41 Less than six months 3 184 Risk Ratio (M-H Fixed 95 CI) 078 [045 138]
42 Six months or more 2 73 Risk Ratio (M-H Fixed 95 CI) 102 [043 240]
5 Number of deaths related
to rejection at maximum
follow-up
1 102 Risk Ratio (M-H Fixed 95 CI) 030 [001 712]
51 UDCA versus placebo 1 102 Risk Ratio (M-H Fixed 95 CI) 030 [001 712]
6 Number of retransplantations at
maximum follow-up
2 132 Risk Ratio (M-H Fixed 95 CI) 076 [020 286]
7 Number of patients with acute
cellular rejection at maximum
follow-up
7 339 Risk Ratio (M-H Fixed 95 CI) 089 [074 106]
71 UDCA versus placebo or
no treatment
6 306 Risk Ratio (M-H Fixed 95 CI) 089 [074 108]
72 TUDCA versus no
treatment
1 33 Risk Ratio (M-H Fixed 95 CI) 085 [045 160]
8 Subgroup analysis number of
patients with acute cellular
rejection according to time of
start of bile acid
7 339 Risk Ratio (M-H Fixed 95 CI) 089 [074 106]
32Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
81 Less than three days after
transplantation
2 134 Risk Ratio (M-H Fixed 95 CI) 084 [063 111]
82 Three days or more after
liver transplantation
5 205 Risk Ratio (M-H Fixed 95 CI) 092 [072 117]
9 Subgroup analysis number
of patients with acute
cellular rejection according to
treatment duration
7 339 Risk Ratio (M-H Fixed 95 CI) 089 [074 106]
91 Less than six months 5 266 Risk Ratio (M-H Fixed 95 CI) 087 [071 107]
92 Six months or more 2 73 Risk Ratio (M-H Fixed 95 CI) 094 [065 136]
10 Number of patients with
chronic rejection at maximum
follow-up
3 184 Risk Ratio (M-H Fixed 95 CI) 028 [008 095]
11 Number of patients with
steroid-resistant rejection at
maximum follow-up
4 234 Risk Ratio (M-H Fixed 95 CI) 077 [047 127]
12 Serum bilirubin (mgdl) at the
end of treatment
1 30 Mean Difference (IV Fixed 95 CI) 26 [-096 616]
13 Number of days of
hospitalisation after liver
transplantation
1 52 Mean Difference (IV Fixed 95 CI) -85 [-1667 -033]
14 Adverse events 3 187 Risk Ratio (M-H Fixed 95 CI) 088 [030 260]
Analysis 11 Comparison 1 Bile acids for liver-transplanted patients Outcome 1 All-cause mortality at
maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 1 All-cause mortality at maximum follow-up
Study or subgroup Favours bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 UDCA versus placebo or no treatment
Barnes 1997 228 724 253 024 [ 006 107 ]
Fleckenstein 1998 214 416 125 057 [ 012 266 ]
Keiding 1997 1454 1048 355 124 [ 061 254 ]
Sama 1991 520 620 201 083 [ 030 229 ]
Subtotal (95 CI) 116 108 935 080 [ 049 130 ]
Total events 23 (Favours bile acids) 27 (Control)
Heterogeneity Chi2 = 416 df = 3 (P = 025) I2 =28
Test for overall effect Z = 091 (P = 036)
01 02 05 1 2 5 10
Favours bile acids Favours control
(Continued )
33Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Favours bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
2 TUDCA versus no treatment
Angelico 1999 316 217 65 159 [ 030 833 ]
Subtotal (95 CI) 16 17 65 159 [ 030 833 ]
Total events 3 (Favours bile acids) 2 (Control)
Heterogeneity not applicable
Test for overall effect Z = 055 (P = 058)
Total (95 CI) 132 125 1000 085 [ 053 136 ]
Total events 26 (Favours bile acids) 29 (Control)
Heterogeneity Chi2 = 466 df = 4 (P = 032) I2 =14
Test for overall effect Z = 069 (P = 049)
01 02 05 1 2 5 10
Favours bile acids Favours control
Analysis 12 Comparison 1 Bile acids for liver-transplanted patients Outcome 2 All-cause mortality worst-
best case and best-worst case scenarios
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 2 All-cause mortality worst-best case and best-worst case scenarios
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 Worst-best case scenario
Angelico 1999 516 217 65 266 [ 060 1180 ]
Barnes 1997 828 724 253 098 [ 042 230 ]
Fleckenstein 1998 314 416 125 086 [ 023 319 ]
Keiding 1997 1954 1048 355 169 [ 087 327 ]
Sama 1991 520 620 201 083 [ 030 229 ]
Subtotal (95 CI) 132 125 1000 130 [ 086 196 ]
Total events 40 (Bile acids) 29 (Control)
Heterogeneity Chi2 = 303 df = 4 (P = 055) I2 =00
Test for overall effect Z = 123 (P = 022)
2 Best-worst case scenario
005 02 1 5 20
Favours bile acids Favours control
(Continued )
34Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Angelico 1999 316 417 90 080 [ 021 302 ]
Barnes 1997 228 1124 274 016 [ 004 063 ]
Fleckenstein 1998 214 616 130 038 [ 009 159 ]
Keiding 1997 1454 1548 368 083 [ 045 154 ]
Sama 1991 520 620 139 083 [ 030 229 ]
Subtotal (95 CI) 132 125 1000 058 [ 038 090 ]
Total events 26 (Bile acids) 42 (Control)
Heterogeneity Chi2 = 567 df = 4 (P = 023) I2 =29
Test for overall effect Z = 247 (P = 0014)
005 02 1 5 20
Favours bile acids Favours control
Analysis 13 Comparison 1 Bile acids for liver-transplanted patients Outcome 3 Subgroup analyses all-
cause mortality at maximum follow-up according to time of start of bile acids
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 3 Subgroup analyses all-cause mortality at maximum follow-up according to time of start of bile acids
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 Less than three days after transplantation
Keiding 1997 1454 1048 355 124 [ 061 254 ]
Subtotal (95 CI) 54 48 355 124 [ 061 254 ]
Total events 14 (Bile acids) 10 (Control)
Heterogeneity not applicable
Test for overall effect Z = 060 (P = 055)
2 Three days or more after transplantation
Angelico 1999 316 217 65 159 [ 030 833 ]
Barnes 1997 228 724 253 024 [ 006 107 ]
Fleckenstein 1998 214 416 125 057 [ 012 266 ]
Sama 1991 520 620 201 083 [ 030 229 ]
005 02 1 5 20
Favours bile acids Favours control
(Continued )
35Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Subtotal (95 CI) 78 77 645 063 [ 033 120 ]
Total events 12 (Bile acids) 19 (Control)
Heterogeneity Chi2 = 310 df = 3 (P = 038) I2 =3
Test for overall effect Z = 141 (P = 016)
Total (95 CI) 132 125 1000 085 [ 053 136 ]
Total events 26 (Bile acids) 29 (Control)
Heterogeneity Chi2 = 466 df = 4 (P = 032) I2 =14
Test for overall effect Z = 069 (P = 049)
005 02 1 5 20
Favours bile acids Favours control
Analysis 14 Comparison 1 Bile acids for liver-transplanted patients Outcome 4 Subgroup analyses all
cause mortality at maximum follow-up according to treatment duration
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 4 Subgroup analyses all cause mortality at maximum follow-up according to treatment duration
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 Less than six months
Barnes 1997 228 724 253 024 [ 006 107 ]
Fleckenstein 1998 214 416 125 057 [ 012 266 ]
Keiding 1997 1454 1048 355 124 [ 061 254 ]
Subtotal (95 CI) 96 88 734 078 [ 045 138 ]
Total events 18 (Bile acids) 21 (Control)
Heterogeneity Chi2 = 417 df = 2 (P = 012) I2 =52
Test for overall effect Z = 084 (P = 040)
2 Six months or more
Angelico 1999 316 217 65 159 [ 030 833 ]
Sama 1991 520 620 201 083 [ 030 229 ]
Subtotal (95 CI) 36 37 266 102 [ 043 240 ]
Total events 8 (Bile acids) 8 (Control)
Heterogeneity Chi2 = 043 df = 1 (P = 051) I2 =00
005 02 1 5 20
Favours bile acids Favours control
(Continued )
36Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Test for overall effect Z = 004 (P = 097)
Total (95 CI) 132 125 1000 085 [ 053 136 ]
Total events 26 (Bile acids) 29 (Control)
Heterogeneity Chi2 = 466 df = 4 (P = 032) I2 =14
Test for overall effect Z = 069 (P = 049)
005 02 1 5 20
Favours bile acids Favours control
Analysis 15 Comparison 1 Bile acids for liver-transplanted patients Outcome 5 Number of deaths related
to rejection at maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 5 Number of deaths related to rejection at maximum follow-up
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 UDCA versus placebo
Keiding 1997 054 148 1000 030 [ 001 712 ]
Total (95 CI) 54 48 1000 030 [ 001 712 ]
Total events 0 (Bile acids) 1 (Control)
Heterogeneity not applicable
Test for overall effect Z = 075 (P = 045)
0001 001 01 1 10 100 1000
Favours bile acids Favours control
37Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 16 Comparison 1 Bile acids for liver-transplanted patients Outcome 6 Number of
retransplantations at maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 6 Number of retransplantations at maximum follow-up
Study or subgroup Bile acids Placebo Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Fleckenstein 1998 214 016 100 567 [ 029 10891 ]
Keiding 1997 154 448 900 022 [ 003 192 ]
Total (95 CI) 68 64 1000 076 [ 020 286 ]
Total events 3 (Bile acids) 4 (Placebo)
Heterogeneity Chi2 = 303 df = 1 (P = 008) I2 =67
Test for overall effect Z = 040 (P = 069)
0001 001 01 1 10 100 1000
Favours bile acids Favours placebo
Analysis 17 Comparison 1 Bile acids for liver-transplanted patients Outcome 7 Number of patients with
acute cellular rejection at maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 7 Number of patients with acute cellular rejection at maximum follow-up
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 UDCA versus placebo or no treatment
Barnes 1997 1728 1724 180 086 [ 058 127 ]
Fleckenstein 1998 814 916 83 102 [ 054 190 ]
Keiding 1997 3554 3248 333 097 [ 073 129 ]
Koneru 1993 316 916 89 033 [ 011 101 ]
Pageaux 1995 926 924 92 092 [ 044 193 ]
Sama 1991 1320 1320 128 100 [ 063 158 ]
Subtotal (95 CI) 158 148 905 089 [ 074 108 ]
01 02 05 1 2 5 10
Favours bile acids Favours control
(Continued )
38Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Total events 85 (Bile acids) 89 (Control)
Heterogeneity Chi2 = 387 df = 5 (P = 057) I2 =00
Test for overall effect Z = 120 (P = 023)
2 TUDCA versus no treatment
Angelico 1999 816 1017 95 085 [ 045 160 ]
Subtotal (95 CI) 16 17 95 085 [ 045 160 ]
Total events 8 (Bile acids) 10 (Control)
Heterogeneity not applicable
Test for overall effect Z = 050 (P = 061)
Total (95 CI) 174 165 1000 089 [ 074 106 ]
Total events 93 (Bile acids) 99 (Control)
Heterogeneity Chi2 = 392 df = 6 (P = 069) I2 =00
Test for overall effect Z = 130 (P = 019)
01 02 05 1 2 5 10
Favours bile acids Favours control
Analysis 18 Comparison 1 Bile acids for liver-transplanted patients Outcome 8 Subgroup analysis
number of patients with acute cellular rejection according to time of start of bile acid
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 8 Subgroup analysis number of patients with acute cellular rejection according to time of start of bile acid
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 Less than three days after transplantation
Keiding 1997 3554 3248 333 097 [ 073 129 ]
Koneru 1993 316 916 89 033 [ 011 101 ]
Subtotal (95 CI) 70 64 422 084 [ 063 111 ]
Total events 38 (Bile acids) 41 (Control)
Heterogeneity Chi2 = 374 df = 1 (P = 005) I2 =73
Test for overall effect Z = 124 (P = 022)
2 Three days or more after liver transplantation
Angelico 1999 816 1017 95 085 [ 045 160 ]
01 02 05 1 2 5 10
Favours bile acids Favours control
(Continued )
39Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Barnes 1997 1728 1724 180 086 [ 058 127 ]
Fleckenstein 1998 814 916 83 102 [ 054 190 ]
Pageaux 1995 926 924 92 092 [ 044 193 ]
Sama 1991 1320 1320 128 100 [ 063 158 ]
Subtotal (95 CI) 104 101 578 092 [ 072 117 ]
Total events 55 (Bile acids) 58 (Control)
Heterogeneity Chi2 = 041 df = 4 (P = 098) I2 =00
Test for overall effect Z = 067 (P = 050)
Total (95 CI) 174 165 1000 089 [ 074 106 ]
Total events 93 (Bile acids) 99 (Control)
Heterogeneity Chi2 = 392 df = 6 (P = 069) I2 =00
Test for overall effect Z = 130 (P = 019)
01 02 05 1 2 5 10
Favours bile acids Favours control
40Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 19 Comparison 1 Bile acids for liver-transplanted patients Outcome 9 Subgroup analysis
number of patients with acute cellular rejection according to treatment duration
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 9 Subgroup analysis number of patients with acute cellular rejection according to treatment duration
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 Less than six months
Barnes 1997 1728 1724 180 086 [ 058 127 ]
Fleckenstein 1998 814 916 83 102 [ 054 190 ]
Keiding 1997 3554 3248 333 097 [ 073 129 ]
Koneru 1993 316 916 89 033 [ 011 101 ]
Pageaux 1995 926 924 92 092 [ 044 193 ]
Subtotal (95 CI) 138 128 777 087 [ 071 107 ]
Total events 72 (Bile acids) 76 (Control)
Heterogeneity Chi2 = 374 df = 4 (P = 044) I2 =00
Test for overall effect Z = 129 (P = 020)
2 Six months or more
Angelico 1999 816 1017 95 085 [ 045 160 ]
Sama 1991 1320 1320 128 100 [ 063 158 ]
Subtotal (95 CI) 36 37 223 094 [ 065 136 ]
Total events 21 (Bile acids) 23 (Control)
Heterogeneity Chi2 = 017 df = 1 (P = 068) I2 =00
Test for overall effect Z = 035 (P = 073)
Total (95 CI) 174 165 1000 089 [ 074 106 ]
Total events 93 (Bile acids) 99 (Control)
Heterogeneity Chi2 = 392 df = 6 (P = 069) I2 =00
Test for overall effect Z = 130 (P = 019)
01 02 05 1 2 5 10
Favours bile acids Favours control
41Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 110 Comparison 1 Bile acids for liver-transplanted patients Outcome 10 Number of patients
with chronic rejection at maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 10 Number of patients with chronic rejection at maximum follow-up
Study or subgroup Bile acids Placebo Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Barnes 1997 128 624 611 014 [ 002 110 ]
Fleckenstein 1998 114 116 88 114 [ 008 1663 ]
Keiding 1997 154 348 300 030 [ 003 275 ]
Total (95 CI) 96 88 1000 028 [ 008 095 ]
Total events 3 (Bile acids) 10 (Placebo)
Heterogeneity Chi2 = 148 df = 2 (P = 048) I2 =00
Test for overall effect Z = 204 (P = 0041)
0001 001 01 1 10 100 1000
Favours bile acids Favours placebo
Analysis 111 Comparison 1 Bile acids for liver-transplanted patients Outcome 11 Number of patients
with steroid-resistant rejection at maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 11 Number of patients with steroid-resistant rejection at maximum follow-up
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Barnes 1997 328 724 277 037 [ 011 127 ]
Fleckenstein 1998 314 316 103 114 [ 027 478 ]
Keiding 1997 1454 1548 583 083 [ 045 154 ]
Pageaux 1995 226 124 38 185 [ 018 1908 ]
Total (95 CI) 122 112 1000 077 [ 047 127 ]
Total events 22 (Bile acids) 26 (Control)
Heterogeneity Chi2 = 226 df = 3 (P = 052) I2 =00
Test for overall effect Z = 102 (P = 031)
001 01 1 10 100
Favours bile acids Favours placebo
42Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 112 Comparison 1 Bile acids for liver-transplanted patients Outcome 12 Serum bilirubin (mgdl)
at the end of treatment
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 12 Serum bilirubin (mgdl) at the end of treatment
Study or subgroup Bile acids Placebo Mean Difference Weight Mean Difference
N Mean(SD) N Mean(SD) IVFixed95 CI IVFixed95 CI
Fleckenstein 1998 14 319 (68) 16 059 (022) 1000 260 [ -096 616 ]
Total (95 CI) 14 16 1000 260 [ -096 616 ]
Heterogeneity not applicable
Test for overall effect Z = 143 (P = 015)
-10 -5 0 5 10
Favours bile acids Favours placebo
Analysis 113 Comparison 1 Bile acids for liver-transplanted patients Outcome 13 Number of days of
hospitalisation after liver transplantation
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 13 Number of days of hospitalisation after liver transplantation
Study or subgroup Bile acids Placebo Mean Difference Weight Mean Difference
N Mean(SD) N Mean(SD) IVFixed95 CI IVFixed95 CI
Barnes 1997 28 25 (17) 24 335 (13) 1000 -850 [ -1667 -033 ]
Total (95 CI) 28 24 1000 -850 [ -1667 -033 ]
Heterogeneity not applicable
Test for overall effect Z = 204 (P = 0041)
-100 -50 0 50 100
Favours bile acids Favours placebo
43Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 114 Comparison 1 Bile acids for liver-transplanted patients Outcome 14 Adverse events
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 14 Adverse events
Study or subgroup Bile acids Placebo Risk Ratio Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Angelico 1999 016 017 00 [ 00 00 ]
Barnes 1997 128 124 086 [ 006 1298 ]
Keiding 1997 554 548 089 [ 027 288 ]
Total (95 CI) 98 89 088 [ 030 260 ]
Total events 6 (Bile acids) 6 (Placebo)
Heterogeneity Chi2 = 000 df = 1 (P = 098) I2 =00
Test for overall effect Z = 022 (P = 082)
001 01 1 10 100
Favours bile acids Favours placebo
A P P E N D I C E S
Appendix 1 Search strategies
Data Base Date of Search Search Strategy
The Cochrane Hepato-Biliary Group Con-
trolled Trials Register
September 2009 1 rsquoliver transplantationrsquo and rsquochenodeoxy-
cholicrsquo
2 rsquoliver transplantationrsquo and rsquocholicrsquo
3 rsquoliver transplantationrsquo and rsquodeoxycholicrsquo
4 rsquoliver transplantationrsquo and rsquoglycochen-
odeoxycholicrsquo
5 rsquoliver transplantationrsquo and rsquoglycocholicrsquo
6 rsquoliver transplantationrsquo and rsquoglycodeoxy-
cholicrsquo
7 rsquoliver transplantationrsquo and rsquoglycolitho-
cholicrsquo
8 rsquoliver transplantationrsquo and rsquohyodeoxy-
cholicrsquo
9 rsquoliver transplantationrsquo and rsquolithocholicrsquo
10 rsquoliver transplantationrsquo and rsquotaurochen-
odeoxycholicrsquo
44Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
11 rsquoliver transplantationrsquo and rsquotauro-
cholicrsquo
12 rsquoliver transplantationrsquo and rsquotaurodehy-
drocholicrsquo
13 rsquoliver transplantationrsquo and rsquotau-
rodeoxycholicrsquo
14 rsquoliver transplantationrsquo and rsquotauroglyco-
cholicrsquo
15 rsquoliver transplantationrsquo and rsquotaurolitho-
cholicrsquo
16 rsquoliver transplantationrsquo and rsquotaurosel-
cholicrsquo
17 rsquoliver transplantationrsquo and rsquotaurourso-
cholicrsquo
18 rsquoliver transplantationrsquo and rsquotaurour-
sodeoxycholicrsquo
19 rsquoliver transplantationrsquo and rsquoursocholicrsquo
20 rsquoliver transplantationrsquo and rsquoursodeoxy-
cholicrsquo
The Cochrane Central Register of Con-
trolled Trials in The Cochrane Library
Issue 3 2009 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
6 3 or 4
7 5 and 6
MEDLINE September 2009 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
45Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
6 3 or 4
7 5 and 6
8 RANDOMIZED-CONTROLLED-
TRIAL ME
9 RANDOM
10 8 or 9
11 7 and 10
EMBASE September 2009 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
6 3 or 4
7 5 and 6
8 RANDOMIZED-CONTROLLED-
TRIAL ME
9 RANDOM
10 8 or 9
11 7 and 10
46Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
Science Citation Index Expanded September 2009 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
6 3 or 4
7 5 and 6
8 RANDOMIZED-CONTROLLED-
TRIAL ME
9 RANDOM
10 8 or 9
11 7 and 10
The Chinese Biomedical Database Searched from January 1980 to April 2002 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
47Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
6 3 or 4
7 5 and 6
8 RANDOMIZED-CONTROLLED-
TRIAL ME
9 RANDOM
10 8 or 9
11 7 and 10
W H A T rsquo S N E W
Last assessed as up-to-date 8 February 2010
18 September 2009 New citation required but conclusions have not
changed
This review is an updated version of a review that was
published for the first time in Issue 3 2005 of TheCochrane Library by Chen 2003b
18 September 2009 New search has been performed No new studies fulfilled the inclusion criteria
H I S T O R Y
Protocol first published Issue 3 2003
Review first published Issue 3 2005
C O N T R I B U T I O N S O F A U T H O R S
GP and VG independently performed searches of relevant databases GP validated the search selected trials for inclusion contacted
the authors of the trials performed data extraction and data analysis and drafted the systematic review VG revised the review update
CG and DS revised the review update solved discrepancies of data extraction validated data analyses and provided consultation
D E C L A R A T I O N S O F I N T E R E S T
None known
48Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
S O U R C E S O F S U P P O R T
Internal sources
bull Copenhagen Trial Unit Denmark
External sources
bull Danish Medical Research Councilrsquos Grant on Getting Research into Practice (GRIP) Denmark
D I F F E R E N C E S B E T W E E N P R O T O C O L A N D R E V I E W
We assessed the risk of bias in the included studies for another four domains that were added to the review protocol (incomplete
outcome data selective outcome reporting baseline imbalance and early stopping of trial) In general the text of the risk of bias
domains were updated following Higgins 2008 Trials were considered at low risk of bias when judged as adequate in all domains
Quasi-randomised studies observational and case-control studies were included for the report of adverse events
We performed trial sequential analysis for outcomes demonstrating a statistically significant result
I N D E X T E R M S
Medical Subject Headings (MeSH)
lowastLiver Transplantation Cholagogues and Choleretics [lowasttherapeutic use] Graft Rejection [lowastprevention amp control] Randomized Con-
trolled Trials as Topic Taurochenodeoxycholic Acid [lowasttherapeutic use] Ursodeoxycholic Acid [lowasttherapeutic use]
MeSH check words
Humans
49Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Keiding 1997 Fleckenstein 1998) compared UDCA with placebo
or no intervention and demonstrated that UDCA did not signifi-
cantly reduce the number of patients with acute cellular rejection
after liver transplantation (RR 089 95 CI 074 to 108 85
158 (538) versus 89148 (601)) Neither did the Angelico
1999 trial demonstrate significant reduction of the number of pa-
tients with acute cellular rejection with TUDCA (RR 085 95
CI 045 to 160) 816 (500) versus 1017 (588) (Analysis
17)
Subgroup analyses
Two trials (Koneru 1993 Keiding 1997) in which the patients
started bile acids intake less than three days after liver transplan-
tation did not demonstrate any significant reduction of the risk
of acute cellular rejection by bile acids (RR 084 95 CI 063 to
111) 3870 (543) versus 4164 (641) The other five tri-
als (Sama 1991 Pageaux 1995 Barnes 1997 Fleckenstein 1998
Angelico 1999) in which the patients were started on bile acid
intake three days or more after liver transplantation did not find
a significant reduction of the risk of acute cellular rejection by bile
acids (RR 092 95 CI 072 to 117) 55104 (529) versus 58
101 (574) (Analysis 18) There was no significant difference
between the two estimates
Bile acids did not significantly reduce the risk of acute cellular
rejection in the five trials (Koneru 1993 Pageaux 1995 Barnes
1997 Keiding 1997 Fleckenstein 1998) in which the patients
received treatment with bile acids less than six months (RR 087
95 CI 071 to 107) 72138 (522) versus 76128 (594)
Neither did bile acids in the two other trials (Sama 1991 Angelico
1999) in which the patients received bile acids for more than six
months (RR 094 95 CI 065 to 136) 2136 (583) versus
2337 (622) (Analysis 19) There were no significant difference
between the two estimates
Number of patients with chronic rejection
Three trials comparing UDCA versus placebo (Barnes 1997
Keiding 1997 Fleckenstein 1998) reported the number of patients
with chronic rejection after liver transplantation UDCA signifi-
cantly reduced the number of patients with chronic rejection in
the fixed-effect model analysis (RR 028 95 CI 008 to 095)
396 (31) versus 1088 (114) (Analysis 110) but not in the
random-effects model analysis (RR 030 95 CI 008 to 113) 3
96 (31) versus 1088 (114) There was no statistically signifi-
cant heterogeneity (I2 0) We performed trial sequential analysis
for the available data from three trials (Figure 3) with heterogene-
ity corrected required information size based on proportion of this
outcome of 12 in the control group a relative risk reduction of
50 in the intervention group at a type I error of 5 and a type
II error of 10 We obtained a required information size of 957
patients UDCA was not able to reach or break the trial sequential
monitoring boundary and only 183 out of 957 (19) patients
were randomised regarding this outcome
11Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Figure 3 Trial sequential analysis for the number of patients with chronic rejection at maximum follow-up
We calculated the heterogeneity-corrected required information size (HCRIS) based on a proportion of 12 of
the patients in the placebo group with chronic rejection at maximum follow-up a 50 risk ratio reduction in
the bile acid group an alpha of 5 a beta of 10 and a heterogeneity of 0 Only 184 patients have been
randomised reporting this outcome which is only 19 of the HCRIS of 957 patients The cumulative Z-score
crosses the conventional boundaries for P 005 but not the monitoring boundaries
Number of patients with steroid-resistant rejection
Four trials (Pageaux 1995 Barnes 1997 Keiding 1997
Fleckenstein 1998) reported the number of patients with steroid-
resistant rejection These trials demonstrated that UDCA did not
significantly reduce the number of patients with steroid-resistant
rejection when compared with placebo (22122 (18) versus 26
112 (232) (RR 077 95 CI 047 to 127) (Analysis 111)
There was no significant heterogeneity (I2 0)
Liver biochemistry
The Fleckenstein 1998 trial reported serum bilirubin levels after
a three-month-treatment period in 30 liver-transplanted patients
There was no statistically significant difference in serum bilirubin
levels between the UDCA group and the placebo group (MD 260
mgdl 95 CI -096 to 616 mgdl) (Analysis 112)
No data were available for other liver biochemical variables
Cost-effectiveness
One trial (Barnes 1997) with 52 liver-transplanted patients re-
ported the days of hospitalisation after liver transplantation
UDCA significantly decreased the number of days of hospitali-
sation when compared with placebo (MD -850 days 95 CI -
1667 to -033 days) (Analysis 113) We were not able to extract
other medical cost from the trials
Adverse events
Among all the included and excluded trials only four reported on
adverse events however adverse events only occurred in two of
the included trials (Barnes 1997 Keiding 1997) There were no
significant differences regarding adverse events (RR 088 95 CI
030 to 260) 6112 (54) versus 6105 (57) (Analysis 114)
In the Barnes 1997 trial diarrhoea was reported by two patients
(one in the UDCA group and one in the placebo group) In the
Keiding 1997 trial five UDCA patients and five placebo patients
stopped intake of the trial medicine because of diarrhoea or dif-
ficulties in swallowing the capsules The remaining included trial
by Angelico 1999 stated that no adverse events occurred during
the study period The excluded trial by Assy 2007 was the only
one reporting on a case of mild diarrhoea in one patient in the
12Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
intervention group No other excluded studies reported on adverse
events (see Table 1)
Quality of life
None of the included studies assessed quality of life as an outcome
Other subgroup analyses
We planned to perform subgroup analyses regarding the risk of
bias of trials the dosage of bile acid and any co-intervention
However none of the trials were considered to be of low risk of
bias they all used a similar dosage of bile acid and patients in all
trials received similar immunosuppressive treatment as co-inter-
ventions (steroids azathioprine and cyclosporine or tacrolimus)
after liver transplantation Therefore we were not able to perform
the planned subgroup analyses
Funnel plot asymmetry
We did not draw a funnel plot analysis due to the limited number
of trials included in the present review
D I S C U S S I O N
In the update of this review we included no new trials assessing
the use of bile acids for liver-transplanted patients The analyses
of the seven previously included trials showed that bile acids did
not significantly affect mortality acute cellular rejection steroid-
resistant rejection retransplantation or serum bilirubin Bile acids
might significantly decrease the length of hospital stay and the
number of patients with chronic rejection included in these tri-
als but more supportive evidence is needed The number of pa-
tients with chronic rejection was not significantly influenced by
bile acids when a random-effects model was used and length of
stay was assessed in one single trial Furthermore none of the trials
were considered to be of low risk of bias and few patients were en-
rolled Therefore our positive findings may be due to bias (Schulz
1995 Moher 1998 Kjaergard 2001 Wood 2008) or random er-
rors (Wetterslev 2008 Brok 2009 Thorlund 2009) On the other
hand we are not able to exclude type II errors (that is finding
no significant differences when in fact they exist) due to the low
number of participants Therefore this topic could be of potential
interest in future large randomised trials with adequate control of
bias
All-cause mortality at one year after liver transplantation is re-
ported to be about 20 (Thuluvath 2003) which we also ob-
served for the patients included in the present review According to
our subgroup analyses neither UDCA nor TUDCA significantly
decreased all-cause mortality We also performed a subgroup anal-
ysis regarding treatment duration but we were not able to find any
difference between short (less than six months) and long treatment
duration (six months or more) Thus bile acids do not seem to
have statistically significant effects in reducing all-cause mortal-
ity after liver transplantation We performed both worst-best-case
scenario and best-worst-case scenario analyses In the worst-best-
case scenario bile acids did not differ significantly from placebo or
no intervention regarding all-cause mortality However bile acids
significantly decreased all-cause mortality in the best-worst-case
scenario analysis However such an analysis is very extreme and
may not be realistic We have also found that UDCA may be able
to decrease the risk of chronic rejection in liver-transplanted pa-
tients but trial sequential analysis could not confirm this result
Due to a limited number of patients (Ioannidis 2001) we are not
able to exclude the possibility that it may be relevant to perform
placebo-controlled trials with low risk of bias on the use of bile
acids for liver-transplanted patients
We looked into the causes of deaths that were reported by the trials
and only one trial reported one death related to rejection At the
same time the number of retransplantations was 3 among 68 liver-
transplanted patients who received treatment with UDCA and 4
among 64 liver-transplanted patients who received treatment with
placebo We noticed that all patients in the included trials received
co-interventions of standard triple-drug regimens (steroids aza-
thioprine and cyclosporine or tacrolimus) which were able to
control the possible acute or chronic rejection and prevent deaths
due to allograft rejection (FK506 1994)
The assumption that UDCA might reduce the incidence of acute
graft rejection came from the findings that UDCA could regulate
major histocompatibility complex antigen expression in bile ducts
and liver endothelia and inhibit lymphocyte activity (Calmus
1990 Terasaki 1991 Perez 2009) However in the present review
bile acids did not significantly reduce the risk of acute cellular re-
jection in liver-transplanted patients Considering that acute cellu-
lar rejection is commonly found within a few days after liver trans-
plantation (Vierling 1992) some might argue that the adminis-
tration of bile acids was started too late to prevent acute cellular
rejection We performed subgroup analyses regarding the time bile
acids were started and no statistically significant difference was
found Furthermore bile acids were not able to decrease the risk
of steroid-resistant rejection Therefore the lack of effects of bile
acids does not seem to be due to a delayed start to bile acid ad-
ministration after liver transplantation However it is a possibility
that one should start bile acids intake before liver transplantation
A retrospective study found that rejection rates differed signifi-
cantly between patients with primary biliary cirrhosis treated with
or without UDCA before liver transplantation (Heathcote 1999)
One could argue whether UDCA-induced delay in transplantation
has an adverse effect on post-transplantation outcome Since we
did not find any prospective randomised clinical trials addressing
this issue further research might be needed Furthermore some
studies may provide an explanation why UDCA was not able to
prevent acute cellular rejection These studies found that UDCA
did not appear to change the expression of major histocompatibil-
ity complex class II antigens but rather major histocompatibility
complex class I antigens (Calmus 1990) The initial mechanism
of acute rejection is thought to be recognition of MHC class II
13Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
antigens by CD4+ T cells (Vierling 1992) Moreover the inhibi-
tion of the production of interleukin-2 by peripheral blood lym-
phocytes with UDCA (Heuman 1993) might be negated by the
immunosuppressive treatment after liver transplantation (van den
Berg 1998) so that UDCA is unable to demonstrate effects on
graft rejection In a recent study by Assy 2007 a significant re-
duction in the mean dose of immunosuppressive medications was
achieved in stable liver graft recipients treated with UDCA indi-
cating a possible influence of UDCA on rejection mechanisms
In accordance with previous systematic reviews (Chen 2003a
Chen 2007 Gong 2008) bile acids were not associated with the
occurrence of serious adverse events or any major occurrence of
adverse events
In summary our results do not support or refute the use of bile
acids (UDCA and TUDCA) additional to standard immunosup-
pressive treatment in liver-transplanted patients
A U T H O R S rsquo C O N C L U S I O N SImplications for practice
There seems to be no evidence to support or refute the use of bile
acids for liver-transplanted patients receiving standard immuno-
suppressive treatment
Implications for research
We need more randomised placebo-controlled clinical trials with
enough statistical power and low risk of bias to explore the poten-
tial effects of bile acids on chronic rejection and mortality in liver-
transplanted patients Such trials should also consider evaluation
of quality of life and length of hospitalisation Such trials may
consider starting bile acid and placebo interventions before liver
transplantation we were not able to identify any randomised trials
addressing this regimen Such trials ought to be reported accord-
ing to the CONSORT statement (wwwconsort-statementorg)
However before embarking on such trials the effects of bile acids
in other patient groups should be scrutinised as they may have
small or negative effects
A C K N O W L E D G E M E N T S
We thank all the patients and investigators who were involved in
the clinical trials mentioned in this review We thank Wendong
Chen for his work and contribution on the previous version of this
review We thank the staff of The Cochrane Hepato-Biliary Group
Editorial Team especially Dimitrinka Nikolova and Sarah Louise
Klingenberg for excellent collaboration and assistance during the
update of this review
Peer Reviewers Carlo Merkel Italy M Tomikawa Japan
Contact Editor Bodil Als-Nielsen Denmark
R E F E R E N C E S
References to studies included in this review
Angelico 1999 published data only
Angelico M Tisone G Baiocchi L Palmieri G Pisani F Negrini S
et alOne-year pilot study on tauroursodeoxycholic acid as an
adjuvant treatment after liver transplantation Italian Journal of
Gastroenterology and Hepatology 199931(6)462ndash8 [MEDLINE
10575563]
Barnes 1997 published data onlylowast Barnes D Talenti D Cammell G Goormastic M Farquhar L
Henderson M et alA randomized clinical trial of ursodeoxycholic
acid as adjuvant treatment to prevent liver transplant rejection
Hepatology 199726(4)853ndash7 [MEDLINE 9328304]
Barnes D Talenti D Goormastic M Farquhar L Cammell G
Henderson M et alUrsodeoxycholic acid (UDCA) reduces hepatic
allograft rejection after orthotopic liver transplantation (OLT) - a
prospective randomized placebo-controlled double-blind trial
Hepatology 199522149A
Fleckenstein 1998 published data only
Fleckenstein JF Paredes M Thuluvath PJ A prospective
randomized double-blind trial evaluating the efficacy of
ursodeoxycholic acid in prevention of liver transplant rejection
Liver Transplantation and Surgery 19984(4)276ndash9 [MEDLINE
9649640]
Keiding 1997 published data only
Keiding S Hockerstedt K Bjoro K Bondesen S Hjortrup A
Isoniemi H et alThe Nordic multicenter double-blind randomized
controlled trial of prophylactic ursodeoxycholic acid in liver
transplant patients Transplantation 199763(11)1591ndash4
[MEDLINE 9197351]
Koneru 1993 published data only
Koneru B Tint GS Wilson DJ Leevy CB Salen F Randomised
prospective trial of ursodeoxycholic acid in liver transplant
recipients Hepatology 199318336A
Pageaux 1995 published data only
Pageaux GP Blanc P Perrigault PF Navarro F Fabre JM Souche B
et alFailure of ursodeoxycholic acid to prevent acute cellular
rejection after liver transplantation Journal of Hepatology 199523
(2)119ndash22 [MEDLINE 7499781]
Sama 1991 published data only
Sama C Mazziotti A Grigioni W Morselli AM Chianura A
Stefanini GF et alUrsodeoxycholic acid administration does not
14Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
prevent rejection after OLT Journal of Hepatology 199113(Suppl
2)68
References to studies excluded from this review
Assy 2007 published data only
Assy N Adams PC Myers P Simon V Minuk GY Wall W et
alRandomized controlled trial of total immunosuppression
withdrawal in liver transplant recipients role of ursodeoxycholic
acid Transplantation 200783(12)1571ndash6 [MEDLINE
17589339]
Clavien 1996 published data only
Clavien PA Sharara AI Camargo CA Jr Harland RC Fitz JG
Evidence that ursodeoxycholic acid prevents steroid-resistant
rejection in adult liver transplantation Clinical Transplantation
199610(6 Pt 2)658ndash62 [MEDLINE 8996761]
Friman 1992 published data only
Friman S Persson H Schersten T Svanvik J Karlberg I Adjuvant
treatment with ursodeoxycholic acid reduces acute rejection after
liver transplantation Transplantation Proceedings 199224(1)
389ndash90 [MEDLINE 1539328]
Heathcote 1999 published data onlylowast Heathcote EJ Stone J Cauch-Dudek K Poupon R Chazouilleres
O Lindor KD et alEffect of pretransplantation ursodeoxycholic
acid therapy on the outcome of liver transplantation in patients
with primary biliary cirrhosis Liver Transplantation and Surgery
19995(4)269ndash74 [MEDLINE 10388499]
Henriksson 1991 published data only
Henriksson BA Persson H Friman S Wangberg B Svanvik J
Karlberg I Adjuvant ursodeoxycholic acid prevents acute rejection
in liver transplant recipients Transplantation Proceedings 199123
(3)1971 [MEDLINE 2063453]
Persson 1990 published data only
Persson H Friman S Schersten T Svanvik J Karlberg I
Ursodeoxycholic acid for prevention of acute rejection in liver
transplant recipients Lancet 1990336(8706)52ndash3 [MEDLINE
1973232]
Rafael 1995 published data only
Rafael E Duraj F Rudstrom H Wilczek H Ericzon B Effect of
ursodeoxycholic acid treatment for cholestasis in liver transplant
recipients Transplantation Proceedings 199527(6)3501ndash2
[MEDLINE 8540069]
Sama 1998 published data only
Sama C Morselli-Labate AM Grazi GL Mastroianni A Danesi G
Pianta P et alUrsodeoxycholic acid in liver transplantation effect
on cholestasis and rejection Gastroenterology 1998114(4 Suppl)
A1332
Additional references
Adams 1990
Adams DH Neuberger JM Patterns of graft rejection following
liver transplantation Journal of Hepatology 199010(1)113ndash9
[MEDLINE 2407770]
Al-Quaiz 1994
Al-Quaiz M OrsquoGrady J Tredger J Williams R Variable effect of
ursodeoxycholic acid on cyclosporin absorption after orthotopic
liver transplantation Transplant International 19947(3)190ndash4
[MEDLINE 8060468]
Armstrong 1982
Armstrong MJ Carey MC The hydrophobic-hydrophilic balance
of bile salt Inverse correlation between reverse phase high
performance liquid chromatographic mobilities and micellar
cholesterol-solubilizing capacities Journal of Lipid Research 1982
23(1)70ndash80 [MEDLINE 7057113]
Ascher 1988
Ascher NL Stock PG Baumgardner GL Payne WD Najarian JS
Infection and rejection of primary hepatic transplant in 93
consecutive patients treated with triple immunosuppressive therapy
Surgery Gynecology amp Obstetrics 1988167(6)474ndash84
[MEDLINE 3055368]
Brok 2008
Brok J Thorlund K Gluud C Wetterslev J Trial sequential
analysis reveals insufficient information size and potentially false
positive results in many meta-analyses Journal of Clinical
Epidemiology 200861(8)763ndash9 [MEDLINE 18411040]
Brok 2009
Brok J Thorlund K Wetterslev J Gluud C Apparently conclusive
meta-analysis may be inconclusive - Trial sequential analysis
adjustment of random error risk due to repetitive testing of
accumulating data in apparently conclusive neonatal meta-analysis
International Journal of Epidemiology 200938(1)298ndash303
[MEDLINE 18824466]
Calmus 1990
Calmus Y Gane P Rouger P Poupon R Hepatic expression of class
I and class II major histocompatibility complex molecules in
primary biliary cirrhosis effect of ursodeoxycholic acid Hepatology
199011(1)12ndash5 [MEDLINE 2403961]
Calmus 1992
Calmus Y Arvieux C Gane P Boucher E Nordlinger B Rouger P
et alCholestasis induces major histocompatibility complex class I
expression in hepatocytes Gastroenterology 1992102(4 Pt 1)
1371ndash7 [MEDLINE 1551542]
Chen 2003a
Chen W Gluud C Bile acids for primary sclerosing cholangitis
Cochrane Database of Systematic Reviews 2003 Issue 2 [DOI
10100214651858CD003626]
Chen 2007
Chen W Liu J Gluud C Bile acids for viral hepatitis Cochrane
Database of Systematic Reviews 2007 Issue 4 [DOI 101002
14651858CD003181pub2]
Cheng 2002
Cheng K Ashby D Smyth R Ursodeoxycholic acid for cystic
fibrosis-related liver disease Cochrane Database of Systematic
Reviews 2002 Issue 2 [DOI 10100214651858CD000222]
Corbani 2008
Corbani A Burroughs AK Intrahepatic cholestasis after liver
transplantation Clinics in Liver Disease 200812(1)111ndash29
[MEDLINE 18242500]
DeMets 1987
DeMets DL Methods for combining randomised clinical trials
strengths and limitations Statistics in Medicine 19876(3)341ndash50
[MEDLINE 3616287]
15Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
DerSimonian 1986
DerSimonian R Laird N Meta-analysis in clinical trials Controlled
Clinical Trials 19867(3)177ndash88 [MEDLINE 3802833]
Egger 1997
Egger M Davey Smith G Schneider M Minder C Bias in meta-
analysis detected by a simple graphical test BMJ (Clinical Research
Ed) 1997315(7109)629ndash34 [MEDLINE 9310563]
Ericzon 1990
Ericzon BG Eusufzai S Kubota K Einarsson K Angelin B
Characteristics of biliary lipid metabolism after liver
transplantation Hepatology 199012(5)1222ndash8 [MEDLINE
2227822]
FK506 1994
The US Multicenter FK506 Liver Study Group A comparison of
tacrolimus (FK506) and cyclosporine for immunosuppression in
liver transplantation New England Journal of Medicine 1994331
(17)1110ndash5 [MEDLINE 7523946]
Friman 1994
Friman S Svanvik J A possible role of ursodeoxycholic acid in liver
transplantation Scandinavian Journal of Gastroenterology 1994204
62ndash4 [MEDLINE 7824880]
Fuchs 1999
Fuchs M Stange EF Metabolism of bile acids In Johannes
Bircher Jean-Pierre Benhamou Neil McIntyre Mario Rizzetto
Juan Rodes editor(s) Oxford Textbook of Clinical Hepatology 2
Vol 1 Oxford Oxford University Press 1999223ndash56
Fusai 2006
Fusai G Dhaliwal P Rolando N Sabin CA Patch D Davidson BR
et alIncidence and risk factors for the development of prolonged
and severe intrahepatic cholestasis after liver transplantation Liver
Transplantation 200612(11)1626ndash33 [DOI 101002lt20870]
Gluud 2001
Gluud C Alcoholic hepatitis no glucocorticosteroids In
Leuschner U James OFW Dancygier H editor(s) Steatohepatitis
(NASH and ASH) Falk Symposium 121 Lancaster Kluwer
Academic Publisher 2001322ndash42
Gluud 2010
Gluud C Nikolova D Klingenberg SL Alexakis N Als-Nielsen B
Colli A et alCochrane Hepato-Biliary Group About The
Cochrane Collaboration (Cochrane Review Groups (CRGs))
2010 Issue 1 Art No LIVER
Gong 2008
Gong Y Huang ZB Christiansen E Gluud C Ursodeoxycholic
acid for primary biliary cirrhosis Cochrane Database of Systematic
Reviews 2008 Issue 3 [DOI 101002
14651858CD000551pub2]
Haddad 2006
Haddad EM McAlister VC Renouf E Malthaner R Kjaer MS
Gluud LL Cyclosporin versus tacrolimus for liver transplanted
patients Cochrane Database of Systematic Reviews 2006 Issue 4
[DOI 10100214651858CD005161pub2]
Heuman 1993
Heuman DM Hepatoprotective properties of ursodeoxycholic acid
Gastroenterology 1993104(6)1865ndash9 [MEDLINE 8500748]
Higgins 2008
Higgins PTJ Green S editors Cochrane Handbook for Systematic
Reviews of Interventions West Sussex England Wiley-Blackwell
2008
Hirschfield 2009
Hirschfield GM Gibbs P Griffiths WJH Adult liver
transplantation what non-specialists need to know BMJ (Clinical
Research Ed) 2009338(b1670)1321ndash7 [DOI 101136
bmjb1670]
Hussain 2002
Hussain HK Nghiem HV Imaging of hepatic transplantation
Clinics in Liver Disease 20026(1)247ndash70 [MEDLINE
11933592]
ICH-GCP 1997
International Conference on Harmonisation Expert Working
Group Code of Federal Regulations amp International Conference on
Harmonization Guidelines Media Parexel Barnett 1997
Ioannidis 2001
Ioannidis JPA Lau J Evolution of treatment effects over time
Empirical insight from recursive cumulative meta analyses
Proceedings of the National Academy of Sciences 200198(3)831ndash6
IWP 1995
International Working Party Terminology for hepatic allograft
rejection Hepatology 199522(2)648ndash54 [MEDLINE 7635435]
Kjaergard 2001
Kjaergard LL Villumsen J Gluud C Reported methodological
quality and discrepancies between large and small randomised trials
in meta-analyses Annals of Internal Medicine 2001135(11)982ndash9
[MEDLINE 11730399]
Klintmalm 1989
Klintmalm GB Nery JR Husberg BS Gonwa TA Tillery GW
Rejection in liver transplantation Hepatology 198910(6)978ndash85
[MEDLINE 2583691]
Knechtle 2009
Knechtle SJ Kwun J Unique aspects of rejection and tolerance in
liver transplantation Seminars in Liver Disease 200929(1)91ndash101
[MEDLINE 19235662]
Krams 1993
Krams SM Ascher NL Martinez OM New immunologic insights
into mechanisms of allograft rejection Gastroenterology Clinics of
North America 199318(2)374ndash7 [MEDLINE 8509176]
Lan 1983
Lan KKG DeMets DL Discrete sequential boundaries for clinical
trials Biometrika 198370659ndash63
Merion 1989
Merion RM Gorski DH Burtch GD Turcotte JG Colletti LM
Campbell DA Jr Bile refeeding after liver transplantation and
avoidance of intravenous cyclosporine Surgery 1989106(4)
604ndash9 [MEDLINE 2799635]
Moher 1998
Moher D Pham B Jones A Cook DJ Jadad AR Moher M et
alDoes quality of reports of randomised trials affect estimates of
intervention efficacy reported in meta-analyses Lancet 1998352
(9128)609ndash13 [MEDLINE 9746022]
16Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Neuberger 1999
Neuberger J Incidence timing and risk factors for acute and
chronic rejection Liver Transplantation and Surgery 19995(4 Suppl
1)S30ndashS36 [MEDLINE 10431015]
Okolicsanyi 1986
Okolicsanyi L Lirussi F Strazzabosco M Jemmolo RM Orlando R
Nassuato G et alThe effect of drugs on bile flow and composition
An overview Drugs 198631(5)430ndash48 [MEDLINE 2872047]
Palmer 1972
Palmer RH Bile acids liver injury and liver disease Archives of
Internal Medicine 1972130(4)606ndash17 [MEDLINE 4627840]
Perez 2009
Perez MJ Briz O Bile-acid-induced cell injury and protection
World Journal of Gastroenterology 200915(14)1677ndash89
[MEDLINE 19360911]
Pogue 1997
Pogue JM Yusuf S Cumulating evidence from randomized trials
Utilizing sequential monitoring boundaries for cumulative meta-
analysis Controlled Clinical Trials 199718(6)580ndash93
[MEDLINE 9408720]
Pogue 1998
Pogue J Yusuf S Overcoming the limitations of current meta-
analysis of randomised controlled trials Lancet 1998351(9095)
45ndash52 [MEDLINE 9433436]
RevMan 2008
The Nordic Cochrane Centre The Cochrane Collaboration
Review Manager (RevMan) 50 Copenhagen The Nordic
Cochrane Centre The Cochrane Collaboration 2008
Royle 2003
Royle P Milne R Literature searching for randomized controlled
trials used in Cochrane reviews rapid versus exhaustive searches
International Journal of Technology Assessment in Health Care 2003
19(4)591ndash603
Schulz 1995
Schulz KF Chalmers I Hayer R Altman D Empirical evidence of
bias JAMA 1995273(5)408ndash12 [MEDLINE 7823387]
Sharara 1995
Sharara AI Camargo CA Clavien PA Ursodeoxycholic acid
prevents steroid resistant rejection in liver transplant recipients
Gastroenterology 1995108A1168
Sholmerich 1984
Sholmerich J Becher MS Schmidt KH Schubert R Kremer B
Felhaus S et alInfluence of hydroxylation and conjugation of bile
salts on their membrane damaging properties Hepatology 19844
(4)661ndash7 [MEDLINE 6745854]
Soderdahl 1998
Soderdahl G Nowak G Duraj F Wang FH Einarsson C Ericzon
BG Ursodeoxycholic acid increased bile flow and affects bile
composition in the early postoperative phase following liver
transplantation Transplantation International 199811(Suppl 1)
S231ndashS238 [MEDLINE 9664985]
Terasaki 1991
Terasaki S Nakanuma Y Ogino H Unoura M Kobayashi K
Hepatocellular and biliary expression of HLA antigens in primary
biliary cirrhosis before and after ursodeoxycholic acid therapy
American Journal of Gastroenterology 199186(9)1194ndash9
[MEDLINE 1882800]
Thalheimer 2002
Thalheimer U Capra F Liver transplantation making the best out
of what we have Digestive Diseases and Sciences 200247(5)
945ndash53 [MEDLINE 12018919]
Thorlund 2009
Thorlund K Devereaux PJ Wetterslev J Guyatt G Ioannidis JP
Thabane L et alCan trial sequential monitoring boundaries reduce
spurious inferences from meta-analyses International Journal of
Epidemiology 200938(1)276ndash86 [MEDLINE 18824467]
Thuluvath 2003
Thuluvath PJ Yoo HY Thompson RE A model to predict survival
at one month one year and five years after liver transplantation
based on pretransplant clinical characteristics Liver Transplantation
20039(5)527ndash32 [MEDLINE 12740799]
van den Berg 1998
van den Berg AP Twilhaar WN Mesander G van Son WJ van der
Bij W Klompmaker IJ et alQuantitation of immunosuppression
by flow cytometric measurement of the capacity of T cells for
interleukin-2 production Transplantation 199865(8)1066ndash71
[MEDLINE 9583867]
Vierling 1992
Vierling J Immunologic mechanisms of hepatic allograft rejection
Seminars in Liver Disease 199212(1)16ndash27 [MEDLINE
1570548]
Wetterslev 2008
Wetterslev J Thorlund K Brok J Gluud C Trial sequential
analysis may establish when firm evidence is reached in cumulative
meta-analysis Journal of Clinical Epidemiology 200861(1)64ndash75
[MEDLINE 18083463]
Wiesner 1992
Wiesner RH Acute cellular rejection following liver
transplantation incidence risk factors and outcome in the
NIDDK Liver Transplant Database (LTD) study Gastroenterology
1992102A910
Wood 2008
Wood L Egger M Gluud LL Schulz KF Juni P Altman DG et
alEmpirical evidence of bias in treatment effect estimates in
controlled trials with different interventions and outcomes meta-
epidemiological study BMJ (Clinical Research Ed) 2008336
(7644)601ndash5 [MEDLINE 18316340]
Yoshikawa 1998
Yoshikawa M Matsui Y Kawamoto H Toyohara M Matsumura
K Yamao J et alIntragastric administration of ursodeoxycholic
acid suppresses immunoglobulin secretion by lymphocytes from
liver but not from peripheral blood spleen or Peyerrsquos patches in
mice International Journal of Immunopharmacology 199820(1-3)
29ndash38 [MEDLINE 9717080]
References to other published versions of this review
17Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Chen 2003b
Chen W Gluud C Bile acids for liver transplanted patients
Cochrane Database of Systematic Reviews 2005 Issue 3 [DOI
10100214651858CD005442]lowast Indicates the major publication for the study
18Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
C H A R A C T E R I S T I C S O F S T U D I E S
Characteristics of included studies [ordered by study ID]
Angelico 1999
Methods Study design open-label randomised one-year pilot study
Participants Country Italy
Publication language English
Inclusion criteria
- patients who underwent liver transplantation from April 1994 to December 1994
Exclusion criteria
- not mentioned
Participants
Two patients in TUDCA group and two patients in control group were excluded from
the basic information of participants by the study due to withdrawal
- TUDCA group (n = 14)
Mean age (years +- SD)
467 +- 84
Ratio of sex (malefemale) 122
Origins of liver diseases
hepatitis C cirrhosis (9) hepatitis B cirrhosis (2) hepatitis B and C cirrhosis (1) cryp-
togenic cirrhosis (2) alcoholic cirrhosis (0) Wilson cirrhosis (0)
- Control group (n = 15)
Mean age (years +- SD)
474 +- 74
Ratio of sex (malefemale) 123
Origins of liver diseases
hepatitis C cirrhosis (7) hepatitis B cirrhosis (2) hepatitis B and C cirrhosis (2) cryp-
togenic cirrhosis (2) alcoholic cirrhosis (1) Wilson cirrhosis (1)
Interventions TUDCA group
- Dose 500 mgday in two divided doses
- Route orally
- Duration the treatment was started on day 5 after transplantation and continued for
one year
Control group
- no treatment
Co-interventions all patients received standard triple-drug regimens (steroids azathio-
prine and cyclosporine or tacrolimus)
Outcomes All cause mortality
Number of patients with rejection after liver transplantation
Notes Letter was sent to the authors in September 2009 A reply with additional information
was received shortly after
Risk of bias
19Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Angelico 1999 (Continued)
Item Authorsrsquo judgement Description
Adequate sequence generation Yes Computer generated table
Allocation concealment Unclear No information provided
Blinding No Not performed
Incomplete outcome data addressed
All outcomes
Yes Withdrawal two patients from the
TUDCA group and two patients from the
placebo group Three of them died due to
transplant non-function in the first postop-
erative week and one patient was regrafted
due to thrombosis of hepatic artery
Free of selective reporting Unclear Post-transplant cholestasis and liver bio-
chemistry specified as outcomes Differ-
ence reported as not significant but no ac-
tual data given
Sample size calculation No Not reported
Intention-to-treat analysis No Not stated and not used
Baseline imbalance Unclear Not enough information provided
Early stopping of trial Unclear Not enough information provided
Barnes 1997
Methods Study design randomised placebo-controlled double-blind trial
Participants Country United States
Publication language English
Inclusion criteria
- patients aged 18 years or older who underwent liver transplantation at the Cleveland
Clinic Foundation from April 1992 through June of 1994
Exclusion criteria
- patients who were found to have cancer at surgically resected margins of the biliary
tree
- patents who underwent retransplantation
Participants
- UDCA group (n = 28)
Mean age (years +- SD)
505 +- 116
Ratio of sex (malefemale) 1810
Child class A 7
20Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Barnes 1997 (Continued)
B 13
and C 8
Origins of liver diseases Laennecrsquos cirrhosis 4
PBC 3
cryptogenic cirrhosis 6
hepatitis Ccirrhosis 4
hepatitis Bcirrhosis 3
autoimmune hepatitis with cirrhosis 3
PSC 2
other 3
- Placebo group (n = 24)
Mean age (years +- SD)
507 +- 93
Ratio of sex (malefemale) 159
Child class A 6
B 14
and C 4
Origins of liver diseases Laennecrsquos cirrhosis 9
PBC 5
cryptogenic cirrhosis 1
hepatitis Ccirrhosis 1
hepatitis Bcirrhosis 1
autoimmune hepatitis with cirrhosis 1
PSC 2
other 4
Interventions UDCA group
- Dose 10-15 mgkg body weightday in divided doses
- Route orally
- Duration immediately after intestinal transit recovery usually between postoperative
days three and five and continue for three months
Placebo group
- identical-appearing capsules administered in the same quantity and manner
Co-interventions all patients received standard triple-drug regimens (steroids azathio-
prine and cyclosporine or tacrolimus)
Outcomes All cause mortality
Number of patients with acute cellular rejection
Number of patients with chronic rejection
Number of patients with steroid-resistant rejection
Number of days of hospitalisation
Adverse events
Notes Letter was sent to the authors in September 2009 A reply with additional information
was received shortly after
Risk of bias
Item Authorsrsquo judgement Description
21Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Barnes 1997 (Continued)
Adequate sequence generation Yes Computer generated table
Allocation concealment Unclear No information provided
Blinding Yes Quote ldquorandomised to receive either
UDCA or an identical placebo capsulerdquo
Incomplete outcome data addressed
All outcomes
Yes Mean follow-up time 18 months Ten pa-
tients withdrawn from study 6 in UDCA
group and 4 in placebo group Reasons
for withdrawal were reported Four patients
died in the placebo group
Free of selective reporting Yes All expected outcomes reported
Sample size calculation Unclear The trial reported the method of sample
size calculation but the actual number of
patients needed was not reported
Intention-to-treat analysis Yes Stated and used
Baseline imbalance Unclear Not enough information provided
Early stopping of trial Unclear The number of patients needed to gain the
actual power was not reported Whether
the trial was terminated early is not clear
Fleckenstein 1998
Methods Study design prospective randomised double-blind trial
Participants Country United States
Publication language English
Inclusion criteria
- patients who underwent liver transplantation at the Johns Hopkins Hospital
Exclusion criteria
- patients who were under 18 years old undergoing repeat transplantation had primary
graft nonfunction or refused consent
Participants
- UDCA group (n = 14)
Mean age (years +- SD)
443 +- 127
Ratio of sex (malefemale) 68
Origins of liver diseases hepatitis C 6
alcohol 2
autoimmune 1
PBC 2
22Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Fleckenstein 1998 (Continued)
PSC 1
autoimmune cholangiopathy 1
hepatitis B 1
- Placebo group (n = 16)
Mean age (years +- SD)
496 +- 109
Ratio of sex (malefemale) 124
Origins of liver diseases hepatitis C 3
alcohol 3
autoimmune 3
PBC 1
PSC 2
cryptogenic 2
hepatitis B 1
alpha1-antitrypsin deficiency 1
Interventions UDCA group
- Dose 15 mgkg body weightday in divided doses
- Route orally
- Duration immediately after intestinal transit recovery usually between postoperative
days three and five and continue for three months
Placebo group
- Identical-appearing capsules administered in the same quantity and manner
Co-interventions all patients received standard triple-drug regimens (steroids azathio-
prine and cyclosporine or tacrolimus)
Outcomes All cause mortality
Number with retransplantation
Number of patients with acute cellular rejection
Number of patients with chronic rejection
Serum bilirubin levels at the end of treatment
Notes Follow-up time nine months
Letter was sent to the authors in September 2009 No reply was received
Risk of bias
Item Authorsrsquo judgement Description
Adequate sequence generation Unclear No information provided
Allocation concealment Unclear No information provided
Blinding Yes Method of blinding not described but
probably adequate
Incomplete outcome data addressed
All outcomes
Yes Withdrawal one patient from the UDCA
group and two patients from the placebo
group because of capsule size
23Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Fleckenstein 1998 (Continued)
Free of selective reporting Unclear Outcomes were not completely described
Sample size calculation No Not reported
Intention-to-treat analysis Yes Quote ldquoThree patients withdrew after in-
clusionThey were included in the statis-
tical analysisrdquo
Baseline imbalance Unclear Not enough information provided
Early stopping of trial Unclear Not enough information provided
Keiding 1997
Methods Study design prospective randomised placebo-controlled multicenter study
Participants Country Denmark Finland Norway and Sweden
Publication language English
Inclusion criteria
- patients who underwent liver transplantation in Denmark Finland Norway and Swe-
den from September 1 1992 to May 31 1994
Exclusion criteria
- patients with malignant diseases
Participants
The age of the children ranged from 0 to 13 years (median 15) and the age of adults
ranged from 14 to 59 years old (median 44) MaleFemale ratio was 96 for children and
4344 for adults
- UDCA group (n = 54)
Origins of liver diseases
paracetamol intoxication 1 hepatitis B 1 autoimmune hepatitis 0 biliary atresia 2
metabolic diseases 7 neonatal hepatitis 2 PBC 13 post hepatitis cirrhosis 8 PSC 3
cryptogenic cirrhosis 7 alcoholic cirrhosis 2 other reasons 8
- Placebo group (n = 48)
Origins of liver diseases paracetamol intoxication 1 hepatitis B 0 autoimmune hepatitis
1 biliary atresia 3 metabolic diseases 11 neonatal hepatitis 0 PBC 7 post hepatitis
cirrhosis 5 PSC 7 cryptogenic cirrhosis 2 alcoholic cirrhosis 6 other reasons 5
Interventions UDCA group
- Dose 15 mgkg body weightday in two or three divided doses
- Route orally
- Duration immediately after intestinal transit recovery usually between postoperative
days three and five and continue for three months
Placebo group
- Identical-appearing capsules administered in the same quantity and manner
Co-interventions all patients received standard triple-drug regimens (steroids azathio-
prine and cyclosporine or tacrolimus)
24Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Keiding 1997 (Continued)
Outcomes All cause mortality
Number of deaths related to rejection
Number of patients with acute cellular rejection
Number of patients with chronic rejection
Number of patients with steroid-resistant rejection
Adverse events
Notes Letter was sent to the authors in September 2009 No reply was received
Risk of bias
Item Authorsrsquo judgement Description
Adequate sequence generation Unclear Patients were randomised at a ratio of 11
Allocation concealment Yes Quote ldquo The allocation was performed in
blocks of 10 patients using the sealed serial
envelope methodrdquo
Blinding Yes Quote ldquoThe UDCA and the placebo cap-
sules had identical appearance and tasterdquo
Incomplete outcome data addressed
All outcomes
Yes Follow-up time 12 months Five UDCA
patients and five placebo patients withdrew
from study Reasons were reported
Free of selective reporting Unclear Insufficient information
Sample size calculation Yes Performed and allowed for a difference in
the incidence of at least one episode of
acute rejection of 50 between the treat-
ment and placebo groups with 90 statisti-
cal power and a significance level of P value
less than 005 The calculated sample size
was 80 patients
Intention-to-treat analysis Yes Stated and used
Baseline imbalance Yes The study seems to be free of baseline im-
balance
Early stopping of trial Yes Study attained the pre-specified sample
size
25Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Koneru 1993
Methods Study design randomised controlled trial
Participants Country United States
Publication language English
Inclusion criteria
- patients who underwent liver transplantation
Exclusion criteria
- not mentioned
Participants
- UDCA group (n = 16)
Mean age (years +- SD)
no information
Ratio of sex (malefemale) no information
Origins of liver diseases
no information
- Control group (n = 16)
Mean age (years +- SD)
no information
Ratio of sex (malefemale) no information
Origins of liver diseases
no information
Interventions UDCA group
- Dose 900 mgday
- Route orally
- Duration immediately after intestinal transit recovery usually between postoperative
days three and five and continue for three months
Control group
- no treatment
Co-interventions all patients received standard triple-drug regimens (steroids azathio-
prine and cyclosporine)
Outcomes Number of patients with retransplantation due to rejection
Number of patients with rejection episodes
Notes Abstract
Letter was sent to the authors in September 2009 No reply was received
Risk of bias
Item Authorsrsquo judgement Description
Adequate sequence generation Unclear No information provided
Allocation concealment Unclear No information provided
Blinding No Not performed
26Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Koneru 1993 (Continued)
Incomplete outcome data addressed
All outcomes
Unclear The study gives the impression that there
were no withdrawals but this was not ex-
plicitly stated
Free of selective reporting Unclear Insufficient information provided
Sample size calculation No Not performed
Intention-to-treat analysis Unclear No information provided
Baseline imbalance Unclear Not enough information provided
Early stopping of trial Unclear Not enough information provided
Pageaux 1995
Methods Study design double-blind randomised study
Participants Country France
Publication language English
Inclusion criteria
- patients who underwent liver transplantation
Exclusion criteria
- not mentioned
Participants
- UDCA group (n=26)
Mean age (years +- SD)
47 +- 10
Ratio of sex (malefemale) 179
Origins of liver diseases alcoholic cirrhosis 14
post-hepatic B cirrhosis 2
post-hepatitis C cirrhosis 4
PBC 2
liver cancer 2
fulminant hepatitis 1
miscellaneous 1
- Placebo group (n = 24)
Mean age (years +- SD)
51+- 9
Ratio of sex (malefemale) 159
Origins of liver diseases alcoholic cirrhosis 10
post-hepatic B cirrhosis 0
post-hepatic C cirrhosis 6
PBC 3
liver cancer 4
fulminant hepatitis 0
miscellaneous 1
27Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Pageaux 1995 (Continued)
Interventions UDCA group
- Dose 600 mgday in three divided doses
- Route orally
- Duration immediately after intestinal transit recovery usually between postoperative
days three and five and continue for two months
Placebo group
- identical-appearing capsules administered in the same quantity and manner
Co-interventions all patients received standard triple-drug regimens (steroids azathio-
prine and cyclosporine or tacrolimus)
Outcomes Number of patients with acute cellular rejection
Number of patients with steroid-resistant rejection
Notes Letter was sent to the authors in September 2009 No reply was received
Risk of bias
Item Authorsrsquo judgement Description
Adequate sequence generation Unclear No information provided
Allocation concealment Unclear No information provided
Blinding Unclear Method of blinding not described
Incomplete outcome data addressed
All outcomes
Yes Five patients died from non-immunologi-
cal causes before the end of the first month
and were excluded from the study Reasons
were reported
Free of selective reporting Unclear Not enough information provided
Sample size calculation No Not performed
Intention-to-treat analysis No Not stated and not used
Baseline imbalance Unclear Not enough information provided
Early stopping of trial Unclear Not enough information provided
Sama 1991
Methods Study design randomised controlled trial
Participants Country Italy
Publication language English
Inclusion criteria
28Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Sama 1991 (Continued)
- patients who underwent liver transplantation
Exclusion criteria
- not mentioned
Participants
- UDCA group (n = 20)
Mean age (years +- SD)
no information
Ratio of sex (malefemale) no information
Origins of liver diseases
no information
- Control group (n = 20)
Mean age (years +- SD)
no information
Ratio of sex (malefemale) no information
Origins of liver diseases
no information
Interventions UDCA group
- Dose 600 mgday in two divided doses
- Route orally
- Duration immediately after intestinal transit recovery usually between postoperative
day five and day seven and continue for six months
Control group
- no treatment
Co-interventions all patients received standard immunosuppressive treatment (steroids
and cyclosporine)
Outcomes All cause mortality
Number of patients with acute cellular rejection
Notes Abstract
Letter was sent to the authors in September 2009 No reply was received
Risk of bias
Item Authorsrsquo judgement Description
Adequate sequence generation Unclear A randomisation list was performed before
patients were admitted to the trial (infor-
mation from principal author)
Allocation concealment Unclear No information provided
Blinding Unclear The principle author provided information
that the study was made according to a
single-blind randomised protocol The pri-
mary outcome was the occurrence of biopsy
proven rejection episodes The pathologists
were blind but the patients were not
29Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Sama 1991 (Continued)
Incomplete outcome data addressed
All outcomes
Unclear Five patients from the UDCA group and
six patients from the placebo group were
excluded Reasons for exclusion were not
fully stated
Free of selective reporting No Data about survival of patients were not
adequately reported
Sample size calculation No Not performed
Intention-to-treat analysis No Not stated and not used
Baseline imbalance Unclear Basic characteristics of patients not re-
ported
Early stopping of trial Unclear Not enough information provided
UDCA = ursodeoxycholic acid
TUDCA = tauroursodeoxycholic acid
PBC = primary biliary cirrhosis
PSC = primary sclerosing cholangitis
OKT3 = anti-CD3 monoclonal antibody
Characteristics of excluded studies [ordered by study ID]
Assy 2007 A randomised controlled trial that included only recipients of liver transplantation with stable graft function and
no episodes of rejection for at least 2 years that were then offered total immunosuppression withdrawal Fourteen
patients received UDCA (15 mgkg body weightday) and 12 received placebo Rejection occurred in 43 and
75 of patients respectively (no significant difference) None developed chronic rejection After follow-up two
patients were free of immunosuppression 80 were steroid free and 50 were able to reduce their dose of
cyclosporine
Clavien 1996 Case series Fifty consecutive liver-transplanted patients were treated with a standard cyclosporine immunosup-
pressive regimen Twenty three of the 43 survivors developed an episode of rejection and UDCA (10 mgkg
weightday) was initiated Only one patient had a second episode of rejection
Friman 1992 Observational study Thirty-three liver-transplanted patients received 10 mg UDCAkg body weightday for
median of 10 months (range four to 21 months) Eight historical liver-transplanted patients served as control
group The rejection incidence was significantly lower in the patients who received the treatment with UDCA
Biochemistry one month after transplantation demonstrated significantly lower average values of aminotrans-
ferases and alkaline phosphatases in patients treated with UDCA than in the control group
30Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
Heathcote 1999 Observational study From 1987 to 1996 37 UDCA treated and 53 placebo treated patients with primary biliary
cirrhosis were referred for transplantation Posttransplantation survival rates at one month were 939 in the
UDCA group and 884 in the placebo group and one year survival rates were 903 and 784 respectively
(no significant differences) However rejection (type not defined - a secondary outcome measure) occurred
significantly less often in the UDCA group (429) than in placebo group (688)
Henriksson 1991 Observational study All patients in this study were given sequential quadruple immunosuppression with anti-
lymphocyte globulin azathioprine steroids and cyclosporine All patients with primary graft function (n = 11)
were treated with 10 mg UDCAkg body weightday starting during the first postoperative week Patients who
received liver transplantation in the first 6 months of 1989 (n = 8) served as controls In the control group one
patient died after 9 months with chronic graft dysfunction and six patients had rejection episodes during the
first postoperative month All patients in the UDCA group were alive without rejection episodes
Persson 1990 Observational study All 11 adult patients transplanted between August 1989 and January 1990 with primary
graft function were treated with 10 mg UDCA kg body weightday Eight patients transplanted during the first
half of 1989 served as control UDCA was started during the first postoperative week and the treatment was
continued for six months All patients in the UDCA treated group survived with satisfactory graft function In
the control group six patients had at least one rejection episode needing treatment during the first postoperative
month
Rafael 1995 Observational study Seventeen patients who underwent liver transplantation between February 1990 and April
1993 and developed biliary complications after transplantation were retrospectively analysed regarding treatment
with UDCA UDCA was given in a dose of 500 to 1000 mgday Ten patients were treated for at least one year while
seven patients were treated for 14 to 250 days UDCA significantly improved gammaglutamyl transpeptidase in
liver graft recipients with biliary complications There was also a trend towards improvement in serum bilirubin
and alanine transaminase values
Sama 1998 Observational study Thirty-four patients who underwent liver transplantation between January 1995 and June
1996 were included in the study Seventeen were treated with UDCA 10 mgkg body weightday during 6
months while 17 served as controls on the basis of having undergone liver transplantation closest to UDCA
patients A significant decrease in serum bilirubin levels was observed in UDCA patients There was a significantly
higher incidence of recurrent hepatitis in the control group
UDCA ursodeoxycholic acid
31Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
D A T A A N D A N A L Y S E S
Comparison 1 Bile acids for liver-transplanted patients
Outcome or subgroup titleNo of
studies
No of
participants Statistical method Effect size
1 All-cause mortality at maximum
follow-up
5 257 Risk Ratio (M-H Fixed 95 CI) 085 [053 136]
11 UDCA versus placebo or
no treatment
4 224 Risk Ratio (M-H Fixed 95 CI) 080 [049 130]
12 TUDCA versus no
treatment
1 33 Risk Ratio (M-H Fixed 95 CI) 159 [030 833]
2 All-cause mortality worst-best
case and best-worst case
scenarios
5 Risk Ratio (M-H Fixed 95 CI) Subtotals only
21 Worst-best case scenario 5 257 Risk Ratio (M-H Fixed 95 CI) 130 [086 196]
22 Best-worst case scenario 5 257 Risk Ratio (M-H Fixed 95 CI) 058 [038 090]
3 Subgroup analyses all-cause
mortality at maximum
follow-up according to time of
start of bile acids
5 257 Risk Ratio (M-H Fixed 95 CI) 085 [053 136]
31 Less than three days after
transplantation
1 102 Risk Ratio (M-H Fixed 95 CI) 124 [061 254]
32 Three days or more after
transplantation
4 155 Risk Ratio (M-H Fixed 95 CI) 063 [033 120]
4 Subgroup analyses all cause
mortality at maximum
follow-up according to
treatment duration
5 257 Risk Ratio (M-H Fixed 95 CI) 085 [053 136]
41 Less than six months 3 184 Risk Ratio (M-H Fixed 95 CI) 078 [045 138]
42 Six months or more 2 73 Risk Ratio (M-H Fixed 95 CI) 102 [043 240]
5 Number of deaths related
to rejection at maximum
follow-up
1 102 Risk Ratio (M-H Fixed 95 CI) 030 [001 712]
51 UDCA versus placebo 1 102 Risk Ratio (M-H Fixed 95 CI) 030 [001 712]
6 Number of retransplantations at
maximum follow-up
2 132 Risk Ratio (M-H Fixed 95 CI) 076 [020 286]
7 Number of patients with acute
cellular rejection at maximum
follow-up
7 339 Risk Ratio (M-H Fixed 95 CI) 089 [074 106]
71 UDCA versus placebo or
no treatment
6 306 Risk Ratio (M-H Fixed 95 CI) 089 [074 108]
72 TUDCA versus no
treatment
1 33 Risk Ratio (M-H Fixed 95 CI) 085 [045 160]
8 Subgroup analysis number of
patients with acute cellular
rejection according to time of
start of bile acid
7 339 Risk Ratio (M-H Fixed 95 CI) 089 [074 106]
32Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
81 Less than three days after
transplantation
2 134 Risk Ratio (M-H Fixed 95 CI) 084 [063 111]
82 Three days or more after
liver transplantation
5 205 Risk Ratio (M-H Fixed 95 CI) 092 [072 117]
9 Subgroup analysis number
of patients with acute
cellular rejection according to
treatment duration
7 339 Risk Ratio (M-H Fixed 95 CI) 089 [074 106]
91 Less than six months 5 266 Risk Ratio (M-H Fixed 95 CI) 087 [071 107]
92 Six months or more 2 73 Risk Ratio (M-H Fixed 95 CI) 094 [065 136]
10 Number of patients with
chronic rejection at maximum
follow-up
3 184 Risk Ratio (M-H Fixed 95 CI) 028 [008 095]
11 Number of patients with
steroid-resistant rejection at
maximum follow-up
4 234 Risk Ratio (M-H Fixed 95 CI) 077 [047 127]
12 Serum bilirubin (mgdl) at the
end of treatment
1 30 Mean Difference (IV Fixed 95 CI) 26 [-096 616]
13 Number of days of
hospitalisation after liver
transplantation
1 52 Mean Difference (IV Fixed 95 CI) -85 [-1667 -033]
14 Adverse events 3 187 Risk Ratio (M-H Fixed 95 CI) 088 [030 260]
Analysis 11 Comparison 1 Bile acids for liver-transplanted patients Outcome 1 All-cause mortality at
maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 1 All-cause mortality at maximum follow-up
Study or subgroup Favours bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 UDCA versus placebo or no treatment
Barnes 1997 228 724 253 024 [ 006 107 ]
Fleckenstein 1998 214 416 125 057 [ 012 266 ]
Keiding 1997 1454 1048 355 124 [ 061 254 ]
Sama 1991 520 620 201 083 [ 030 229 ]
Subtotal (95 CI) 116 108 935 080 [ 049 130 ]
Total events 23 (Favours bile acids) 27 (Control)
Heterogeneity Chi2 = 416 df = 3 (P = 025) I2 =28
Test for overall effect Z = 091 (P = 036)
01 02 05 1 2 5 10
Favours bile acids Favours control
(Continued )
33Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Favours bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
2 TUDCA versus no treatment
Angelico 1999 316 217 65 159 [ 030 833 ]
Subtotal (95 CI) 16 17 65 159 [ 030 833 ]
Total events 3 (Favours bile acids) 2 (Control)
Heterogeneity not applicable
Test for overall effect Z = 055 (P = 058)
Total (95 CI) 132 125 1000 085 [ 053 136 ]
Total events 26 (Favours bile acids) 29 (Control)
Heterogeneity Chi2 = 466 df = 4 (P = 032) I2 =14
Test for overall effect Z = 069 (P = 049)
01 02 05 1 2 5 10
Favours bile acids Favours control
Analysis 12 Comparison 1 Bile acids for liver-transplanted patients Outcome 2 All-cause mortality worst-
best case and best-worst case scenarios
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 2 All-cause mortality worst-best case and best-worst case scenarios
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 Worst-best case scenario
Angelico 1999 516 217 65 266 [ 060 1180 ]
Barnes 1997 828 724 253 098 [ 042 230 ]
Fleckenstein 1998 314 416 125 086 [ 023 319 ]
Keiding 1997 1954 1048 355 169 [ 087 327 ]
Sama 1991 520 620 201 083 [ 030 229 ]
Subtotal (95 CI) 132 125 1000 130 [ 086 196 ]
Total events 40 (Bile acids) 29 (Control)
Heterogeneity Chi2 = 303 df = 4 (P = 055) I2 =00
Test for overall effect Z = 123 (P = 022)
2 Best-worst case scenario
005 02 1 5 20
Favours bile acids Favours control
(Continued )
34Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Angelico 1999 316 417 90 080 [ 021 302 ]
Barnes 1997 228 1124 274 016 [ 004 063 ]
Fleckenstein 1998 214 616 130 038 [ 009 159 ]
Keiding 1997 1454 1548 368 083 [ 045 154 ]
Sama 1991 520 620 139 083 [ 030 229 ]
Subtotal (95 CI) 132 125 1000 058 [ 038 090 ]
Total events 26 (Bile acids) 42 (Control)
Heterogeneity Chi2 = 567 df = 4 (P = 023) I2 =29
Test for overall effect Z = 247 (P = 0014)
005 02 1 5 20
Favours bile acids Favours control
Analysis 13 Comparison 1 Bile acids for liver-transplanted patients Outcome 3 Subgroup analyses all-
cause mortality at maximum follow-up according to time of start of bile acids
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 3 Subgroup analyses all-cause mortality at maximum follow-up according to time of start of bile acids
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 Less than three days after transplantation
Keiding 1997 1454 1048 355 124 [ 061 254 ]
Subtotal (95 CI) 54 48 355 124 [ 061 254 ]
Total events 14 (Bile acids) 10 (Control)
Heterogeneity not applicable
Test for overall effect Z = 060 (P = 055)
2 Three days or more after transplantation
Angelico 1999 316 217 65 159 [ 030 833 ]
Barnes 1997 228 724 253 024 [ 006 107 ]
Fleckenstein 1998 214 416 125 057 [ 012 266 ]
Sama 1991 520 620 201 083 [ 030 229 ]
005 02 1 5 20
Favours bile acids Favours control
(Continued )
35Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Subtotal (95 CI) 78 77 645 063 [ 033 120 ]
Total events 12 (Bile acids) 19 (Control)
Heterogeneity Chi2 = 310 df = 3 (P = 038) I2 =3
Test for overall effect Z = 141 (P = 016)
Total (95 CI) 132 125 1000 085 [ 053 136 ]
Total events 26 (Bile acids) 29 (Control)
Heterogeneity Chi2 = 466 df = 4 (P = 032) I2 =14
Test for overall effect Z = 069 (P = 049)
005 02 1 5 20
Favours bile acids Favours control
Analysis 14 Comparison 1 Bile acids for liver-transplanted patients Outcome 4 Subgroup analyses all
cause mortality at maximum follow-up according to treatment duration
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 4 Subgroup analyses all cause mortality at maximum follow-up according to treatment duration
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 Less than six months
Barnes 1997 228 724 253 024 [ 006 107 ]
Fleckenstein 1998 214 416 125 057 [ 012 266 ]
Keiding 1997 1454 1048 355 124 [ 061 254 ]
Subtotal (95 CI) 96 88 734 078 [ 045 138 ]
Total events 18 (Bile acids) 21 (Control)
Heterogeneity Chi2 = 417 df = 2 (P = 012) I2 =52
Test for overall effect Z = 084 (P = 040)
2 Six months or more
Angelico 1999 316 217 65 159 [ 030 833 ]
Sama 1991 520 620 201 083 [ 030 229 ]
Subtotal (95 CI) 36 37 266 102 [ 043 240 ]
Total events 8 (Bile acids) 8 (Control)
Heterogeneity Chi2 = 043 df = 1 (P = 051) I2 =00
005 02 1 5 20
Favours bile acids Favours control
(Continued )
36Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Test for overall effect Z = 004 (P = 097)
Total (95 CI) 132 125 1000 085 [ 053 136 ]
Total events 26 (Bile acids) 29 (Control)
Heterogeneity Chi2 = 466 df = 4 (P = 032) I2 =14
Test for overall effect Z = 069 (P = 049)
005 02 1 5 20
Favours bile acids Favours control
Analysis 15 Comparison 1 Bile acids for liver-transplanted patients Outcome 5 Number of deaths related
to rejection at maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 5 Number of deaths related to rejection at maximum follow-up
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 UDCA versus placebo
Keiding 1997 054 148 1000 030 [ 001 712 ]
Total (95 CI) 54 48 1000 030 [ 001 712 ]
Total events 0 (Bile acids) 1 (Control)
Heterogeneity not applicable
Test for overall effect Z = 075 (P = 045)
0001 001 01 1 10 100 1000
Favours bile acids Favours control
37Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 16 Comparison 1 Bile acids for liver-transplanted patients Outcome 6 Number of
retransplantations at maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 6 Number of retransplantations at maximum follow-up
Study or subgroup Bile acids Placebo Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Fleckenstein 1998 214 016 100 567 [ 029 10891 ]
Keiding 1997 154 448 900 022 [ 003 192 ]
Total (95 CI) 68 64 1000 076 [ 020 286 ]
Total events 3 (Bile acids) 4 (Placebo)
Heterogeneity Chi2 = 303 df = 1 (P = 008) I2 =67
Test for overall effect Z = 040 (P = 069)
0001 001 01 1 10 100 1000
Favours bile acids Favours placebo
Analysis 17 Comparison 1 Bile acids for liver-transplanted patients Outcome 7 Number of patients with
acute cellular rejection at maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 7 Number of patients with acute cellular rejection at maximum follow-up
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 UDCA versus placebo or no treatment
Barnes 1997 1728 1724 180 086 [ 058 127 ]
Fleckenstein 1998 814 916 83 102 [ 054 190 ]
Keiding 1997 3554 3248 333 097 [ 073 129 ]
Koneru 1993 316 916 89 033 [ 011 101 ]
Pageaux 1995 926 924 92 092 [ 044 193 ]
Sama 1991 1320 1320 128 100 [ 063 158 ]
Subtotal (95 CI) 158 148 905 089 [ 074 108 ]
01 02 05 1 2 5 10
Favours bile acids Favours control
(Continued )
38Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Total events 85 (Bile acids) 89 (Control)
Heterogeneity Chi2 = 387 df = 5 (P = 057) I2 =00
Test for overall effect Z = 120 (P = 023)
2 TUDCA versus no treatment
Angelico 1999 816 1017 95 085 [ 045 160 ]
Subtotal (95 CI) 16 17 95 085 [ 045 160 ]
Total events 8 (Bile acids) 10 (Control)
Heterogeneity not applicable
Test for overall effect Z = 050 (P = 061)
Total (95 CI) 174 165 1000 089 [ 074 106 ]
Total events 93 (Bile acids) 99 (Control)
Heterogeneity Chi2 = 392 df = 6 (P = 069) I2 =00
Test for overall effect Z = 130 (P = 019)
01 02 05 1 2 5 10
Favours bile acids Favours control
Analysis 18 Comparison 1 Bile acids for liver-transplanted patients Outcome 8 Subgroup analysis
number of patients with acute cellular rejection according to time of start of bile acid
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 8 Subgroup analysis number of patients with acute cellular rejection according to time of start of bile acid
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 Less than three days after transplantation
Keiding 1997 3554 3248 333 097 [ 073 129 ]
Koneru 1993 316 916 89 033 [ 011 101 ]
Subtotal (95 CI) 70 64 422 084 [ 063 111 ]
Total events 38 (Bile acids) 41 (Control)
Heterogeneity Chi2 = 374 df = 1 (P = 005) I2 =73
Test for overall effect Z = 124 (P = 022)
2 Three days or more after liver transplantation
Angelico 1999 816 1017 95 085 [ 045 160 ]
01 02 05 1 2 5 10
Favours bile acids Favours control
(Continued )
39Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Barnes 1997 1728 1724 180 086 [ 058 127 ]
Fleckenstein 1998 814 916 83 102 [ 054 190 ]
Pageaux 1995 926 924 92 092 [ 044 193 ]
Sama 1991 1320 1320 128 100 [ 063 158 ]
Subtotal (95 CI) 104 101 578 092 [ 072 117 ]
Total events 55 (Bile acids) 58 (Control)
Heterogeneity Chi2 = 041 df = 4 (P = 098) I2 =00
Test for overall effect Z = 067 (P = 050)
Total (95 CI) 174 165 1000 089 [ 074 106 ]
Total events 93 (Bile acids) 99 (Control)
Heterogeneity Chi2 = 392 df = 6 (P = 069) I2 =00
Test for overall effect Z = 130 (P = 019)
01 02 05 1 2 5 10
Favours bile acids Favours control
40Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 19 Comparison 1 Bile acids for liver-transplanted patients Outcome 9 Subgroup analysis
number of patients with acute cellular rejection according to treatment duration
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 9 Subgroup analysis number of patients with acute cellular rejection according to treatment duration
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 Less than six months
Barnes 1997 1728 1724 180 086 [ 058 127 ]
Fleckenstein 1998 814 916 83 102 [ 054 190 ]
Keiding 1997 3554 3248 333 097 [ 073 129 ]
Koneru 1993 316 916 89 033 [ 011 101 ]
Pageaux 1995 926 924 92 092 [ 044 193 ]
Subtotal (95 CI) 138 128 777 087 [ 071 107 ]
Total events 72 (Bile acids) 76 (Control)
Heterogeneity Chi2 = 374 df = 4 (P = 044) I2 =00
Test for overall effect Z = 129 (P = 020)
2 Six months or more
Angelico 1999 816 1017 95 085 [ 045 160 ]
Sama 1991 1320 1320 128 100 [ 063 158 ]
Subtotal (95 CI) 36 37 223 094 [ 065 136 ]
Total events 21 (Bile acids) 23 (Control)
Heterogeneity Chi2 = 017 df = 1 (P = 068) I2 =00
Test for overall effect Z = 035 (P = 073)
Total (95 CI) 174 165 1000 089 [ 074 106 ]
Total events 93 (Bile acids) 99 (Control)
Heterogeneity Chi2 = 392 df = 6 (P = 069) I2 =00
Test for overall effect Z = 130 (P = 019)
01 02 05 1 2 5 10
Favours bile acids Favours control
41Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 110 Comparison 1 Bile acids for liver-transplanted patients Outcome 10 Number of patients
with chronic rejection at maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 10 Number of patients with chronic rejection at maximum follow-up
Study or subgroup Bile acids Placebo Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Barnes 1997 128 624 611 014 [ 002 110 ]
Fleckenstein 1998 114 116 88 114 [ 008 1663 ]
Keiding 1997 154 348 300 030 [ 003 275 ]
Total (95 CI) 96 88 1000 028 [ 008 095 ]
Total events 3 (Bile acids) 10 (Placebo)
Heterogeneity Chi2 = 148 df = 2 (P = 048) I2 =00
Test for overall effect Z = 204 (P = 0041)
0001 001 01 1 10 100 1000
Favours bile acids Favours placebo
Analysis 111 Comparison 1 Bile acids for liver-transplanted patients Outcome 11 Number of patients
with steroid-resistant rejection at maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 11 Number of patients with steroid-resistant rejection at maximum follow-up
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Barnes 1997 328 724 277 037 [ 011 127 ]
Fleckenstein 1998 314 316 103 114 [ 027 478 ]
Keiding 1997 1454 1548 583 083 [ 045 154 ]
Pageaux 1995 226 124 38 185 [ 018 1908 ]
Total (95 CI) 122 112 1000 077 [ 047 127 ]
Total events 22 (Bile acids) 26 (Control)
Heterogeneity Chi2 = 226 df = 3 (P = 052) I2 =00
Test for overall effect Z = 102 (P = 031)
001 01 1 10 100
Favours bile acids Favours placebo
42Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 112 Comparison 1 Bile acids for liver-transplanted patients Outcome 12 Serum bilirubin (mgdl)
at the end of treatment
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 12 Serum bilirubin (mgdl) at the end of treatment
Study or subgroup Bile acids Placebo Mean Difference Weight Mean Difference
N Mean(SD) N Mean(SD) IVFixed95 CI IVFixed95 CI
Fleckenstein 1998 14 319 (68) 16 059 (022) 1000 260 [ -096 616 ]
Total (95 CI) 14 16 1000 260 [ -096 616 ]
Heterogeneity not applicable
Test for overall effect Z = 143 (P = 015)
-10 -5 0 5 10
Favours bile acids Favours placebo
Analysis 113 Comparison 1 Bile acids for liver-transplanted patients Outcome 13 Number of days of
hospitalisation after liver transplantation
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 13 Number of days of hospitalisation after liver transplantation
Study or subgroup Bile acids Placebo Mean Difference Weight Mean Difference
N Mean(SD) N Mean(SD) IVFixed95 CI IVFixed95 CI
Barnes 1997 28 25 (17) 24 335 (13) 1000 -850 [ -1667 -033 ]
Total (95 CI) 28 24 1000 -850 [ -1667 -033 ]
Heterogeneity not applicable
Test for overall effect Z = 204 (P = 0041)
-100 -50 0 50 100
Favours bile acids Favours placebo
43Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 114 Comparison 1 Bile acids for liver-transplanted patients Outcome 14 Adverse events
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 14 Adverse events
Study or subgroup Bile acids Placebo Risk Ratio Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Angelico 1999 016 017 00 [ 00 00 ]
Barnes 1997 128 124 086 [ 006 1298 ]
Keiding 1997 554 548 089 [ 027 288 ]
Total (95 CI) 98 89 088 [ 030 260 ]
Total events 6 (Bile acids) 6 (Placebo)
Heterogeneity Chi2 = 000 df = 1 (P = 098) I2 =00
Test for overall effect Z = 022 (P = 082)
001 01 1 10 100
Favours bile acids Favours placebo
A P P E N D I C E S
Appendix 1 Search strategies
Data Base Date of Search Search Strategy
The Cochrane Hepato-Biliary Group Con-
trolled Trials Register
September 2009 1 rsquoliver transplantationrsquo and rsquochenodeoxy-
cholicrsquo
2 rsquoliver transplantationrsquo and rsquocholicrsquo
3 rsquoliver transplantationrsquo and rsquodeoxycholicrsquo
4 rsquoliver transplantationrsquo and rsquoglycochen-
odeoxycholicrsquo
5 rsquoliver transplantationrsquo and rsquoglycocholicrsquo
6 rsquoliver transplantationrsquo and rsquoglycodeoxy-
cholicrsquo
7 rsquoliver transplantationrsquo and rsquoglycolitho-
cholicrsquo
8 rsquoliver transplantationrsquo and rsquohyodeoxy-
cholicrsquo
9 rsquoliver transplantationrsquo and rsquolithocholicrsquo
10 rsquoliver transplantationrsquo and rsquotaurochen-
odeoxycholicrsquo
44Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
11 rsquoliver transplantationrsquo and rsquotauro-
cholicrsquo
12 rsquoliver transplantationrsquo and rsquotaurodehy-
drocholicrsquo
13 rsquoliver transplantationrsquo and rsquotau-
rodeoxycholicrsquo
14 rsquoliver transplantationrsquo and rsquotauroglyco-
cholicrsquo
15 rsquoliver transplantationrsquo and rsquotaurolitho-
cholicrsquo
16 rsquoliver transplantationrsquo and rsquotaurosel-
cholicrsquo
17 rsquoliver transplantationrsquo and rsquotaurourso-
cholicrsquo
18 rsquoliver transplantationrsquo and rsquotaurour-
sodeoxycholicrsquo
19 rsquoliver transplantationrsquo and rsquoursocholicrsquo
20 rsquoliver transplantationrsquo and rsquoursodeoxy-
cholicrsquo
The Cochrane Central Register of Con-
trolled Trials in The Cochrane Library
Issue 3 2009 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
6 3 or 4
7 5 and 6
MEDLINE September 2009 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
45Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
6 3 or 4
7 5 and 6
8 RANDOMIZED-CONTROLLED-
TRIAL ME
9 RANDOM
10 8 or 9
11 7 and 10
EMBASE September 2009 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
6 3 or 4
7 5 and 6
8 RANDOMIZED-CONTROLLED-
TRIAL ME
9 RANDOM
10 8 or 9
11 7 and 10
46Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
Science Citation Index Expanded September 2009 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
6 3 or 4
7 5 and 6
8 RANDOMIZED-CONTROLLED-
TRIAL ME
9 RANDOM
10 8 or 9
11 7 and 10
The Chinese Biomedical Database Searched from January 1980 to April 2002 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
47Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
6 3 or 4
7 5 and 6
8 RANDOMIZED-CONTROLLED-
TRIAL ME
9 RANDOM
10 8 or 9
11 7 and 10
W H A T rsquo S N E W
Last assessed as up-to-date 8 February 2010
18 September 2009 New citation required but conclusions have not
changed
This review is an updated version of a review that was
published for the first time in Issue 3 2005 of TheCochrane Library by Chen 2003b
18 September 2009 New search has been performed No new studies fulfilled the inclusion criteria
H I S T O R Y
Protocol first published Issue 3 2003
Review first published Issue 3 2005
C O N T R I B U T I O N S O F A U T H O R S
GP and VG independently performed searches of relevant databases GP validated the search selected trials for inclusion contacted
the authors of the trials performed data extraction and data analysis and drafted the systematic review VG revised the review update
CG and DS revised the review update solved discrepancies of data extraction validated data analyses and provided consultation
D E C L A R A T I O N S O F I N T E R E S T
None known
48Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
S O U R C E S O F S U P P O R T
Internal sources
bull Copenhagen Trial Unit Denmark
External sources
bull Danish Medical Research Councilrsquos Grant on Getting Research into Practice (GRIP) Denmark
D I F F E R E N C E S B E T W E E N P R O T O C O L A N D R E V I E W
We assessed the risk of bias in the included studies for another four domains that were added to the review protocol (incomplete
outcome data selective outcome reporting baseline imbalance and early stopping of trial) In general the text of the risk of bias
domains were updated following Higgins 2008 Trials were considered at low risk of bias when judged as adequate in all domains
Quasi-randomised studies observational and case-control studies were included for the report of adverse events
We performed trial sequential analysis for outcomes demonstrating a statistically significant result
I N D E X T E R M S
Medical Subject Headings (MeSH)
lowastLiver Transplantation Cholagogues and Choleretics [lowasttherapeutic use] Graft Rejection [lowastprevention amp control] Randomized Con-
trolled Trials as Topic Taurochenodeoxycholic Acid [lowasttherapeutic use] Ursodeoxycholic Acid [lowasttherapeutic use]
MeSH check words
Humans
49Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Figure 3 Trial sequential analysis for the number of patients with chronic rejection at maximum follow-up
We calculated the heterogeneity-corrected required information size (HCRIS) based on a proportion of 12 of
the patients in the placebo group with chronic rejection at maximum follow-up a 50 risk ratio reduction in
the bile acid group an alpha of 5 a beta of 10 and a heterogeneity of 0 Only 184 patients have been
randomised reporting this outcome which is only 19 of the HCRIS of 957 patients The cumulative Z-score
crosses the conventional boundaries for P 005 but not the monitoring boundaries
Number of patients with steroid-resistant rejection
Four trials (Pageaux 1995 Barnes 1997 Keiding 1997
Fleckenstein 1998) reported the number of patients with steroid-
resistant rejection These trials demonstrated that UDCA did not
significantly reduce the number of patients with steroid-resistant
rejection when compared with placebo (22122 (18) versus 26
112 (232) (RR 077 95 CI 047 to 127) (Analysis 111)
There was no significant heterogeneity (I2 0)
Liver biochemistry
The Fleckenstein 1998 trial reported serum bilirubin levels after
a three-month-treatment period in 30 liver-transplanted patients
There was no statistically significant difference in serum bilirubin
levels between the UDCA group and the placebo group (MD 260
mgdl 95 CI -096 to 616 mgdl) (Analysis 112)
No data were available for other liver biochemical variables
Cost-effectiveness
One trial (Barnes 1997) with 52 liver-transplanted patients re-
ported the days of hospitalisation after liver transplantation
UDCA significantly decreased the number of days of hospitali-
sation when compared with placebo (MD -850 days 95 CI -
1667 to -033 days) (Analysis 113) We were not able to extract
other medical cost from the trials
Adverse events
Among all the included and excluded trials only four reported on
adverse events however adverse events only occurred in two of
the included trials (Barnes 1997 Keiding 1997) There were no
significant differences regarding adverse events (RR 088 95 CI
030 to 260) 6112 (54) versus 6105 (57) (Analysis 114)
In the Barnes 1997 trial diarrhoea was reported by two patients
(one in the UDCA group and one in the placebo group) In the
Keiding 1997 trial five UDCA patients and five placebo patients
stopped intake of the trial medicine because of diarrhoea or dif-
ficulties in swallowing the capsules The remaining included trial
by Angelico 1999 stated that no adverse events occurred during
the study period The excluded trial by Assy 2007 was the only
one reporting on a case of mild diarrhoea in one patient in the
12Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
intervention group No other excluded studies reported on adverse
events (see Table 1)
Quality of life
None of the included studies assessed quality of life as an outcome
Other subgroup analyses
We planned to perform subgroup analyses regarding the risk of
bias of trials the dosage of bile acid and any co-intervention
However none of the trials were considered to be of low risk of
bias they all used a similar dosage of bile acid and patients in all
trials received similar immunosuppressive treatment as co-inter-
ventions (steroids azathioprine and cyclosporine or tacrolimus)
after liver transplantation Therefore we were not able to perform
the planned subgroup analyses
Funnel plot asymmetry
We did not draw a funnel plot analysis due to the limited number
of trials included in the present review
D I S C U S S I O N
In the update of this review we included no new trials assessing
the use of bile acids for liver-transplanted patients The analyses
of the seven previously included trials showed that bile acids did
not significantly affect mortality acute cellular rejection steroid-
resistant rejection retransplantation or serum bilirubin Bile acids
might significantly decrease the length of hospital stay and the
number of patients with chronic rejection included in these tri-
als but more supportive evidence is needed The number of pa-
tients with chronic rejection was not significantly influenced by
bile acids when a random-effects model was used and length of
stay was assessed in one single trial Furthermore none of the trials
were considered to be of low risk of bias and few patients were en-
rolled Therefore our positive findings may be due to bias (Schulz
1995 Moher 1998 Kjaergard 2001 Wood 2008) or random er-
rors (Wetterslev 2008 Brok 2009 Thorlund 2009) On the other
hand we are not able to exclude type II errors (that is finding
no significant differences when in fact they exist) due to the low
number of participants Therefore this topic could be of potential
interest in future large randomised trials with adequate control of
bias
All-cause mortality at one year after liver transplantation is re-
ported to be about 20 (Thuluvath 2003) which we also ob-
served for the patients included in the present review According to
our subgroup analyses neither UDCA nor TUDCA significantly
decreased all-cause mortality We also performed a subgroup anal-
ysis regarding treatment duration but we were not able to find any
difference between short (less than six months) and long treatment
duration (six months or more) Thus bile acids do not seem to
have statistically significant effects in reducing all-cause mortal-
ity after liver transplantation We performed both worst-best-case
scenario and best-worst-case scenario analyses In the worst-best-
case scenario bile acids did not differ significantly from placebo or
no intervention regarding all-cause mortality However bile acids
significantly decreased all-cause mortality in the best-worst-case
scenario analysis However such an analysis is very extreme and
may not be realistic We have also found that UDCA may be able
to decrease the risk of chronic rejection in liver-transplanted pa-
tients but trial sequential analysis could not confirm this result
Due to a limited number of patients (Ioannidis 2001) we are not
able to exclude the possibility that it may be relevant to perform
placebo-controlled trials with low risk of bias on the use of bile
acids for liver-transplanted patients
We looked into the causes of deaths that were reported by the trials
and only one trial reported one death related to rejection At the
same time the number of retransplantations was 3 among 68 liver-
transplanted patients who received treatment with UDCA and 4
among 64 liver-transplanted patients who received treatment with
placebo We noticed that all patients in the included trials received
co-interventions of standard triple-drug regimens (steroids aza-
thioprine and cyclosporine or tacrolimus) which were able to
control the possible acute or chronic rejection and prevent deaths
due to allograft rejection (FK506 1994)
The assumption that UDCA might reduce the incidence of acute
graft rejection came from the findings that UDCA could regulate
major histocompatibility complex antigen expression in bile ducts
and liver endothelia and inhibit lymphocyte activity (Calmus
1990 Terasaki 1991 Perez 2009) However in the present review
bile acids did not significantly reduce the risk of acute cellular re-
jection in liver-transplanted patients Considering that acute cellu-
lar rejection is commonly found within a few days after liver trans-
plantation (Vierling 1992) some might argue that the adminis-
tration of bile acids was started too late to prevent acute cellular
rejection We performed subgroup analyses regarding the time bile
acids were started and no statistically significant difference was
found Furthermore bile acids were not able to decrease the risk
of steroid-resistant rejection Therefore the lack of effects of bile
acids does not seem to be due to a delayed start to bile acid ad-
ministration after liver transplantation However it is a possibility
that one should start bile acids intake before liver transplantation
A retrospective study found that rejection rates differed signifi-
cantly between patients with primary biliary cirrhosis treated with
or without UDCA before liver transplantation (Heathcote 1999)
One could argue whether UDCA-induced delay in transplantation
has an adverse effect on post-transplantation outcome Since we
did not find any prospective randomised clinical trials addressing
this issue further research might be needed Furthermore some
studies may provide an explanation why UDCA was not able to
prevent acute cellular rejection These studies found that UDCA
did not appear to change the expression of major histocompatibil-
ity complex class II antigens but rather major histocompatibility
complex class I antigens (Calmus 1990) The initial mechanism
of acute rejection is thought to be recognition of MHC class II
13Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
antigens by CD4+ T cells (Vierling 1992) Moreover the inhibi-
tion of the production of interleukin-2 by peripheral blood lym-
phocytes with UDCA (Heuman 1993) might be negated by the
immunosuppressive treatment after liver transplantation (van den
Berg 1998) so that UDCA is unable to demonstrate effects on
graft rejection In a recent study by Assy 2007 a significant re-
duction in the mean dose of immunosuppressive medications was
achieved in stable liver graft recipients treated with UDCA indi-
cating a possible influence of UDCA on rejection mechanisms
In accordance with previous systematic reviews (Chen 2003a
Chen 2007 Gong 2008) bile acids were not associated with the
occurrence of serious adverse events or any major occurrence of
adverse events
In summary our results do not support or refute the use of bile
acids (UDCA and TUDCA) additional to standard immunosup-
pressive treatment in liver-transplanted patients
A U T H O R S rsquo C O N C L U S I O N SImplications for practice
There seems to be no evidence to support or refute the use of bile
acids for liver-transplanted patients receiving standard immuno-
suppressive treatment
Implications for research
We need more randomised placebo-controlled clinical trials with
enough statistical power and low risk of bias to explore the poten-
tial effects of bile acids on chronic rejection and mortality in liver-
transplanted patients Such trials should also consider evaluation
of quality of life and length of hospitalisation Such trials may
consider starting bile acid and placebo interventions before liver
transplantation we were not able to identify any randomised trials
addressing this regimen Such trials ought to be reported accord-
ing to the CONSORT statement (wwwconsort-statementorg)
However before embarking on such trials the effects of bile acids
in other patient groups should be scrutinised as they may have
small or negative effects
A C K N O W L E D G E M E N T S
We thank all the patients and investigators who were involved in
the clinical trials mentioned in this review We thank Wendong
Chen for his work and contribution on the previous version of this
review We thank the staff of The Cochrane Hepato-Biliary Group
Editorial Team especially Dimitrinka Nikolova and Sarah Louise
Klingenberg for excellent collaboration and assistance during the
update of this review
Peer Reviewers Carlo Merkel Italy M Tomikawa Japan
Contact Editor Bodil Als-Nielsen Denmark
R E F E R E N C E S
References to studies included in this review
Angelico 1999 published data only
Angelico M Tisone G Baiocchi L Palmieri G Pisani F Negrini S
et alOne-year pilot study on tauroursodeoxycholic acid as an
adjuvant treatment after liver transplantation Italian Journal of
Gastroenterology and Hepatology 199931(6)462ndash8 [MEDLINE
10575563]
Barnes 1997 published data onlylowast Barnes D Talenti D Cammell G Goormastic M Farquhar L
Henderson M et alA randomized clinical trial of ursodeoxycholic
acid as adjuvant treatment to prevent liver transplant rejection
Hepatology 199726(4)853ndash7 [MEDLINE 9328304]
Barnes D Talenti D Goormastic M Farquhar L Cammell G
Henderson M et alUrsodeoxycholic acid (UDCA) reduces hepatic
allograft rejection after orthotopic liver transplantation (OLT) - a
prospective randomized placebo-controlled double-blind trial
Hepatology 199522149A
Fleckenstein 1998 published data only
Fleckenstein JF Paredes M Thuluvath PJ A prospective
randomized double-blind trial evaluating the efficacy of
ursodeoxycholic acid in prevention of liver transplant rejection
Liver Transplantation and Surgery 19984(4)276ndash9 [MEDLINE
9649640]
Keiding 1997 published data only
Keiding S Hockerstedt K Bjoro K Bondesen S Hjortrup A
Isoniemi H et alThe Nordic multicenter double-blind randomized
controlled trial of prophylactic ursodeoxycholic acid in liver
transplant patients Transplantation 199763(11)1591ndash4
[MEDLINE 9197351]
Koneru 1993 published data only
Koneru B Tint GS Wilson DJ Leevy CB Salen F Randomised
prospective trial of ursodeoxycholic acid in liver transplant
recipients Hepatology 199318336A
Pageaux 1995 published data only
Pageaux GP Blanc P Perrigault PF Navarro F Fabre JM Souche B
et alFailure of ursodeoxycholic acid to prevent acute cellular
rejection after liver transplantation Journal of Hepatology 199523
(2)119ndash22 [MEDLINE 7499781]
Sama 1991 published data only
Sama C Mazziotti A Grigioni W Morselli AM Chianura A
Stefanini GF et alUrsodeoxycholic acid administration does not
14Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
prevent rejection after OLT Journal of Hepatology 199113(Suppl
2)68
References to studies excluded from this review
Assy 2007 published data only
Assy N Adams PC Myers P Simon V Minuk GY Wall W et
alRandomized controlled trial of total immunosuppression
withdrawal in liver transplant recipients role of ursodeoxycholic
acid Transplantation 200783(12)1571ndash6 [MEDLINE
17589339]
Clavien 1996 published data only
Clavien PA Sharara AI Camargo CA Jr Harland RC Fitz JG
Evidence that ursodeoxycholic acid prevents steroid-resistant
rejection in adult liver transplantation Clinical Transplantation
199610(6 Pt 2)658ndash62 [MEDLINE 8996761]
Friman 1992 published data only
Friman S Persson H Schersten T Svanvik J Karlberg I Adjuvant
treatment with ursodeoxycholic acid reduces acute rejection after
liver transplantation Transplantation Proceedings 199224(1)
389ndash90 [MEDLINE 1539328]
Heathcote 1999 published data onlylowast Heathcote EJ Stone J Cauch-Dudek K Poupon R Chazouilleres
O Lindor KD et alEffect of pretransplantation ursodeoxycholic
acid therapy on the outcome of liver transplantation in patients
with primary biliary cirrhosis Liver Transplantation and Surgery
19995(4)269ndash74 [MEDLINE 10388499]
Henriksson 1991 published data only
Henriksson BA Persson H Friman S Wangberg B Svanvik J
Karlberg I Adjuvant ursodeoxycholic acid prevents acute rejection
in liver transplant recipients Transplantation Proceedings 199123
(3)1971 [MEDLINE 2063453]
Persson 1990 published data only
Persson H Friman S Schersten T Svanvik J Karlberg I
Ursodeoxycholic acid for prevention of acute rejection in liver
transplant recipients Lancet 1990336(8706)52ndash3 [MEDLINE
1973232]
Rafael 1995 published data only
Rafael E Duraj F Rudstrom H Wilczek H Ericzon B Effect of
ursodeoxycholic acid treatment for cholestasis in liver transplant
recipients Transplantation Proceedings 199527(6)3501ndash2
[MEDLINE 8540069]
Sama 1998 published data only
Sama C Morselli-Labate AM Grazi GL Mastroianni A Danesi G
Pianta P et alUrsodeoxycholic acid in liver transplantation effect
on cholestasis and rejection Gastroenterology 1998114(4 Suppl)
A1332
Additional references
Adams 1990
Adams DH Neuberger JM Patterns of graft rejection following
liver transplantation Journal of Hepatology 199010(1)113ndash9
[MEDLINE 2407770]
Al-Quaiz 1994
Al-Quaiz M OrsquoGrady J Tredger J Williams R Variable effect of
ursodeoxycholic acid on cyclosporin absorption after orthotopic
liver transplantation Transplant International 19947(3)190ndash4
[MEDLINE 8060468]
Armstrong 1982
Armstrong MJ Carey MC The hydrophobic-hydrophilic balance
of bile salt Inverse correlation between reverse phase high
performance liquid chromatographic mobilities and micellar
cholesterol-solubilizing capacities Journal of Lipid Research 1982
23(1)70ndash80 [MEDLINE 7057113]
Ascher 1988
Ascher NL Stock PG Baumgardner GL Payne WD Najarian JS
Infection and rejection of primary hepatic transplant in 93
consecutive patients treated with triple immunosuppressive therapy
Surgery Gynecology amp Obstetrics 1988167(6)474ndash84
[MEDLINE 3055368]
Brok 2008
Brok J Thorlund K Gluud C Wetterslev J Trial sequential
analysis reveals insufficient information size and potentially false
positive results in many meta-analyses Journal of Clinical
Epidemiology 200861(8)763ndash9 [MEDLINE 18411040]
Brok 2009
Brok J Thorlund K Wetterslev J Gluud C Apparently conclusive
meta-analysis may be inconclusive - Trial sequential analysis
adjustment of random error risk due to repetitive testing of
accumulating data in apparently conclusive neonatal meta-analysis
International Journal of Epidemiology 200938(1)298ndash303
[MEDLINE 18824466]
Calmus 1990
Calmus Y Gane P Rouger P Poupon R Hepatic expression of class
I and class II major histocompatibility complex molecules in
primary biliary cirrhosis effect of ursodeoxycholic acid Hepatology
199011(1)12ndash5 [MEDLINE 2403961]
Calmus 1992
Calmus Y Arvieux C Gane P Boucher E Nordlinger B Rouger P
et alCholestasis induces major histocompatibility complex class I
expression in hepatocytes Gastroenterology 1992102(4 Pt 1)
1371ndash7 [MEDLINE 1551542]
Chen 2003a
Chen W Gluud C Bile acids for primary sclerosing cholangitis
Cochrane Database of Systematic Reviews 2003 Issue 2 [DOI
10100214651858CD003626]
Chen 2007
Chen W Liu J Gluud C Bile acids for viral hepatitis Cochrane
Database of Systematic Reviews 2007 Issue 4 [DOI 101002
14651858CD003181pub2]
Cheng 2002
Cheng K Ashby D Smyth R Ursodeoxycholic acid for cystic
fibrosis-related liver disease Cochrane Database of Systematic
Reviews 2002 Issue 2 [DOI 10100214651858CD000222]
Corbani 2008
Corbani A Burroughs AK Intrahepatic cholestasis after liver
transplantation Clinics in Liver Disease 200812(1)111ndash29
[MEDLINE 18242500]
DeMets 1987
DeMets DL Methods for combining randomised clinical trials
strengths and limitations Statistics in Medicine 19876(3)341ndash50
[MEDLINE 3616287]
15Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
DerSimonian 1986
DerSimonian R Laird N Meta-analysis in clinical trials Controlled
Clinical Trials 19867(3)177ndash88 [MEDLINE 3802833]
Egger 1997
Egger M Davey Smith G Schneider M Minder C Bias in meta-
analysis detected by a simple graphical test BMJ (Clinical Research
Ed) 1997315(7109)629ndash34 [MEDLINE 9310563]
Ericzon 1990
Ericzon BG Eusufzai S Kubota K Einarsson K Angelin B
Characteristics of biliary lipid metabolism after liver
transplantation Hepatology 199012(5)1222ndash8 [MEDLINE
2227822]
FK506 1994
The US Multicenter FK506 Liver Study Group A comparison of
tacrolimus (FK506) and cyclosporine for immunosuppression in
liver transplantation New England Journal of Medicine 1994331
(17)1110ndash5 [MEDLINE 7523946]
Friman 1994
Friman S Svanvik J A possible role of ursodeoxycholic acid in liver
transplantation Scandinavian Journal of Gastroenterology 1994204
62ndash4 [MEDLINE 7824880]
Fuchs 1999
Fuchs M Stange EF Metabolism of bile acids In Johannes
Bircher Jean-Pierre Benhamou Neil McIntyre Mario Rizzetto
Juan Rodes editor(s) Oxford Textbook of Clinical Hepatology 2
Vol 1 Oxford Oxford University Press 1999223ndash56
Fusai 2006
Fusai G Dhaliwal P Rolando N Sabin CA Patch D Davidson BR
et alIncidence and risk factors for the development of prolonged
and severe intrahepatic cholestasis after liver transplantation Liver
Transplantation 200612(11)1626ndash33 [DOI 101002lt20870]
Gluud 2001
Gluud C Alcoholic hepatitis no glucocorticosteroids In
Leuschner U James OFW Dancygier H editor(s) Steatohepatitis
(NASH and ASH) Falk Symposium 121 Lancaster Kluwer
Academic Publisher 2001322ndash42
Gluud 2010
Gluud C Nikolova D Klingenberg SL Alexakis N Als-Nielsen B
Colli A et alCochrane Hepato-Biliary Group About The
Cochrane Collaboration (Cochrane Review Groups (CRGs))
2010 Issue 1 Art No LIVER
Gong 2008
Gong Y Huang ZB Christiansen E Gluud C Ursodeoxycholic
acid for primary biliary cirrhosis Cochrane Database of Systematic
Reviews 2008 Issue 3 [DOI 101002
14651858CD000551pub2]
Haddad 2006
Haddad EM McAlister VC Renouf E Malthaner R Kjaer MS
Gluud LL Cyclosporin versus tacrolimus for liver transplanted
patients Cochrane Database of Systematic Reviews 2006 Issue 4
[DOI 10100214651858CD005161pub2]
Heuman 1993
Heuman DM Hepatoprotective properties of ursodeoxycholic acid
Gastroenterology 1993104(6)1865ndash9 [MEDLINE 8500748]
Higgins 2008
Higgins PTJ Green S editors Cochrane Handbook for Systematic
Reviews of Interventions West Sussex England Wiley-Blackwell
2008
Hirschfield 2009
Hirschfield GM Gibbs P Griffiths WJH Adult liver
transplantation what non-specialists need to know BMJ (Clinical
Research Ed) 2009338(b1670)1321ndash7 [DOI 101136
bmjb1670]
Hussain 2002
Hussain HK Nghiem HV Imaging of hepatic transplantation
Clinics in Liver Disease 20026(1)247ndash70 [MEDLINE
11933592]
ICH-GCP 1997
International Conference on Harmonisation Expert Working
Group Code of Federal Regulations amp International Conference on
Harmonization Guidelines Media Parexel Barnett 1997
Ioannidis 2001
Ioannidis JPA Lau J Evolution of treatment effects over time
Empirical insight from recursive cumulative meta analyses
Proceedings of the National Academy of Sciences 200198(3)831ndash6
IWP 1995
International Working Party Terminology for hepatic allograft
rejection Hepatology 199522(2)648ndash54 [MEDLINE 7635435]
Kjaergard 2001
Kjaergard LL Villumsen J Gluud C Reported methodological
quality and discrepancies between large and small randomised trials
in meta-analyses Annals of Internal Medicine 2001135(11)982ndash9
[MEDLINE 11730399]
Klintmalm 1989
Klintmalm GB Nery JR Husberg BS Gonwa TA Tillery GW
Rejection in liver transplantation Hepatology 198910(6)978ndash85
[MEDLINE 2583691]
Knechtle 2009
Knechtle SJ Kwun J Unique aspects of rejection and tolerance in
liver transplantation Seminars in Liver Disease 200929(1)91ndash101
[MEDLINE 19235662]
Krams 1993
Krams SM Ascher NL Martinez OM New immunologic insights
into mechanisms of allograft rejection Gastroenterology Clinics of
North America 199318(2)374ndash7 [MEDLINE 8509176]
Lan 1983
Lan KKG DeMets DL Discrete sequential boundaries for clinical
trials Biometrika 198370659ndash63
Merion 1989
Merion RM Gorski DH Burtch GD Turcotte JG Colletti LM
Campbell DA Jr Bile refeeding after liver transplantation and
avoidance of intravenous cyclosporine Surgery 1989106(4)
604ndash9 [MEDLINE 2799635]
Moher 1998
Moher D Pham B Jones A Cook DJ Jadad AR Moher M et
alDoes quality of reports of randomised trials affect estimates of
intervention efficacy reported in meta-analyses Lancet 1998352
(9128)609ndash13 [MEDLINE 9746022]
16Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Neuberger 1999
Neuberger J Incidence timing and risk factors for acute and
chronic rejection Liver Transplantation and Surgery 19995(4 Suppl
1)S30ndashS36 [MEDLINE 10431015]
Okolicsanyi 1986
Okolicsanyi L Lirussi F Strazzabosco M Jemmolo RM Orlando R
Nassuato G et alThe effect of drugs on bile flow and composition
An overview Drugs 198631(5)430ndash48 [MEDLINE 2872047]
Palmer 1972
Palmer RH Bile acids liver injury and liver disease Archives of
Internal Medicine 1972130(4)606ndash17 [MEDLINE 4627840]
Perez 2009
Perez MJ Briz O Bile-acid-induced cell injury and protection
World Journal of Gastroenterology 200915(14)1677ndash89
[MEDLINE 19360911]
Pogue 1997
Pogue JM Yusuf S Cumulating evidence from randomized trials
Utilizing sequential monitoring boundaries for cumulative meta-
analysis Controlled Clinical Trials 199718(6)580ndash93
[MEDLINE 9408720]
Pogue 1998
Pogue J Yusuf S Overcoming the limitations of current meta-
analysis of randomised controlled trials Lancet 1998351(9095)
45ndash52 [MEDLINE 9433436]
RevMan 2008
The Nordic Cochrane Centre The Cochrane Collaboration
Review Manager (RevMan) 50 Copenhagen The Nordic
Cochrane Centre The Cochrane Collaboration 2008
Royle 2003
Royle P Milne R Literature searching for randomized controlled
trials used in Cochrane reviews rapid versus exhaustive searches
International Journal of Technology Assessment in Health Care 2003
19(4)591ndash603
Schulz 1995
Schulz KF Chalmers I Hayer R Altman D Empirical evidence of
bias JAMA 1995273(5)408ndash12 [MEDLINE 7823387]
Sharara 1995
Sharara AI Camargo CA Clavien PA Ursodeoxycholic acid
prevents steroid resistant rejection in liver transplant recipients
Gastroenterology 1995108A1168
Sholmerich 1984
Sholmerich J Becher MS Schmidt KH Schubert R Kremer B
Felhaus S et alInfluence of hydroxylation and conjugation of bile
salts on their membrane damaging properties Hepatology 19844
(4)661ndash7 [MEDLINE 6745854]
Soderdahl 1998
Soderdahl G Nowak G Duraj F Wang FH Einarsson C Ericzon
BG Ursodeoxycholic acid increased bile flow and affects bile
composition in the early postoperative phase following liver
transplantation Transplantation International 199811(Suppl 1)
S231ndashS238 [MEDLINE 9664985]
Terasaki 1991
Terasaki S Nakanuma Y Ogino H Unoura M Kobayashi K
Hepatocellular and biliary expression of HLA antigens in primary
biliary cirrhosis before and after ursodeoxycholic acid therapy
American Journal of Gastroenterology 199186(9)1194ndash9
[MEDLINE 1882800]
Thalheimer 2002
Thalheimer U Capra F Liver transplantation making the best out
of what we have Digestive Diseases and Sciences 200247(5)
945ndash53 [MEDLINE 12018919]
Thorlund 2009
Thorlund K Devereaux PJ Wetterslev J Guyatt G Ioannidis JP
Thabane L et alCan trial sequential monitoring boundaries reduce
spurious inferences from meta-analyses International Journal of
Epidemiology 200938(1)276ndash86 [MEDLINE 18824467]
Thuluvath 2003
Thuluvath PJ Yoo HY Thompson RE A model to predict survival
at one month one year and five years after liver transplantation
based on pretransplant clinical characteristics Liver Transplantation
20039(5)527ndash32 [MEDLINE 12740799]
van den Berg 1998
van den Berg AP Twilhaar WN Mesander G van Son WJ van der
Bij W Klompmaker IJ et alQuantitation of immunosuppression
by flow cytometric measurement of the capacity of T cells for
interleukin-2 production Transplantation 199865(8)1066ndash71
[MEDLINE 9583867]
Vierling 1992
Vierling J Immunologic mechanisms of hepatic allograft rejection
Seminars in Liver Disease 199212(1)16ndash27 [MEDLINE
1570548]
Wetterslev 2008
Wetterslev J Thorlund K Brok J Gluud C Trial sequential
analysis may establish when firm evidence is reached in cumulative
meta-analysis Journal of Clinical Epidemiology 200861(1)64ndash75
[MEDLINE 18083463]
Wiesner 1992
Wiesner RH Acute cellular rejection following liver
transplantation incidence risk factors and outcome in the
NIDDK Liver Transplant Database (LTD) study Gastroenterology
1992102A910
Wood 2008
Wood L Egger M Gluud LL Schulz KF Juni P Altman DG et
alEmpirical evidence of bias in treatment effect estimates in
controlled trials with different interventions and outcomes meta-
epidemiological study BMJ (Clinical Research Ed) 2008336
(7644)601ndash5 [MEDLINE 18316340]
Yoshikawa 1998
Yoshikawa M Matsui Y Kawamoto H Toyohara M Matsumura
K Yamao J et alIntragastric administration of ursodeoxycholic
acid suppresses immunoglobulin secretion by lymphocytes from
liver but not from peripheral blood spleen or Peyerrsquos patches in
mice International Journal of Immunopharmacology 199820(1-3)
29ndash38 [MEDLINE 9717080]
References to other published versions of this review
17Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Chen 2003b
Chen W Gluud C Bile acids for liver transplanted patients
Cochrane Database of Systematic Reviews 2005 Issue 3 [DOI
10100214651858CD005442]lowast Indicates the major publication for the study
18Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
C H A R A C T E R I S T I C S O F S T U D I E S
Characteristics of included studies [ordered by study ID]
Angelico 1999
Methods Study design open-label randomised one-year pilot study
Participants Country Italy
Publication language English
Inclusion criteria
- patients who underwent liver transplantation from April 1994 to December 1994
Exclusion criteria
- not mentioned
Participants
Two patients in TUDCA group and two patients in control group were excluded from
the basic information of participants by the study due to withdrawal
- TUDCA group (n = 14)
Mean age (years +- SD)
467 +- 84
Ratio of sex (malefemale) 122
Origins of liver diseases
hepatitis C cirrhosis (9) hepatitis B cirrhosis (2) hepatitis B and C cirrhosis (1) cryp-
togenic cirrhosis (2) alcoholic cirrhosis (0) Wilson cirrhosis (0)
- Control group (n = 15)
Mean age (years +- SD)
474 +- 74
Ratio of sex (malefemale) 123
Origins of liver diseases
hepatitis C cirrhosis (7) hepatitis B cirrhosis (2) hepatitis B and C cirrhosis (2) cryp-
togenic cirrhosis (2) alcoholic cirrhosis (1) Wilson cirrhosis (1)
Interventions TUDCA group
- Dose 500 mgday in two divided doses
- Route orally
- Duration the treatment was started on day 5 after transplantation and continued for
one year
Control group
- no treatment
Co-interventions all patients received standard triple-drug regimens (steroids azathio-
prine and cyclosporine or tacrolimus)
Outcomes All cause mortality
Number of patients with rejection after liver transplantation
Notes Letter was sent to the authors in September 2009 A reply with additional information
was received shortly after
Risk of bias
19Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Angelico 1999 (Continued)
Item Authorsrsquo judgement Description
Adequate sequence generation Yes Computer generated table
Allocation concealment Unclear No information provided
Blinding No Not performed
Incomplete outcome data addressed
All outcomes
Yes Withdrawal two patients from the
TUDCA group and two patients from the
placebo group Three of them died due to
transplant non-function in the first postop-
erative week and one patient was regrafted
due to thrombosis of hepatic artery
Free of selective reporting Unclear Post-transplant cholestasis and liver bio-
chemistry specified as outcomes Differ-
ence reported as not significant but no ac-
tual data given
Sample size calculation No Not reported
Intention-to-treat analysis No Not stated and not used
Baseline imbalance Unclear Not enough information provided
Early stopping of trial Unclear Not enough information provided
Barnes 1997
Methods Study design randomised placebo-controlled double-blind trial
Participants Country United States
Publication language English
Inclusion criteria
- patients aged 18 years or older who underwent liver transplantation at the Cleveland
Clinic Foundation from April 1992 through June of 1994
Exclusion criteria
- patients who were found to have cancer at surgically resected margins of the biliary
tree
- patents who underwent retransplantation
Participants
- UDCA group (n = 28)
Mean age (years +- SD)
505 +- 116
Ratio of sex (malefemale) 1810
Child class A 7
20Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Barnes 1997 (Continued)
B 13
and C 8
Origins of liver diseases Laennecrsquos cirrhosis 4
PBC 3
cryptogenic cirrhosis 6
hepatitis Ccirrhosis 4
hepatitis Bcirrhosis 3
autoimmune hepatitis with cirrhosis 3
PSC 2
other 3
- Placebo group (n = 24)
Mean age (years +- SD)
507 +- 93
Ratio of sex (malefemale) 159
Child class A 6
B 14
and C 4
Origins of liver diseases Laennecrsquos cirrhosis 9
PBC 5
cryptogenic cirrhosis 1
hepatitis Ccirrhosis 1
hepatitis Bcirrhosis 1
autoimmune hepatitis with cirrhosis 1
PSC 2
other 4
Interventions UDCA group
- Dose 10-15 mgkg body weightday in divided doses
- Route orally
- Duration immediately after intestinal transit recovery usually between postoperative
days three and five and continue for three months
Placebo group
- identical-appearing capsules administered in the same quantity and manner
Co-interventions all patients received standard triple-drug regimens (steroids azathio-
prine and cyclosporine or tacrolimus)
Outcomes All cause mortality
Number of patients with acute cellular rejection
Number of patients with chronic rejection
Number of patients with steroid-resistant rejection
Number of days of hospitalisation
Adverse events
Notes Letter was sent to the authors in September 2009 A reply with additional information
was received shortly after
Risk of bias
Item Authorsrsquo judgement Description
21Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Barnes 1997 (Continued)
Adequate sequence generation Yes Computer generated table
Allocation concealment Unclear No information provided
Blinding Yes Quote ldquorandomised to receive either
UDCA or an identical placebo capsulerdquo
Incomplete outcome data addressed
All outcomes
Yes Mean follow-up time 18 months Ten pa-
tients withdrawn from study 6 in UDCA
group and 4 in placebo group Reasons
for withdrawal were reported Four patients
died in the placebo group
Free of selective reporting Yes All expected outcomes reported
Sample size calculation Unclear The trial reported the method of sample
size calculation but the actual number of
patients needed was not reported
Intention-to-treat analysis Yes Stated and used
Baseline imbalance Unclear Not enough information provided
Early stopping of trial Unclear The number of patients needed to gain the
actual power was not reported Whether
the trial was terminated early is not clear
Fleckenstein 1998
Methods Study design prospective randomised double-blind trial
Participants Country United States
Publication language English
Inclusion criteria
- patients who underwent liver transplantation at the Johns Hopkins Hospital
Exclusion criteria
- patients who were under 18 years old undergoing repeat transplantation had primary
graft nonfunction or refused consent
Participants
- UDCA group (n = 14)
Mean age (years +- SD)
443 +- 127
Ratio of sex (malefemale) 68
Origins of liver diseases hepatitis C 6
alcohol 2
autoimmune 1
PBC 2
22Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Fleckenstein 1998 (Continued)
PSC 1
autoimmune cholangiopathy 1
hepatitis B 1
- Placebo group (n = 16)
Mean age (years +- SD)
496 +- 109
Ratio of sex (malefemale) 124
Origins of liver diseases hepatitis C 3
alcohol 3
autoimmune 3
PBC 1
PSC 2
cryptogenic 2
hepatitis B 1
alpha1-antitrypsin deficiency 1
Interventions UDCA group
- Dose 15 mgkg body weightday in divided doses
- Route orally
- Duration immediately after intestinal transit recovery usually between postoperative
days three and five and continue for three months
Placebo group
- Identical-appearing capsules administered in the same quantity and manner
Co-interventions all patients received standard triple-drug regimens (steroids azathio-
prine and cyclosporine or tacrolimus)
Outcomes All cause mortality
Number with retransplantation
Number of patients with acute cellular rejection
Number of patients with chronic rejection
Serum bilirubin levels at the end of treatment
Notes Follow-up time nine months
Letter was sent to the authors in September 2009 No reply was received
Risk of bias
Item Authorsrsquo judgement Description
Adequate sequence generation Unclear No information provided
Allocation concealment Unclear No information provided
Blinding Yes Method of blinding not described but
probably adequate
Incomplete outcome data addressed
All outcomes
Yes Withdrawal one patient from the UDCA
group and two patients from the placebo
group because of capsule size
23Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Fleckenstein 1998 (Continued)
Free of selective reporting Unclear Outcomes were not completely described
Sample size calculation No Not reported
Intention-to-treat analysis Yes Quote ldquoThree patients withdrew after in-
clusionThey were included in the statis-
tical analysisrdquo
Baseline imbalance Unclear Not enough information provided
Early stopping of trial Unclear Not enough information provided
Keiding 1997
Methods Study design prospective randomised placebo-controlled multicenter study
Participants Country Denmark Finland Norway and Sweden
Publication language English
Inclusion criteria
- patients who underwent liver transplantation in Denmark Finland Norway and Swe-
den from September 1 1992 to May 31 1994
Exclusion criteria
- patients with malignant diseases
Participants
The age of the children ranged from 0 to 13 years (median 15) and the age of adults
ranged from 14 to 59 years old (median 44) MaleFemale ratio was 96 for children and
4344 for adults
- UDCA group (n = 54)
Origins of liver diseases
paracetamol intoxication 1 hepatitis B 1 autoimmune hepatitis 0 biliary atresia 2
metabolic diseases 7 neonatal hepatitis 2 PBC 13 post hepatitis cirrhosis 8 PSC 3
cryptogenic cirrhosis 7 alcoholic cirrhosis 2 other reasons 8
- Placebo group (n = 48)
Origins of liver diseases paracetamol intoxication 1 hepatitis B 0 autoimmune hepatitis
1 biliary atresia 3 metabolic diseases 11 neonatal hepatitis 0 PBC 7 post hepatitis
cirrhosis 5 PSC 7 cryptogenic cirrhosis 2 alcoholic cirrhosis 6 other reasons 5
Interventions UDCA group
- Dose 15 mgkg body weightday in two or three divided doses
- Route orally
- Duration immediately after intestinal transit recovery usually between postoperative
days three and five and continue for three months
Placebo group
- Identical-appearing capsules administered in the same quantity and manner
Co-interventions all patients received standard triple-drug regimens (steroids azathio-
prine and cyclosporine or tacrolimus)
24Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Keiding 1997 (Continued)
Outcomes All cause mortality
Number of deaths related to rejection
Number of patients with acute cellular rejection
Number of patients with chronic rejection
Number of patients with steroid-resistant rejection
Adverse events
Notes Letter was sent to the authors in September 2009 No reply was received
Risk of bias
Item Authorsrsquo judgement Description
Adequate sequence generation Unclear Patients were randomised at a ratio of 11
Allocation concealment Yes Quote ldquo The allocation was performed in
blocks of 10 patients using the sealed serial
envelope methodrdquo
Blinding Yes Quote ldquoThe UDCA and the placebo cap-
sules had identical appearance and tasterdquo
Incomplete outcome data addressed
All outcomes
Yes Follow-up time 12 months Five UDCA
patients and five placebo patients withdrew
from study Reasons were reported
Free of selective reporting Unclear Insufficient information
Sample size calculation Yes Performed and allowed for a difference in
the incidence of at least one episode of
acute rejection of 50 between the treat-
ment and placebo groups with 90 statisti-
cal power and a significance level of P value
less than 005 The calculated sample size
was 80 patients
Intention-to-treat analysis Yes Stated and used
Baseline imbalance Yes The study seems to be free of baseline im-
balance
Early stopping of trial Yes Study attained the pre-specified sample
size
25Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Koneru 1993
Methods Study design randomised controlled trial
Participants Country United States
Publication language English
Inclusion criteria
- patients who underwent liver transplantation
Exclusion criteria
- not mentioned
Participants
- UDCA group (n = 16)
Mean age (years +- SD)
no information
Ratio of sex (malefemale) no information
Origins of liver diseases
no information
- Control group (n = 16)
Mean age (years +- SD)
no information
Ratio of sex (malefemale) no information
Origins of liver diseases
no information
Interventions UDCA group
- Dose 900 mgday
- Route orally
- Duration immediately after intestinal transit recovery usually between postoperative
days three and five and continue for three months
Control group
- no treatment
Co-interventions all patients received standard triple-drug regimens (steroids azathio-
prine and cyclosporine)
Outcomes Number of patients with retransplantation due to rejection
Number of patients with rejection episodes
Notes Abstract
Letter was sent to the authors in September 2009 No reply was received
Risk of bias
Item Authorsrsquo judgement Description
Adequate sequence generation Unclear No information provided
Allocation concealment Unclear No information provided
Blinding No Not performed
26Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Koneru 1993 (Continued)
Incomplete outcome data addressed
All outcomes
Unclear The study gives the impression that there
were no withdrawals but this was not ex-
plicitly stated
Free of selective reporting Unclear Insufficient information provided
Sample size calculation No Not performed
Intention-to-treat analysis Unclear No information provided
Baseline imbalance Unclear Not enough information provided
Early stopping of trial Unclear Not enough information provided
Pageaux 1995
Methods Study design double-blind randomised study
Participants Country France
Publication language English
Inclusion criteria
- patients who underwent liver transplantation
Exclusion criteria
- not mentioned
Participants
- UDCA group (n=26)
Mean age (years +- SD)
47 +- 10
Ratio of sex (malefemale) 179
Origins of liver diseases alcoholic cirrhosis 14
post-hepatic B cirrhosis 2
post-hepatitis C cirrhosis 4
PBC 2
liver cancer 2
fulminant hepatitis 1
miscellaneous 1
- Placebo group (n = 24)
Mean age (years +- SD)
51+- 9
Ratio of sex (malefemale) 159
Origins of liver diseases alcoholic cirrhosis 10
post-hepatic B cirrhosis 0
post-hepatic C cirrhosis 6
PBC 3
liver cancer 4
fulminant hepatitis 0
miscellaneous 1
27Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Pageaux 1995 (Continued)
Interventions UDCA group
- Dose 600 mgday in three divided doses
- Route orally
- Duration immediately after intestinal transit recovery usually between postoperative
days three and five and continue for two months
Placebo group
- identical-appearing capsules administered in the same quantity and manner
Co-interventions all patients received standard triple-drug regimens (steroids azathio-
prine and cyclosporine or tacrolimus)
Outcomes Number of patients with acute cellular rejection
Number of patients with steroid-resistant rejection
Notes Letter was sent to the authors in September 2009 No reply was received
Risk of bias
Item Authorsrsquo judgement Description
Adequate sequence generation Unclear No information provided
Allocation concealment Unclear No information provided
Blinding Unclear Method of blinding not described
Incomplete outcome data addressed
All outcomes
Yes Five patients died from non-immunologi-
cal causes before the end of the first month
and were excluded from the study Reasons
were reported
Free of selective reporting Unclear Not enough information provided
Sample size calculation No Not performed
Intention-to-treat analysis No Not stated and not used
Baseline imbalance Unclear Not enough information provided
Early stopping of trial Unclear Not enough information provided
Sama 1991
Methods Study design randomised controlled trial
Participants Country Italy
Publication language English
Inclusion criteria
28Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Sama 1991 (Continued)
- patients who underwent liver transplantation
Exclusion criteria
- not mentioned
Participants
- UDCA group (n = 20)
Mean age (years +- SD)
no information
Ratio of sex (malefemale) no information
Origins of liver diseases
no information
- Control group (n = 20)
Mean age (years +- SD)
no information
Ratio of sex (malefemale) no information
Origins of liver diseases
no information
Interventions UDCA group
- Dose 600 mgday in two divided doses
- Route orally
- Duration immediately after intestinal transit recovery usually between postoperative
day five and day seven and continue for six months
Control group
- no treatment
Co-interventions all patients received standard immunosuppressive treatment (steroids
and cyclosporine)
Outcomes All cause mortality
Number of patients with acute cellular rejection
Notes Abstract
Letter was sent to the authors in September 2009 No reply was received
Risk of bias
Item Authorsrsquo judgement Description
Adequate sequence generation Unclear A randomisation list was performed before
patients were admitted to the trial (infor-
mation from principal author)
Allocation concealment Unclear No information provided
Blinding Unclear The principle author provided information
that the study was made according to a
single-blind randomised protocol The pri-
mary outcome was the occurrence of biopsy
proven rejection episodes The pathologists
were blind but the patients were not
29Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Sama 1991 (Continued)
Incomplete outcome data addressed
All outcomes
Unclear Five patients from the UDCA group and
six patients from the placebo group were
excluded Reasons for exclusion were not
fully stated
Free of selective reporting No Data about survival of patients were not
adequately reported
Sample size calculation No Not performed
Intention-to-treat analysis No Not stated and not used
Baseline imbalance Unclear Basic characteristics of patients not re-
ported
Early stopping of trial Unclear Not enough information provided
UDCA = ursodeoxycholic acid
TUDCA = tauroursodeoxycholic acid
PBC = primary biliary cirrhosis
PSC = primary sclerosing cholangitis
OKT3 = anti-CD3 monoclonal antibody
Characteristics of excluded studies [ordered by study ID]
Assy 2007 A randomised controlled trial that included only recipients of liver transplantation with stable graft function and
no episodes of rejection for at least 2 years that were then offered total immunosuppression withdrawal Fourteen
patients received UDCA (15 mgkg body weightday) and 12 received placebo Rejection occurred in 43 and
75 of patients respectively (no significant difference) None developed chronic rejection After follow-up two
patients were free of immunosuppression 80 were steroid free and 50 were able to reduce their dose of
cyclosporine
Clavien 1996 Case series Fifty consecutive liver-transplanted patients were treated with a standard cyclosporine immunosup-
pressive regimen Twenty three of the 43 survivors developed an episode of rejection and UDCA (10 mgkg
weightday) was initiated Only one patient had a second episode of rejection
Friman 1992 Observational study Thirty-three liver-transplanted patients received 10 mg UDCAkg body weightday for
median of 10 months (range four to 21 months) Eight historical liver-transplanted patients served as control
group The rejection incidence was significantly lower in the patients who received the treatment with UDCA
Biochemistry one month after transplantation demonstrated significantly lower average values of aminotrans-
ferases and alkaline phosphatases in patients treated with UDCA than in the control group
30Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
Heathcote 1999 Observational study From 1987 to 1996 37 UDCA treated and 53 placebo treated patients with primary biliary
cirrhosis were referred for transplantation Posttransplantation survival rates at one month were 939 in the
UDCA group and 884 in the placebo group and one year survival rates were 903 and 784 respectively
(no significant differences) However rejection (type not defined - a secondary outcome measure) occurred
significantly less often in the UDCA group (429) than in placebo group (688)
Henriksson 1991 Observational study All patients in this study were given sequential quadruple immunosuppression with anti-
lymphocyte globulin azathioprine steroids and cyclosporine All patients with primary graft function (n = 11)
were treated with 10 mg UDCAkg body weightday starting during the first postoperative week Patients who
received liver transplantation in the first 6 months of 1989 (n = 8) served as controls In the control group one
patient died after 9 months with chronic graft dysfunction and six patients had rejection episodes during the
first postoperative month All patients in the UDCA group were alive without rejection episodes
Persson 1990 Observational study All 11 adult patients transplanted between August 1989 and January 1990 with primary
graft function were treated with 10 mg UDCA kg body weightday Eight patients transplanted during the first
half of 1989 served as control UDCA was started during the first postoperative week and the treatment was
continued for six months All patients in the UDCA treated group survived with satisfactory graft function In
the control group six patients had at least one rejection episode needing treatment during the first postoperative
month
Rafael 1995 Observational study Seventeen patients who underwent liver transplantation between February 1990 and April
1993 and developed biliary complications after transplantation were retrospectively analysed regarding treatment
with UDCA UDCA was given in a dose of 500 to 1000 mgday Ten patients were treated for at least one year while
seven patients were treated for 14 to 250 days UDCA significantly improved gammaglutamyl transpeptidase in
liver graft recipients with biliary complications There was also a trend towards improvement in serum bilirubin
and alanine transaminase values
Sama 1998 Observational study Thirty-four patients who underwent liver transplantation between January 1995 and June
1996 were included in the study Seventeen were treated with UDCA 10 mgkg body weightday during 6
months while 17 served as controls on the basis of having undergone liver transplantation closest to UDCA
patients A significant decrease in serum bilirubin levels was observed in UDCA patients There was a significantly
higher incidence of recurrent hepatitis in the control group
UDCA ursodeoxycholic acid
31Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
D A T A A N D A N A L Y S E S
Comparison 1 Bile acids for liver-transplanted patients
Outcome or subgroup titleNo of
studies
No of
participants Statistical method Effect size
1 All-cause mortality at maximum
follow-up
5 257 Risk Ratio (M-H Fixed 95 CI) 085 [053 136]
11 UDCA versus placebo or
no treatment
4 224 Risk Ratio (M-H Fixed 95 CI) 080 [049 130]
12 TUDCA versus no
treatment
1 33 Risk Ratio (M-H Fixed 95 CI) 159 [030 833]
2 All-cause mortality worst-best
case and best-worst case
scenarios
5 Risk Ratio (M-H Fixed 95 CI) Subtotals only
21 Worst-best case scenario 5 257 Risk Ratio (M-H Fixed 95 CI) 130 [086 196]
22 Best-worst case scenario 5 257 Risk Ratio (M-H Fixed 95 CI) 058 [038 090]
3 Subgroup analyses all-cause
mortality at maximum
follow-up according to time of
start of bile acids
5 257 Risk Ratio (M-H Fixed 95 CI) 085 [053 136]
31 Less than three days after
transplantation
1 102 Risk Ratio (M-H Fixed 95 CI) 124 [061 254]
32 Three days or more after
transplantation
4 155 Risk Ratio (M-H Fixed 95 CI) 063 [033 120]
4 Subgroup analyses all cause
mortality at maximum
follow-up according to
treatment duration
5 257 Risk Ratio (M-H Fixed 95 CI) 085 [053 136]
41 Less than six months 3 184 Risk Ratio (M-H Fixed 95 CI) 078 [045 138]
42 Six months or more 2 73 Risk Ratio (M-H Fixed 95 CI) 102 [043 240]
5 Number of deaths related
to rejection at maximum
follow-up
1 102 Risk Ratio (M-H Fixed 95 CI) 030 [001 712]
51 UDCA versus placebo 1 102 Risk Ratio (M-H Fixed 95 CI) 030 [001 712]
6 Number of retransplantations at
maximum follow-up
2 132 Risk Ratio (M-H Fixed 95 CI) 076 [020 286]
7 Number of patients with acute
cellular rejection at maximum
follow-up
7 339 Risk Ratio (M-H Fixed 95 CI) 089 [074 106]
71 UDCA versus placebo or
no treatment
6 306 Risk Ratio (M-H Fixed 95 CI) 089 [074 108]
72 TUDCA versus no
treatment
1 33 Risk Ratio (M-H Fixed 95 CI) 085 [045 160]
8 Subgroup analysis number of
patients with acute cellular
rejection according to time of
start of bile acid
7 339 Risk Ratio (M-H Fixed 95 CI) 089 [074 106]
32Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
81 Less than three days after
transplantation
2 134 Risk Ratio (M-H Fixed 95 CI) 084 [063 111]
82 Three days or more after
liver transplantation
5 205 Risk Ratio (M-H Fixed 95 CI) 092 [072 117]
9 Subgroup analysis number
of patients with acute
cellular rejection according to
treatment duration
7 339 Risk Ratio (M-H Fixed 95 CI) 089 [074 106]
91 Less than six months 5 266 Risk Ratio (M-H Fixed 95 CI) 087 [071 107]
92 Six months or more 2 73 Risk Ratio (M-H Fixed 95 CI) 094 [065 136]
10 Number of patients with
chronic rejection at maximum
follow-up
3 184 Risk Ratio (M-H Fixed 95 CI) 028 [008 095]
11 Number of patients with
steroid-resistant rejection at
maximum follow-up
4 234 Risk Ratio (M-H Fixed 95 CI) 077 [047 127]
12 Serum bilirubin (mgdl) at the
end of treatment
1 30 Mean Difference (IV Fixed 95 CI) 26 [-096 616]
13 Number of days of
hospitalisation after liver
transplantation
1 52 Mean Difference (IV Fixed 95 CI) -85 [-1667 -033]
14 Adverse events 3 187 Risk Ratio (M-H Fixed 95 CI) 088 [030 260]
Analysis 11 Comparison 1 Bile acids for liver-transplanted patients Outcome 1 All-cause mortality at
maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 1 All-cause mortality at maximum follow-up
Study or subgroup Favours bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 UDCA versus placebo or no treatment
Barnes 1997 228 724 253 024 [ 006 107 ]
Fleckenstein 1998 214 416 125 057 [ 012 266 ]
Keiding 1997 1454 1048 355 124 [ 061 254 ]
Sama 1991 520 620 201 083 [ 030 229 ]
Subtotal (95 CI) 116 108 935 080 [ 049 130 ]
Total events 23 (Favours bile acids) 27 (Control)
Heterogeneity Chi2 = 416 df = 3 (P = 025) I2 =28
Test for overall effect Z = 091 (P = 036)
01 02 05 1 2 5 10
Favours bile acids Favours control
(Continued )
33Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Favours bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
2 TUDCA versus no treatment
Angelico 1999 316 217 65 159 [ 030 833 ]
Subtotal (95 CI) 16 17 65 159 [ 030 833 ]
Total events 3 (Favours bile acids) 2 (Control)
Heterogeneity not applicable
Test for overall effect Z = 055 (P = 058)
Total (95 CI) 132 125 1000 085 [ 053 136 ]
Total events 26 (Favours bile acids) 29 (Control)
Heterogeneity Chi2 = 466 df = 4 (P = 032) I2 =14
Test for overall effect Z = 069 (P = 049)
01 02 05 1 2 5 10
Favours bile acids Favours control
Analysis 12 Comparison 1 Bile acids for liver-transplanted patients Outcome 2 All-cause mortality worst-
best case and best-worst case scenarios
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 2 All-cause mortality worst-best case and best-worst case scenarios
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 Worst-best case scenario
Angelico 1999 516 217 65 266 [ 060 1180 ]
Barnes 1997 828 724 253 098 [ 042 230 ]
Fleckenstein 1998 314 416 125 086 [ 023 319 ]
Keiding 1997 1954 1048 355 169 [ 087 327 ]
Sama 1991 520 620 201 083 [ 030 229 ]
Subtotal (95 CI) 132 125 1000 130 [ 086 196 ]
Total events 40 (Bile acids) 29 (Control)
Heterogeneity Chi2 = 303 df = 4 (P = 055) I2 =00
Test for overall effect Z = 123 (P = 022)
2 Best-worst case scenario
005 02 1 5 20
Favours bile acids Favours control
(Continued )
34Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Angelico 1999 316 417 90 080 [ 021 302 ]
Barnes 1997 228 1124 274 016 [ 004 063 ]
Fleckenstein 1998 214 616 130 038 [ 009 159 ]
Keiding 1997 1454 1548 368 083 [ 045 154 ]
Sama 1991 520 620 139 083 [ 030 229 ]
Subtotal (95 CI) 132 125 1000 058 [ 038 090 ]
Total events 26 (Bile acids) 42 (Control)
Heterogeneity Chi2 = 567 df = 4 (P = 023) I2 =29
Test for overall effect Z = 247 (P = 0014)
005 02 1 5 20
Favours bile acids Favours control
Analysis 13 Comparison 1 Bile acids for liver-transplanted patients Outcome 3 Subgroup analyses all-
cause mortality at maximum follow-up according to time of start of bile acids
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 3 Subgroup analyses all-cause mortality at maximum follow-up according to time of start of bile acids
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 Less than three days after transplantation
Keiding 1997 1454 1048 355 124 [ 061 254 ]
Subtotal (95 CI) 54 48 355 124 [ 061 254 ]
Total events 14 (Bile acids) 10 (Control)
Heterogeneity not applicable
Test for overall effect Z = 060 (P = 055)
2 Three days or more after transplantation
Angelico 1999 316 217 65 159 [ 030 833 ]
Barnes 1997 228 724 253 024 [ 006 107 ]
Fleckenstein 1998 214 416 125 057 [ 012 266 ]
Sama 1991 520 620 201 083 [ 030 229 ]
005 02 1 5 20
Favours bile acids Favours control
(Continued )
35Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Subtotal (95 CI) 78 77 645 063 [ 033 120 ]
Total events 12 (Bile acids) 19 (Control)
Heterogeneity Chi2 = 310 df = 3 (P = 038) I2 =3
Test for overall effect Z = 141 (P = 016)
Total (95 CI) 132 125 1000 085 [ 053 136 ]
Total events 26 (Bile acids) 29 (Control)
Heterogeneity Chi2 = 466 df = 4 (P = 032) I2 =14
Test for overall effect Z = 069 (P = 049)
005 02 1 5 20
Favours bile acids Favours control
Analysis 14 Comparison 1 Bile acids for liver-transplanted patients Outcome 4 Subgroup analyses all
cause mortality at maximum follow-up according to treatment duration
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 4 Subgroup analyses all cause mortality at maximum follow-up according to treatment duration
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 Less than six months
Barnes 1997 228 724 253 024 [ 006 107 ]
Fleckenstein 1998 214 416 125 057 [ 012 266 ]
Keiding 1997 1454 1048 355 124 [ 061 254 ]
Subtotal (95 CI) 96 88 734 078 [ 045 138 ]
Total events 18 (Bile acids) 21 (Control)
Heterogeneity Chi2 = 417 df = 2 (P = 012) I2 =52
Test for overall effect Z = 084 (P = 040)
2 Six months or more
Angelico 1999 316 217 65 159 [ 030 833 ]
Sama 1991 520 620 201 083 [ 030 229 ]
Subtotal (95 CI) 36 37 266 102 [ 043 240 ]
Total events 8 (Bile acids) 8 (Control)
Heterogeneity Chi2 = 043 df = 1 (P = 051) I2 =00
005 02 1 5 20
Favours bile acids Favours control
(Continued )
36Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Test for overall effect Z = 004 (P = 097)
Total (95 CI) 132 125 1000 085 [ 053 136 ]
Total events 26 (Bile acids) 29 (Control)
Heterogeneity Chi2 = 466 df = 4 (P = 032) I2 =14
Test for overall effect Z = 069 (P = 049)
005 02 1 5 20
Favours bile acids Favours control
Analysis 15 Comparison 1 Bile acids for liver-transplanted patients Outcome 5 Number of deaths related
to rejection at maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 5 Number of deaths related to rejection at maximum follow-up
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 UDCA versus placebo
Keiding 1997 054 148 1000 030 [ 001 712 ]
Total (95 CI) 54 48 1000 030 [ 001 712 ]
Total events 0 (Bile acids) 1 (Control)
Heterogeneity not applicable
Test for overall effect Z = 075 (P = 045)
0001 001 01 1 10 100 1000
Favours bile acids Favours control
37Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 16 Comparison 1 Bile acids for liver-transplanted patients Outcome 6 Number of
retransplantations at maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 6 Number of retransplantations at maximum follow-up
Study or subgroup Bile acids Placebo Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Fleckenstein 1998 214 016 100 567 [ 029 10891 ]
Keiding 1997 154 448 900 022 [ 003 192 ]
Total (95 CI) 68 64 1000 076 [ 020 286 ]
Total events 3 (Bile acids) 4 (Placebo)
Heterogeneity Chi2 = 303 df = 1 (P = 008) I2 =67
Test for overall effect Z = 040 (P = 069)
0001 001 01 1 10 100 1000
Favours bile acids Favours placebo
Analysis 17 Comparison 1 Bile acids for liver-transplanted patients Outcome 7 Number of patients with
acute cellular rejection at maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 7 Number of patients with acute cellular rejection at maximum follow-up
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 UDCA versus placebo or no treatment
Barnes 1997 1728 1724 180 086 [ 058 127 ]
Fleckenstein 1998 814 916 83 102 [ 054 190 ]
Keiding 1997 3554 3248 333 097 [ 073 129 ]
Koneru 1993 316 916 89 033 [ 011 101 ]
Pageaux 1995 926 924 92 092 [ 044 193 ]
Sama 1991 1320 1320 128 100 [ 063 158 ]
Subtotal (95 CI) 158 148 905 089 [ 074 108 ]
01 02 05 1 2 5 10
Favours bile acids Favours control
(Continued )
38Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Total events 85 (Bile acids) 89 (Control)
Heterogeneity Chi2 = 387 df = 5 (P = 057) I2 =00
Test for overall effect Z = 120 (P = 023)
2 TUDCA versus no treatment
Angelico 1999 816 1017 95 085 [ 045 160 ]
Subtotal (95 CI) 16 17 95 085 [ 045 160 ]
Total events 8 (Bile acids) 10 (Control)
Heterogeneity not applicable
Test for overall effect Z = 050 (P = 061)
Total (95 CI) 174 165 1000 089 [ 074 106 ]
Total events 93 (Bile acids) 99 (Control)
Heterogeneity Chi2 = 392 df = 6 (P = 069) I2 =00
Test for overall effect Z = 130 (P = 019)
01 02 05 1 2 5 10
Favours bile acids Favours control
Analysis 18 Comparison 1 Bile acids for liver-transplanted patients Outcome 8 Subgroup analysis
number of patients with acute cellular rejection according to time of start of bile acid
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 8 Subgroup analysis number of patients with acute cellular rejection according to time of start of bile acid
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 Less than three days after transplantation
Keiding 1997 3554 3248 333 097 [ 073 129 ]
Koneru 1993 316 916 89 033 [ 011 101 ]
Subtotal (95 CI) 70 64 422 084 [ 063 111 ]
Total events 38 (Bile acids) 41 (Control)
Heterogeneity Chi2 = 374 df = 1 (P = 005) I2 =73
Test for overall effect Z = 124 (P = 022)
2 Three days or more after liver transplantation
Angelico 1999 816 1017 95 085 [ 045 160 ]
01 02 05 1 2 5 10
Favours bile acids Favours control
(Continued )
39Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Barnes 1997 1728 1724 180 086 [ 058 127 ]
Fleckenstein 1998 814 916 83 102 [ 054 190 ]
Pageaux 1995 926 924 92 092 [ 044 193 ]
Sama 1991 1320 1320 128 100 [ 063 158 ]
Subtotal (95 CI) 104 101 578 092 [ 072 117 ]
Total events 55 (Bile acids) 58 (Control)
Heterogeneity Chi2 = 041 df = 4 (P = 098) I2 =00
Test for overall effect Z = 067 (P = 050)
Total (95 CI) 174 165 1000 089 [ 074 106 ]
Total events 93 (Bile acids) 99 (Control)
Heterogeneity Chi2 = 392 df = 6 (P = 069) I2 =00
Test for overall effect Z = 130 (P = 019)
01 02 05 1 2 5 10
Favours bile acids Favours control
40Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 19 Comparison 1 Bile acids for liver-transplanted patients Outcome 9 Subgroup analysis
number of patients with acute cellular rejection according to treatment duration
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 9 Subgroup analysis number of patients with acute cellular rejection according to treatment duration
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 Less than six months
Barnes 1997 1728 1724 180 086 [ 058 127 ]
Fleckenstein 1998 814 916 83 102 [ 054 190 ]
Keiding 1997 3554 3248 333 097 [ 073 129 ]
Koneru 1993 316 916 89 033 [ 011 101 ]
Pageaux 1995 926 924 92 092 [ 044 193 ]
Subtotal (95 CI) 138 128 777 087 [ 071 107 ]
Total events 72 (Bile acids) 76 (Control)
Heterogeneity Chi2 = 374 df = 4 (P = 044) I2 =00
Test for overall effect Z = 129 (P = 020)
2 Six months or more
Angelico 1999 816 1017 95 085 [ 045 160 ]
Sama 1991 1320 1320 128 100 [ 063 158 ]
Subtotal (95 CI) 36 37 223 094 [ 065 136 ]
Total events 21 (Bile acids) 23 (Control)
Heterogeneity Chi2 = 017 df = 1 (P = 068) I2 =00
Test for overall effect Z = 035 (P = 073)
Total (95 CI) 174 165 1000 089 [ 074 106 ]
Total events 93 (Bile acids) 99 (Control)
Heterogeneity Chi2 = 392 df = 6 (P = 069) I2 =00
Test for overall effect Z = 130 (P = 019)
01 02 05 1 2 5 10
Favours bile acids Favours control
41Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 110 Comparison 1 Bile acids for liver-transplanted patients Outcome 10 Number of patients
with chronic rejection at maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 10 Number of patients with chronic rejection at maximum follow-up
Study or subgroup Bile acids Placebo Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Barnes 1997 128 624 611 014 [ 002 110 ]
Fleckenstein 1998 114 116 88 114 [ 008 1663 ]
Keiding 1997 154 348 300 030 [ 003 275 ]
Total (95 CI) 96 88 1000 028 [ 008 095 ]
Total events 3 (Bile acids) 10 (Placebo)
Heterogeneity Chi2 = 148 df = 2 (P = 048) I2 =00
Test for overall effect Z = 204 (P = 0041)
0001 001 01 1 10 100 1000
Favours bile acids Favours placebo
Analysis 111 Comparison 1 Bile acids for liver-transplanted patients Outcome 11 Number of patients
with steroid-resistant rejection at maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 11 Number of patients with steroid-resistant rejection at maximum follow-up
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Barnes 1997 328 724 277 037 [ 011 127 ]
Fleckenstein 1998 314 316 103 114 [ 027 478 ]
Keiding 1997 1454 1548 583 083 [ 045 154 ]
Pageaux 1995 226 124 38 185 [ 018 1908 ]
Total (95 CI) 122 112 1000 077 [ 047 127 ]
Total events 22 (Bile acids) 26 (Control)
Heterogeneity Chi2 = 226 df = 3 (P = 052) I2 =00
Test for overall effect Z = 102 (P = 031)
001 01 1 10 100
Favours bile acids Favours placebo
42Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 112 Comparison 1 Bile acids for liver-transplanted patients Outcome 12 Serum bilirubin (mgdl)
at the end of treatment
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 12 Serum bilirubin (mgdl) at the end of treatment
Study or subgroup Bile acids Placebo Mean Difference Weight Mean Difference
N Mean(SD) N Mean(SD) IVFixed95 CI IVFixed95 CI
Fleckenstein 1998 14 319 (68) 16 059 (022) 1000 260 [ -096 616 ]
Total (95 CI) 14 16 1000 260 [ -096 616 ]
Heterogeneity not applicable
Test for overall effect Z = 143 (P = 015)
-10 -5 0 5 10
Favours bile acids Favours placebo
Analysis 113 Comparison 1 Bile acids for liver-transplanted patients Outcome 13 Number of days of
hospitalisation after liver transplantation
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 13 Number of days of hospitalisation after liver transplantation
Study or subgroup Bile acids Placebo Mean Difference Weight Mean Difference
N Mean(SD) N Mean(SD) IVFixed95 CI IVFixed95 CI
Barnes 1997 28 25 (17) 24 335 (13) 1000 -850 [ -1667 -033 ]
Total (95 CI) 28 24 1000 -850 [ -1667 -033 ]
Heterogeneity not applicable
Test for overall effect Z = 204 (P = 0041)
-100 -50 0 50 100
Favours bile acids Favours placebo
43Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 114 Comparison 1 Bile acids for liver-transplanted patients Outcome 14 Adverse events
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 14 Adverse events
Study or subgroup Bile acids Placebo Risk Ratio Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Angelico 1999 016 017 00 [ 00 00 ]
Barnes 1997 128 124 086 [ 006 1298 ]
Keiding 1997 554 548 089 [ 027 288 ]
Total (95 CI) 98 89 088 [ 030 260 ]
Total events 6 (Bile acids) 6 (Placebo)
Heterogeneity Chi2 = 000 df = 1 (P = 098) I2 =00
Test for overall effect Z = 022 (P = 082)
001 01 1 10 100
Favours bile acids Favours placebo
A P P E N D I C E S
Appendix 1 Search strategies
Data Base Date of Search Search Strategy
The Cochrane Hepato-Biliary Group Con-
trolled Trials Register
September 2009 1 rsquoliver transplantationrsquo and rsquochenodeoxy-
cholicrsquo
2 rsquoliver transplantationrsquo and rsquocholicrsquo
3 rsquoliver transplantationrsquo and rsquodeoxycholicrsquo
4 rsquoliver transplantationrsquo and rsquoglycochen-
odeoxycholicrsquo
5 rsquoliver transplantationrsquo and rsquoglycocholicrsquo
6 rsquoliver transplantationrsquo and rsquoglycodeoxy-
cholicrsquo
7 rsquoliver transplantationrsquo and rsquoglycolitho-
cholicrsquo
8 rsquoliver transplantationrsquo and rsquohyodeoxy-
cholicrsquo
9 rsquoliver transplantationrsquo and rsquolithocholicrsquo
10 rsquoliver transplantationrsquo and rsquotaurochen-
odeoxycholicrsquo
44Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
11 rsquoliver transplantationrsquo and rsquotauro-
cholicrsquo
12 rsquoliver transplantationrsquo and rsquotaurodehy-
drocholicrsquo
13 rsquoliver transplantationrsquo and rsquotau-
rodeoxycholicrsquo
14 rsquoliver transplantationrsquo and rsquotauroglyco-
cholicrsquo
15 rsquoliver transplantationrsquo and rsquotaurolitho-
cholicrsquo
16 rsquoliver transplantationrsquo and rsquotaurosel-
cholicrsquo
17 rsquoliver transplantationrsquo and rsquotaurourso-
cholicrsquo
18 rsquoliver transplantationrsquo and rsquotaurour-
sodeoxycholicrsquo
19 rsquoliver transplantationrsquo and rsquoursocholicrsquo
20 rsquoliver transplantationrsquo and rsquoursodeoxy-
cholicrsquo
The Cochrane Central Register of Con-
trolled Trials in The Cochrane Library
Issue 3 2009 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
6 3 or 4
7 5 and 6
MEDLINE September 2009 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
45Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
6 3 or 4
7 5 and 6
8 RANDOMIZED-CONTROLLED-
TRIAL ME
9 RANDOM
10 8 or 9
11 7 and 10
EMBASE September 2009 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
6 3 or 4
7 5 and 6
8 RANDOMIZED-CONTROLLED-
TRIAL ME
9 RANDOM
10 8 or 9
11 7 and 10
46Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
Science Citation Index Expanded September 2009 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
6 3 or 4
7 5 and 6
8 RANDOMIZED-CONTROLLED-
TRIAL ME
9 RANDOM
10 8 or 9
11 7 and 10
The Chinese Biomedical Database Searched from January 1980 to April 2002 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
47Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
6 3 or 4
7 5 and 6
8 RANDOMIZED-CONTROLLED-
TRIAL ME
9 RANDOM
10 8 or 9
11 7 and 10
W H A T rsquo S N E W
Last assessed as up-to-date 8 February 2010
18 September 2009 New citation required but conclusions have not
changed
This review is an updated version of a review that was
published for the first time in Issue 3 2005 of TheCochrane Library by Chen 2003b
18 September 2009 New search has been performed No new studies fulfilled the inclusion criteria
H I S T O R Y
Protocol first published Issue 3 2003
Review first published Issue 3 2005
C O N T R I B U T I O N S O F A U T H O R S
GP and VG independently performed searches of relevant databases GP validated the search selected trials for inclusion contacted
the authors of the trials performed data extraction and data analysis and drafted the systematic review VG revised the review update
CG and DS revised the review update solved discrepancies of data extraction validated data analyses and provided consultation
D E C L A R A T I O N S O F I N T E R E S T
None known
48Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
S O U R C E S O F S U P P O R T
Internal sources
bull Copenhagen Trial Unit Denmark
External sources
bull Danish Medical Research Councilrsquos Grant on Getting Research into Practice (GRIP) Denmark
D I F F E R E N C E S B E T W E E N P R O T O C O L A N D R E V I E W
We assessed the risk of bias in the included studies for another four domains that were added to the review protocol (incomplete
outcome data selective outcome reporting baseline imbalance and early stopping of trial) In general the text of the risk of bias
domains were updated following Higgins 2008 Trials were considered at low risk of bias when judged as adequate in all domains
Quasi-randomised studies observational and case-control studies were included for the report of adverse events
We performed trial sequential analysis for outcomes demonstrating a statistically significant result
I N D E X T E R M S
Medical Subject Headings (MeSH)
lowastLiver Transplantation Cholagogues and Choleretics [lowasttherapeutic use] Graft Rejection [lowastprevention amp control] Randomized Con-
trolled Trials as Topic Taurochenodeoxycholic Acid [lowasttherapeutic use] Ursodeoxycholic Acid [lowasttherapeutic use]
MeSH check words
Humans
49Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
intervention group No other excluded studies reported on adverse
events (see Table 1)
Quality of life
None of the included studies assessed quality of life as an outcome
Other subgroup analyses
We planned to perform subgroup analyses regarding the risk of
bias of trials the dosage of bile acid and any co-intervention
However none of the trials were considered to be of low risk of
bias they all used a similar dosage of bile acid and patients in all
trials received similar immunosuppressive treatment as co-inter-
ventions (steroids azathioprine and cyclosporine or tacrolimus)
after liver transplantation Therefore we were not able to perform
the planned subgroup analyses
Funnel plot asymmetry
We did not draw a funnel plot analysis due to the limited number
of trials included in the present review
D I S C U S S I O N
In the update of this review we included no new trials assessing
the use of bile acids for liver-transplanted patients The analyses
of the seven previously included trials showed that bile acids did
not significantly affect mortality acute cellular rejection steroid-
resistant rejection retransplantation or serum bilirubin Bile acids
might significantly decrease the length of hospital stay and the
number of patients with chronic rejection included in these tri-
als but more supportive evidence is needed The number of pa-
tients with chronic rejection was not significantly influenced by
bile acids when a random-effects model was used and length of
stay was assessed in one single trial Furthermore none of the trials
were considered to be of low risk of bias and few patients were en-
rolled Therefore our positive findings may be due to bias (Schulz
1995 Moher 1998 Kjaergard 2001 Wood 2008) or random er-
rors (Wetterslev 2008 Brok 2009 Thorlund 2009) On the other
hand we are not able to exclude type II errors (that is finding
no significant differences when in fact they exist) due to the low
number of participants Therefore this topic could be of potential
interest in future large randomised trials with adequate control of
bias
All-cause mortality at one year after liver transplantation is re-
ported to be about 20 (Thuluvath 2003) which we also ob-
served for the patients included in the present review According to
our subgroup analyses neither UDCA nor TUDCA significantly
decreased all-cause mortality We also performed a subgroup anal-
ysis regarding treatment duration but we were not able to find any
difference between short (less than six months) and long treatment
duration (six months or more) Thus bile acids do not seem to
have statistically significant effects in reducing all-cause mortal-
ity after liver transplantation We performed both worst-best-case
scenario and best-worst-case scenario analyses In the worst-best-
case scenario bile acids did not differ significantly from placebo or
no intervention regarding all-cause mortality However bile acids
significantly decreased all-cause mortality in the best-worst-case
scenario analysis However such an analysis is very extreme and
may not be realistic We have also found that UDCA may be able
to decrease the risk of chronic rejection in liver-transplanted pa-
tients but trial sequential analysis could not confirm this result
Due to a limited number of patients (Ioannidis 2001) we are not
able to exclude the possibility that it may be relevant to perform
placebo-controlled trials with low risk of bias on the use of bile
acids for liver-transplanted patients
We looked into the causes of deaths that were reported by the trials
and only one trial reported one death related to rejection At the
same time the number of retransplantations was 3 among 68 liver-
transplanted patients who received treatment with UDCA and 4
among 64 liver-transplanted patients who received treatment with
placebo We noticed that all patients in the included trials received
co-interventions of standard triple-drug regimens (steroids aza-
thioprine and cyclosporine or tacrolimus) which were able to
control the possible acute or chronic rejection and prevent deaths
due to allograft rejection (FK506 1994)
The assumption that UDCA might reduce the incidence of acute
graft rejection came from the findings that UDCA could regulate
major histocompatibility complex antigen expression in bile ducts
and liver endothelia and inhibit lymphocyte activity (Calmus
1990 Terasaki 1991 Perez 2009) However in the present review
bile acids did not significantly reduce the risk of acute cellular re-
jection in liver-transplanted patients Considering that acute cellu-
lar rejection is commonly found within a few days after liver trans-
plantation (Vierling 1992) some might argue that the adminis-
tration of bile acids was started too late to prevent acute cellular
rejection We performed subgroup analyses regarding the time bile
acids were started and no statistically significant difference was
found Furthermore bile acids were not able to decrease the risk
of steroid-resistant rejection Therefore the lack of effects of bile
acids does not seem to be due to a delayed start to bile acid ad-
ministration after liver transplantation However it is a possibility
that one should start bile acids intake before liver transplantation
A retrospective study found that rejection rates differed signifi-
cantly between patients with primary biliary cirrhosis treated with
or without UDCA before liver transplantation (Heathcote 1999)
One could argue whether UDCA-induced delay in transplantation
has an adverse effect on post-transplantation outcome Since we
did not find any prospective randomised clinical trials addressing
this issue further research might be needed Furthermore some
studies may provide an explanation why UDCA was not able to
prevent acute cellular rejection These studies found that UDCA
did not appear to change the expression of major histocompatibil-
ity complex class II antigens but rather major histocompatibility
complex class I antigens (Calmus 1990) The initial mechanism
of acute rejection is thought to be recognition of MHC class II
13Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
antigens by CD4+ T cells (Vierling 1992) Moreover the inhibi-
tion of the production of interleukin-2 by peripheral blood lym-
phocytes with UDCA (Heuman 1993) might be negated by the
immunosuppressive treatment after liver transplantation (van den
Berg 1998) so that UDCA is unable to demonstrate effects on
graft rejection In a recent study by Assy 2007 a significant re-
duction in the mean dose of immunosuppressive medications was
achieved in stable liver graft recipients treated with UDCA indi-
cating a possible influence of UDCA on rejection mechanisms
In accordance with previous systematic reviews (Chen 2003a
Chen 2007 Gong 2008) bile acids were not associated with the
occurrence of serious adverse events or any major occurrence of
adverse events
In summary our results do not support or refute the use of bile
acids (UDCA and TUDCA) additional to standard immunosup-
pressive treatment in liver-transplanted patients
A U T H O R S rsquo C O N C L U S I O N SImplications for practice
There seems to be no evidence to support or refute the use of bile
acids for liver-transplanted patients receiving standard immuno-
suppressive treatment
Implications for research
We need more randomised placebo-controlled clinical trials with
enough statistical power and low risk of bias to explore the poten-
tial effects of bile acids on chronic rejection and mortality in liver-
transplanted patients Such trials should also consider evaluation
of quality of life and length of hospitalisation Such trials may
consider starting bile acid and placebo interventions before liver
transplantation we were not able to identify any randomised trials
addressing this regimen Such trials ought to be reported accord-
ing to the CONSORT statement (wwwconsort-statementorg)
However before embarking on such trials the effects of bile acids
in other patient groups should be scrutinised as they may have
small or negative effects
A C K N O W L E D G E M E N T S
We thank all the patients and investigators who were involved in
the clinical trials mentioned in this review We thank Wendong
Chen for his work and contribution on the previous version of this
review We thank the staff of The Cochrane Hepato-Biliary Group
Editorial Team especially Dimitrinka Nikolova and Sarah Louise
Klingenberg for excellent collaboration and assistance during the
update of this review
Peer Reviewers Carlo Merkel Italy M Tomikawa Japan
Contact Editor Bodil Als-Nielsen Denmark
R E F E R E N C E S
References to studies included in this review
Angelico 1999 published data only
Angelico M Tisone G Baiocchi L Palmieri G Pisani F Negrini S
et alOne-year pilot study on tauroursodeoxycholic acid as an
adjuvant treatment after liver transplantation Italian Journal of
Gastroenterology and Hepatology 199931(6)462ndash8 [MEDLINE
10575563]
Barnes 1997 published data onlylowast Barnes D Talenti D Cammell G Goormastic M Farquhar L
Henderson M et alA randomized clinical trial of ursodeoxycholic
acid as adjuvant treatment to prevent liver transplant rejection
Hepatology 199726(4)853ndash7 [MEDLINE 9328304]
Barnes D Talenti D Goormastic M Farquhar L Cammell G
Henderson M et alUrsodeoxycholic acid (UDCA) reduces hepatic
allograft rejection after orthotopic liver transplantation (OLT) - a
prospective randomized placebo-controlled double-blind trial
Hepatology 199522149A
Fleckenstein 1998 published data only
Fleckenstein JF Paredes M Thuluvath PJ A prospective
randomized double-blind trial evaluating the efficacy of
ursodeoxycholic acid in prevention of liver transplant rejection
Liver Transplantation and Surgery 19984(4)276ndash9 [MEDLINE
9649640]
Keiding 1997 published data only
Keiding S Hockerstedt K Bjoro K Bondesen S Hjortrup A
Isoniemi H et alThe Nordic multicenter double-blind randomized
controlled trial of prophylactic ursodeoxycholic acid in liver
transplant patients Transplantation 199763(11)1591ndash4
[MEDLINE 9197351]
Koneru 1993 published data only
Koneru B Tint GS Wilson DJ Leevy CB Salen F Randomised
prospective trial of ursodeoxycholic acid in liver transplant
recipients Hepatology 199318336A
Pageaux 1995 published data only
Pageaux GP Blanc P Perrigault PF Navarro F Fabre JM Souche B
et alFailure of ursodeoxycholic acid to prevent acute cellular
rejection after liver transplantation Journal of Hepatology 199523
(2)119ndash22 [MEDLINE 7499781]
Sama 1991 published data only
Sama C Mazziotti A Grigioni W Morselli AM Chianura A
Stefanini GF et alUrsodeoxycholic acid administration does not
14Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
prevent rejection after OLT Journal of Hepatology 199113(Suppl
2)68
References to studies excluded from this review
Assy 2007 published data only
Assy N Adams PC Myers P Simon V Minuk GY Wall W et
alRandomized controlled trial of total immunosuppression
withdrawal in liver transplant recipients role of ursodeoxycholic
acid Transplantation 200783(12)1571ndash6 [MEDLINE
17589339]
Clavien 1996 published data only
Clavien PA Sharara AI Camargo CA Jr Harland RC Fitz JG
Evidence that ursodeoxycholic acid prevents steroid-resistant
rejection in adult liver transplantation Clinical Transplantation
199610(6 Pt 2)658ndash62 [MEDLINE 8996761]
Friman 1992 published data only
Friman S Persson H Schersten T Svanvik J Karlberg I Adjuvant
treatment with ursodeoxycholic acid reduces acute rejection after
liver transplantation Transplantation Proceedings 199224(1)
389ndash90 [MEDLINE 1539328]
Heathcote 1999 published data onlylowast Heathcote EJ Stone J Cauch-Dudek K Poupon R Chazouilleres
O Lindor KD et alEffect of pretransplantation ursodeoxycholic
acid therapy on the outcome of liver transplantation in patients
with primary biliary cirrhosis Liver Transplantation and Surgery
19995(4)269ndash74 [MEDLINE 10388499]
Henriksson 1991 published data only
Henriksson BA Persson H Friman S Wangberg B Svanvik J
Karlberg I Adjuvant ursodeoxycholic acid prevents acute rejection
in liver transplant recipients Transplantation Proceedings 199123
(3)1971 [MEDLINE 2063453]
Persson 1990 published data only
Persson H Friman S Schersten T Svanvik J Karlberg I
Ursodeoxycholic acid for prevention of acute rejection in liver
transplant recipients Lancet 1990336(8706)52ndash3 [MEDLINE
1973232]
Rafael 1995 published data only
Rafael E Duraj F Rudstrom H Wilczek H Ericzon B Effect of
ursodeoxycholic acid treatment for cholestasis in liver transplant
recipients Transplantation Proceedings 199527(6)3501ndash2
[MEDLINE 8540069]
Sama 1998 published data only
Sama C Morselli-Labate AM Grazi GL Mastroianni A Danesi G
Pianta P et alUrsodeoxycholic acid in liver transplantation effect
on cholestasis and rejection Gastroenterology 1998114(4 Suppl)
A1332
Additional references
Adams 1990
Adams DH Neuberger JM Patterns of graft rejection following
liver transplantation Journal of Hepatology 199010(1)113ndash9
[MEDLINE 2407770]
Al-Quaiz 1994
Al-Quaiz M OrsquoGrady J Tredger J Williams R Variable effect of
ursodeoxycholic acid on cyclosporin absorption after orthotopic
liver transplantation Transplant International 19947(3)190ndash4
[MEDLINE 8060468]
Armstrong 1982
Armstrong MJ Carey MC The hydrophobic-hydrophilic balance
of bile salt Inverse correlation between reverse phase high
performance liquid chromatographic mobilities and micellar
cholesterol-solubilizing capacities Journal of Lipid Research 1982
23(1)70ndash80 [MEDLINE 7057113]
Ascher 1988
Ascher NL Stock PG Baumgardner GL Payne WD Najarian JS
Infection and rejection of primary hepatic transplant in 93
consecutive patients treated with triple immunosuppressive therapy
Surgery Gynecology amp Obstetrics 1988167(6)474ndash84
[MEDLINE 3055368]
Brok 2008
Brok J Thorlund K Gluud C Wetterslev J Trial sequential
analysis reveals insufficient information size and potentially false
positive results in many meta-analyses Journal of Clinical
Epidemiology 200861(8)763ndash9 [MEDLINE 18411040]
Brok 2009
Brok J Thorlund K Wetterslev J Gluud C Apparently conclusive
meta-analysis may be inconclusive - Trial sequential analysis
adjustment of random error risk due to repetitive testing of
accumulating data in apparently conclusive neonatal meta-analysis
International Journal of Epidemiology 200938(1)298ndash303
[MEDLINE 18824466]
Calmus 1990
Calmus Y Gane P Rouger P Poupon R Hepatic expression of class
I and class II major histocompatibility complex molecules in
primary biliary cirrhosis effect of ursodeoxycholic acid Hepatology
199011(1)12ndash5 [MEDLINE 2403961]
Calmus 1992
Calmus Y Arvieux C Gane P Boucher E Nordlinger B Rouger P
et alCholestasis induces major histocompatibility complex class I
expression in hepatocytes Gastroenterology 1992102(4 Pt 1)
1371ndash7 [MEDLINE 1551542]
Chen 2003a
Chen W Gluud C Bile acids for primary sclerosing cholangitis
Cochrane Database of Systematic Reviews 2003 Issue 2 [DOI
10100214651858CD003626]
Chen 2007
Chen W Liu J Gluud C Bile acids for viral hepatitis Cochrane
Database of Systematic Reviews 2007 Issue 4 [DOI 101002
14651858CD003181pub2]
Cheng 2002
Cheng K Ashby D Smyth R Ursodeoxycholic acid for cystic
fibrosis-related liver disease Cochrane Database of Systematic
Reviews 2002 Issue 2 [DOI 10100214651858CD000222]
Corbani 2008
Corbani A Burroughs AK Intrahepatic cholestasis after liver
transplantation Clinics in Liver Disease 200812(1)111ndash29
[MEDLINE 18242500]
DeMets 1987
DeMets DL Methods for combining randomised clinical trials
strengths and limitations Statistics in Medicine 19876(3)341ndash50
[MEDLINE 3616287]
15Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
DerSimonian 1986
DerSimonian R Laird N Meta-analysis in clinical trials Controlled
Clinical Trials 19867(3)177ndash88 [MEDLINE 3802833]
Egger 1997
Egger M Davey Smith G Schneider M Minder C Bias in meta-
analysis detected by a simple graphical test BMJ (Clinical Research
Ed) 1997315(7109)629ndash34 [MEDLINE 9310563]
Ericzon 1990
Ericzon BG Eusufzai S Kubota K Einarsson K Angelin B
Characteristics of biliary lipid metabolism after liver
transplantation Hepatology 199012(5)1222ndash8 [MEDLINE
2227822]
FK506 1994
The US Multicenter FK506 Liver Study Group A comparison of
tacrolimus (FK506) and cyclosporine for immunosuppression in
liver transplantation New England Journal of Medicine 1994331
(17)1110ndash5 [MEDLINE 7523946]
Friman 1994
Friman S Svanvik J A possible role of ursodeoxycholic acid in liver
transplantation Scandinavian Journal of Gastroenterology 1994204
62ndash4 [MEDLINE 7824880]
Fuchs 1999
Fuchs M Stange EF Metabolism of bile acids In Johannes
Bircher Jean-Pierre Benhamou Neil McIntyre Mario Rizzetto
Juan Rodes editor(s) Oxford Textbook of Clinical Hepatology 2
Vol 1 Oxford Oxford University Press 1999223ndash56
Fusai 2006
Fusai G Dhaliwal P Rolando N Sabin CA Patch D Davidson BR
et alIncidence and risk factors for the development of prolonged
and severe intrahepatic cholestasis after liver transplantation Liver
Transplantation 200612(11)1626ndash33 [DOI 101002lt20870]
Gluud 2001
Gluud C Alcoholic hepatitis no glucocorticosteroids In
Leuschner U James OFW Dancygier H editor(s) Steatohepatitis
(NASH and ASH) Falk Symposium 121 Lancaster Kluwer
Academic Publisher 2001322ndash42
Gluud 2010
Gluud C Nikolova D Klingenberg SL Alexakis N Als-Nielsen B
Colli A et alCochrane Hepato-Biliary Group About The
Cochrane Collaboration (Cochrane Review Groups (CRGs))
2010 Issue 1 Art No LIVER
Gong 2008
Gong Y Huang ZB Christiansen E Gluud C Ursodeoxycholic
acid for primary biliary cirrhosis Cochrane Database of Systematic
Reviews 2008 Issue 3 [DOI 101002
14651858CD000551pub2]
Haddad 2006
Haddad EM McAlister VC Renouf E Malthaner R Kjaer MS
Gluud LL Cyclosporin versus tacrolimus for liver transplanted
patients Cochrane Database of Systematic Reviews 2006 Issue 4
[DOI 10100214651858CD005161pub2]
Heuman 1993
Heuman DM Hepatoprotective properties of ursodeoxycholic acid
Gastroenterology 1993104(6)1865ndash9 [MEDLINE 8500748]
Higgins 2008
Higgins PTJ Green S editors Cochrane Handbook for Systematic
Reviews of Interventions West Sussex England Wiley-Blackwell
2008
Hirschfield 2009
Hirschfield GM Gibbs P Griffiths WJH Adult liver
transplantation what non-specialists need to know BMJ (Clinical
Research Ed) 2009338(b1670)1321ndash7 [DOI 101136
bmjb1670]
Hussain 2002
Hussain HK Nghiem HV Imaging of hepatic transplantation
Clinics in Liver Disease 20026(1)247ndash70 [MEDLINE
11933592]
ICH-GCP 1997
International Conference on Harmonisation Expert Working
Group Code of Federal Regulations amp International Conference on
Harmonization Guidelines Media Parexel Barnett 1997
Ioannidis 2001
Ioannidis JPA Lau J Evolution of treatment effects over time
Empirical insight from recursive cumulative meta analyses
Proceedings of the National Academy of Sciences 200198(3)831ndash6
IWP 1995
International Working Party Terminology for hepatic allograft
rejection Hepatology 199522(2)648ndash54 [MEDLINE 7635435]
Kjaergard 2001
Kjaergard LL Villumsen J Gluud C Reported methodological
quality and discrepancies between large and small randomised trials
in meta-analyses Annals of Internal Medicine 2001135(11)982ndash9
[MEDLINE 11730399]
Klintmalm 1989
Klintmalm GB Nery JR Husberg BS Gonwa TA Tillery GW
Rejection in liver transplantation Hepatology 198910(6)978ndash85
[MEDLINE 2583691]
Knechtle 2009
Knechtle SJ Kwun J Unique aspects of rejection and tolerance in
liver transplantation Seminars in Liver Disease 200929(1)91ndash101
[MEDLINE 19235662]
Krams 1993
Krams SM Ascher NL Martinez OM New immunologic insights
into mechanisms of allograft rejection Gastroenterology Clinics of
North America 199318(2)374ndash7 [MEDLINE 8509176]
Lan 1983
Lan KKG DeMets DL Discrete sequential boundaries for clinical
trials Biometrika 198370659ndash63
Merion 1989
Merion RM Gorski DH Burtch GD Turcotte JG Colletti LM
Campbell DA Jr Bile refeeding after liver transplantation and
avoidance of intravenous cyclosporine Surgery 1989106(4)
604ndash9 [MEDLINE 2799635]
Moher 1998
Moher D Pham B Jones A Cook DJ Jadad AR Moher M et
alDoes quality of reports of randomised trials affect estimates of
intervention efficacy reported in meta-analyses Lancet 1998352
(9128)609ndash13 [MEDLINE 9746022]
16Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Neuberger 1999
Neuberger J Incidence timing and risk factors for acute and
chronic rejection Liver Transplantation and Surgery 19995(4 Suppl
1)S30ndashS36 [MEDLINE 10431015]
Okolicsanyi 1986
Okolicsanyi L Lirussi F Strazzabosco M Jemmolo RM Orlando R
Nassuato G et alThe effect of drugs on bile flow and composition
An overview Drugs 198631(5)430ndash48 [MEDLINE 2872047]
Palmer 1972
Palmer RH Bile acids liver injury and liver disease Archives of
Internal Medicine 1972130(4)606ndash17 [MEDLINE 4627840]
Perez 2009
Perez MJ Briz O Bile-acid-induced cell injury and protection
World Journal of Gastroenterology 200915(14)1677ndash89
[MEDLINE 19360911]
Pogue 1997
Pogue JM Yusuf S Cumulating evidence from randomized trials
Utilizing sequential monitoring boundaries for cumulative meta-
analysis Controlled Clinical Trials 199718(6)580ndash93
[MEDLINE 9408720]
Pogue 1998
Pogue J Yusuf S Overcoming the limitations of current meta-
analysis of randomised controlled trials Lancet 1998351(9095)
45ndash52 [MEDLINE 9433436]
RevMan 2008
The Nordic Cochrane Centre The Cochrane Collaboration
Review Manager (RevMan) 50 Copenhagen The Nordic
Cochrane Centre The Cochrane Collaboration 2008
Royle 2003
Royle P Milne R Literature searching for randomized controlled
trials used in Cochrane reviews rapid versus exhaustive searches
International Journal of Technology Assessment in Health Care 2003
19(4)591ndash603
Schulz 1995
Schulz KF Chalmers I Hayer R Altman D Empirical evidence of
bias JAMA 1995273(5)408ndash12 [MEDLINE 7823387]
Sharara 1995
Sharara AI Camargo CA Clavien PA Ursodeoxycholic acid
prevents steroid resistant rejection in liver transplant recipients
Gastroenterology 1995108A1168
Sholmerich 1984
Sholmerich J Becher MS Schmidt KH Schubert R Kremer B
Felhaus S et alInfluence of hydroxylation and conjugation of bile
salts on their membrane damaging properties Hepatology 19844
(4)661ndash7 [MEDLINE 6745854]
Soderdahl 1998
Soderdahl G Nowak G Duraj F Wang FH Einarsson C Ericzon
BG Ursodeoxycholic acid increased bile flow and affects bile
composition in the early postoperative phase following liver
transplantation Transplantation International 199811(Suppl 1)
S231ndashS238 [MEDLINE 9664985]
Terasaki 1991
Terasaki S Nakanuma Y Ogino H Unoura M Kobayashi K
Hepatocellular and biliary expression of HLA antigens in primary
biliary cirrhosis before and after ursodeoxycholic acid therapy
American Journal of Gastroenterology 199186(9)1194ndash9
[MEDLINE 1882800]
Thalheimer 2002
Thalheimer U Capra F Liver transplantation making the best out
of what we have Digestive Diseases and Sciences 200247(5)
945ndash53 [MEDLINE 12018919]
Thorlund 2009
Thorlund K Devereaux PJ Wetterslev J Guyatt G Ioannidis JP
Thabane L et alCan trial sequential monitoring boundaries reduce
spurious inferences from meta-analyses International Journal of
Epidemiology 200938(1)276ndash86 [MEDLINE 18824467]
Thuluvath 2003
Thuluvath PJ Yoo HY Thompson RE A model to predict survival
at one month one year and five years after liver transplantation
based on pretransplant clinical characteristics Liver Transplantation
20039(5)527ndash32 [MEDLINE 12740799]
van den Berg 1998
van den Berg AP Twilhaar WN Mesander G van Son WJ van der
Bij W Klompmaker IJ et alQuantitation of immunosuppression
by flow cytometric measurement of the capacity of T cells for
interleukin-2 production Transplantation 199865(8)1066ndash71
[MEDLINE 9583867]
Vierling 1992
Vierling J Immunologic mechanisms of hepatic allograft rejection
Seminars in Liver Disease 199212(1)16ndash27 [MEDLINE
1570548]
Wetterslev 2008
Wetterslev J Thorlund K Brok J Gluud C Trial sequential
analysis may establish when firm evidence is reached in cumulative
meta-analysis Journal of Clinical Epidemiology 200861(1)64ndash75
[MEDLINE 18083463]
Wiesner 1992
Wiesner RH Acute cellular rejection following liver
transplantation incidence risk factors and outcome in the
NIDDK Liver Transplant Database (LTD) study Gastroenterology
1992102A910
Wood 2008
Wood L Egger M Gluud LL Schulz KF Juni P Altman DG et
alEmpirical evidence of bias in treatment effect estimates in
controlled trials with different interventions and outcomes meta-
epidemiological study BMJ (Clinical Research Ed) 2008336
(7644)601ndash5 [MEDLINE 18316340]
Yoshikawa 1998
Yoshikawa M Matsui Y Kawamoto H Toyohara M Matsumura
K Yamao J et alIntragastric administration of ursodeoxycholic
acid suppresses immunoglobulin secretion by lymphocytes from
liver but not from peripheral blood spleen or Peyerrsquos patches in
mice International Journal of Immunopharmacology 199820(1-3)
29ndash38 [MEDLINE 9717080]
References to other published versions of this review
17Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Chen 2003b
Chen W Gluud C Bile acids for liver transplanted patients
Cochrane Database of Systematic Reviews 2005 Issue 3 [DOI
10100214651858CD005442]lowast Indicates the major publication for the study
18Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
C H A R A C T E R I S T I C S O F S T U D I E S
Characteristics of included studies [ordered by study ID]
Angelico 1999
Methods Study design open-label randomised one-year pilot study
Participants Country Italy
Publication language English
Inclusion criteria
- patients who underwent liver transplantation from April 1994 to December 1994
Exclusion criteria
- not mentioned
Participants
Two patients in TUDCA group and two patients in control group were excluded from
the basic information of participants by the study due to withdrawal
- TUDCA group (n = 14)
Mean age (years +- SD)
467 +- 84
Ratio of sex (malefemale) 122
Origins of liver diseases
hepatitis C cirrhosis (9) hepatitis B cirrhosis (2) hepatitis B and C cirrhosis (1) cryp-
togenic cirrhosis (2) alcoholic cirrhosis (0) Wilson cirrhosis (0)
- Control group (n = 15)
Mean age (years +- SD)
474 +- 74
Ratio of sex (malefemale) 123
Origins of liver diseases
hepatitis C cirrhosis (7) hepatitis B cirrhosis (2) hepatitis B and C cirrhosis (2) cryp-
togenic cirrhosis (2) alcoholic cirrhosis (1) Wilson cirrhosis (1)
Interventions TUDCA group
- Dose 500 mgday in two divided doses
- Route orally
- Duration the treatment was started on day 5 after transplantation and continued for
one year
Control group
- no treatment
Co-interventions all patients received standard triple-drug regimens (steroids azathio-
prine and cyclosporine or tacrolimus)
Outcomes All cause mortality
Number of patients with rejection after liver transplantation
Notes Letter was sent to the authors in September 2009 A reply with additional information
was received shortly after
Risk of bias
19Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Angelico 1999 (Continued)
Item Authorsrsquo judgement Description
Adequate sequence generation Yes Computer generated table
Allocation concealment Unclear No information provided
Blinding No Not performed
Incomplete outcome data addressed
All outcomes
Yes Withdrawal two patients from the
TUDCA group and two patients from the
placebo group Three of them died due to
transplant non-function in the first postop-
erative week and one patient was regrafted
due to thrombosis of hepatic artery
Free of selective reporting Unclear Post-transplant cholestasis and liver bio-
chemistry specified as outcomes Differ-
ence reported as not significant but no ac-
tual data given
Sample size calculation No Not reported
Intention-to-treat analysis No Not stated and not used
Baseline imbalance Unclear Not enough information provided
Early stopping of trial Unclear Not enough information provided
Barnes 1997
Methods Study design randomised placebo-controlled double-blind trial
Participants Country United States
Publication language English
Inclusion criteria
- patients aged 18 years or older who underwent liver transplantation at the Cleveland
Clinic Foundation from April 1992 through June of 1994
Exclusion criteria
- patients who were found to have cancer at surgically resected margins of the biliary
tree
- patents who underwent retransplantation
Participants
- UDCA group (n = 28)
Mean age (years +- SD)
505 +- 116
Ratio of sex (malefemale) 1810
Child class A 7
20Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Barnes 1997 (Continued)
B 13
and C 8
Origins of liver diseases Laennecrsquos cirrhosis 4
PBC 3
cryptogenic cirrhosis 6
hepatitis Ccirrhosis 4
hepatitis Bcirrhosis 3
autoimmune hepatitis with cirrhosis 3
PSC 2
other 3
- Placebo group (n = 24)
Mean age (years +- SD)
507 +- 93
Ratio of sex (malefemale) 159
Child class A 6
B 14
and C 4
Origins of liver diseases Laennecrsquos cirrhosis 9
PBC 5
cryptogenic cirrhosis 1
hepatitis Ccirrhosis 1
hepatitis Bcirrhosis 1
autoimmune hepatitis with cirrhosis 1
PSC 2
other 4
Interventions UDCA group
- Dose 10-15 mgkg body weightday in divided doses
- Route orally
- Duration immediately after intestinal transit recovery usually between postoperative
days three and five and continue for three months
Placebo group
- identical-appearing capsules administered in the same quantity and manner
Co-interventions all patients received standard triple-drug regimens (steroids azathio-
prine and cyclosporine or tacrolimus)
Outcomes All cause mortality
Number of patients with acute cellular rejection
Number of patients with chronic rejection
Number of patients with steroid-resistant rejection
Number of days of hospitalisation
Adverse events
Notes Letter was sent to the authors in September 2009 A reply with additional information
was received shortly after
Risk of bias
Item Authorsrsquo judgement Description
21Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Barnes 1997 (Continued)
Adequate sequence generation Yes Computer generated table
Allocation concealment Unclear No information provided
Blinding Yes Quote ldquorandomised to receive either
UDCA or an identical placebo capsulerdquo
Incomplete outcome data addressed
All outcomes
Yes Mean follow-up time 18 months Ten pa-
tients withdrawn from study 6 in UDCA
group and 4 in placebo group Reasons
for withdrawal were reported Four patients
died in the placebo group
Free of selective reporting Yes All expected outcomes reported
Sample size calculation Unclear The trial reported the method of sample
size calculation but the actual number of
patients needed was not reported
Intention-to-treat analysis Yes Stated and used
Baseline imbalance Unclear Not enough information provided
Early stopping of trial Unclear The number of patients needed to gain the
actual power was not reported Whether
the trial was terminated early is not clear
Fleckenstein 1998
Methods Study design prospective randomised double-blind trial
Participants Country United States
Publication language English
Inclusion criteria
- patients who underwent liver transplantation at the Johns Hopkins Hospital
Exclusion criteria
- patients who were under 18 years old undergoing repeat transplantation had primary
graft nonfunction or refused consent
Participants
- UDCA group (n = 14)
Mean age (years +- SD)
443 +- 127
Ratio of sex (malefemale) 68
Origins of liver diseases hepatitis C 6
alcohol 2
autoimmune 1
PBC 2
22Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Fleckenstein 1998 (Continued)
PSC 1
autoimmune cholangiopathy 1
hepatitis B 1
- Placebo group (n = 16)
Mean age (years +- SD)
496 +- 109
Ratio of sex (malefemale) 124
Origins of liver diseases hepatitis C 3
alcohol 3
autoimmune 3
PBC 1
PSC 2
cryptogenic 2
hepatitis B 1
alpha1-antitrypsin deficiency 1
Interventions UDCA group
- Dose 15 mgkg body weightday in divided doses
- Route orally
- Duration immediately after intestinal transit recovery usually between postoperative
days three and five and continue for three months
Placebo group
- Identical-appearing capsules administered in the same quantity and manner
Co-interventions all patients received standard triple-drug regimens (steroids azathio-
prine and cyclosporine or tacrolimus)
Outcomes All cause mortality
Number with retransplantation
Number of patients with acute cellular rejection
Number of patients with chronic rejection
Serum bilirubin levels at the end of treatment
Notes Follow-up time nine months
Letter was sent to the authors in September 2009 No reply was received
Risk of bias
Item Authorsrsquo judgement Description
Adequate sequence generation Unclear No information provided
Allocation concealment Unclear No information provided
Blinding Yes Method of blinding not described but
probably adequate
Incomplete outcome data addressed
All outcomes
Yes Withdrawal one patient from the UDCA
group and two patients from the placebo
group because of capsule size
23Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Fleckenstein 1998 (Continued)
Free of selective reporting Unclear Outcomes were not completely described
Sample size calculation No Not reported
Intention-to-treat analysis Yes Quote ldquoThree patients withdrew after in-
clusionThey were included in the statis-
tical analysisrdquo
Baseline imbalance Unclear Not enough information provided
Early stopping of trial Unclear Not enough information provided
Keiding 1997
Methods Study design prospective randomised placebo-controlled multicenter study
Participants Country Denmark Finland Norway and Sweden
Publication language English
Inclusion criteria
- patients who underwent liver transplantation in Denmark Finland Norway and Swe-
den from September 1 1992 to May 31 1994
Exclusion criteria
- patients with malignant diseases
Participants
The age of the children ranged from 0 to 13 years (median 15) and the age of adults
ranged from 14 to 59 years old (median 44) MaleFemale ratio was 96 for children and
4344 for adults
- UDCA group (n = 54)
Origins of liver diseases
paracetamol intoxication 1 hepatitis B 1 autoimmune hepatitis 0 biliary atresia 2
metabolic diseases 7 neonatal hepatitis 2 PBC 13 post hepatitis cirrhosis 8 PSC 3
cryptogenic cirrhosis 7 alcoholic cirrhosis 2 other reasons 8
- Placebo group (n = 48)
Origins of liver diseases paracetamol intoxication 1 hepatitis B 0 autoimmune hepatitis
1 biliary atresia 3 metabolic diseases 11 neonatal hepatitis 0 PBC 7 post hepatitis
cirrhosis 5 PSC 7 cryptogenic cirrhosis 2 alcoholic cirrhosis 6 other reasons 5
Interventions UDCA group
- Dose 15 mgkg body weightday in two or three divided doses
- Route orally
- Duration immediately after intestinal transit recovery usually between postoperative
days three and five and continue for three months
Placebo group
- Identical-appearing capsules administered in the same quantity and manner
Co-interventions all patients received standard triple-drug regimens (steroids azathio-
prine and cyclosporine or tacrolimus)
24Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Keiding 1997 (Continued)
Outcomes All cause mortality
Number of deaths related to rejection
Number of patients with acute cellular rejection
Number of patients with chronic rejection
Number of patients with steroid-resistant rejection
Adverse events
Notes Letter was sent to the authors in September 2009 No reply was received
Risk of bias
Item Authorsrsquo judgement Description
Adequate sequence generation Unclear Patients were randomised at a ratio of 11
Allocation concealment Yes Quote ldquo The allocation was performed in
blocks of 10 patients using the sealed serial
envelope methodrdquo
Blinding Yes Quote ldquoThe UDCA and the placebo cap-
sules had identical appearance and tasterdquo
Incomplete outcome data addressed
All outcomes
Yes Follow-up time 12 months Five UDCA
patients and five placebo patients withdrew
from study Reasons were reported
Free of selective reporting Unclear Insufficient information
Sample size calculation Yes Performed and allowed for a difference in
the incidence of at least one episode of
acute rejection of 50 between the treat-
ment and placebo groups with 90 statisti-
cal power and a significance level of P value
less than 005 The calculated sample size
was 80 patients
Intention-to-treat analysis Yes Stated and used
Baseline imbalance Yes The study seems to be free of baseline im-
balance
Early stopping of trial Yes Study attained the pre-specified sample
size
25Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Koneru 1993
Methods Study design randomised controlled trial
Participants Country United States
Publication language English
Inclusion criteria
- patients who underwent liver transplantation
Exclusion criteria
- not mentioned
Participants
- UDCA group (n = 16)
Mean age (years +- SD)
no information
Ratio of sex (malefemale) no information
Origins of liver diseases
no information
- Control group (n = 16)
Mean age (years +- SD)
no information
Ratio of sex (malefemale) no information
Origins of liver diseases
no information
Interventions UDCA group
- Dose 900 mgday
- Route orally
- Duration immediately after intestinal transit recovery usually between postoperative
days three and five and continue for three months
Control group
- no treatment
Co-interventions all patients received standard triple-drug regimens (steroids azathio-
prine and cyclosporine)
Outcomes Number of patients with retransplantation due to rejection
Number of patients with rejection episodes
Notes Abstract
Letter was sent to the authors in September 2009 No reply was received
Risk of bias
Item Authorsrsquo judgement Description
Adequate sequence generation Unclear No information provided
Allocation concealment Unclear No information provided
Blinding No Not performed
26Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Koneru 1993 (Continued)
Incomplete outcome data addressed
All outcomes
Unclear The study gives the impression that there
were no withdrawals but this was not ex-
plicitly stated
Free of selective reporting Unclear Insufficient information provided
Sample size calculation No Not performed
Intention-to-treat analysis Unclear No information provided
Baseline imbalance Unclear Not enough information provided
Early stopping of trial Unclear Not enough information provided
Pageaux 1995
Methods Study design double-blind randomised study
Participants Country France
Publication language English
Inclusion criteria
- patients who underwent liver transplantation
Exclusion criteria
- not mentioned
Participants
- UDCA group (n=26)
Mean age (years +- SD)
47 +- 10
Ratio of sex (malefemale) 179
Origins of liver diseases alcoholic cirrhosis 14
post-hepatic B cirrhosis 2
post-hepatitis C cirrhosis 4
PBC 2
liver cancer 2
fulminant hepatitis 1
miscellaneous 1
- Placebo group (n = 24)
Mean age (years +- SD)
51+- 9
Ratio of sex (malefemale) 159
Origins of liver diseases alcoholic cirrhosis 10
post-hepatic B cirrhosis 0
post-hepatic C cirrhosis 6
PBC 3
liver cancer 4
fulminant hepatitis 0
miscellaneous 1
27Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Pageaux 1995 (Continued)
Interventions UDCA group
- Dose 600 mgday in three divided doses
- Route orally
- Duration immediately after intestinal transit recovery usually between postoperative
days three and five and continue for two months
Placebo group
- identical-appearing capsules administered in the same quantity and manner
Co-interventions all patients received standard triple-drug regimens (steroids azathio-
prine and cyclosporine or tacrolimus)
Outcomes Number of patients with acute cellular rejection
Number of patients with steroid-resistant rejection
Notes Letter was sent to the authors in September 2009 No reply was received
Risk of bias
Item Authorsrsquo judgement Description
Adequate sequence generation Unclear No information provided
Allocation concealment Unclear No information provided
Blinding Unclear Method of blinding not described
Incomplete outcome data addressed
All outcomes
Yes Five patients died from non-immunologi-
cal causes before the end of the first month
and were excluded from the study Reasons
were reported
Free of selective reporting Unclear Not enough information provided
Sample size calculation No Not performed
Intention-to-treat analysis No Not stated and not used
Baseline imbalance Unclear Not enough information provided
Early stopping of trial Unclear Not enough information provided
Sama 1991
Methods Study design randomised controlled trial
Participants Country Italy
Publication language English
Inclusion criteria
28Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Sama 1991 (Continued)
- patients who underwent liver transplantation
Exclusion criteria
- not mentioned
Participants
- UDCA group (n = 20)
Mean age (years +- SD)
no information
Ratio of sex (malefemale) no information
Origins of liver diseases
no information
- Control group (n = 20)
Mean age (years +- SD)
no information
Ratio of sex (malefemale) no information
Origins of liver diseases
no information
Interventions UDCA group
- Dose 600 mgday in two divided doses
- Route orally
- Duration immediately after intestinal transit recovery usually between postoperative
day five and day seven and continue for six months
Control group
- no treatment
Co-interventions all patients received standard immunosuppressive treatment (steroids
and cyclosporine)
Outcomes All cause mortality
Number of patients with acute cellular rejection
Notes Abstract
Letter was sent to the authors in September 2009 No reply was received
Risk of bias
Item Authorsrsquo judgement Description
Adequate sequence generation Unclear A randomisation list was performed before
patients were admitted to the trial (infor-
mation from principal author)
Allocation concealment Unclear No information provided
Blinding Unclear The principle author provided information
that the study was made according to a
single-blind randomised protocol The pri-
mary outcome was the occurrence of biopsy
proven rejection episodes The pathologists
were blind but the patients were not
29Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Sama 1991 (Continued)
Incomplete outcome data addressed
All outcomes
Unclear Five patients from the UDCA group and
six patients from the placebo group were
excluded Reasons for exclusion were not
fully stated
Free of selective reporting No Data about survival of patients were not
adequately reported
Sample size calculation No Not performed
Intention-to-treat analysis No Not stated and not used
Baseline imbalance Unclear Basic characteristics of patients not re-
ported
Early stopping of trial Unclear Not enough information provided
UDCA = ursodeoxycholic acid
TUDCA = tauroursodeoxycholic acid
PBC = primary biliary cirrhosis
PSC = primary sclerosing cholangitis
OKT3 = anti-CD3 monoclonal antibody
Characteristics of excluded studies [ordered by study ID]
Assy 2007 A randomised controlled trial that included only recipients of liver transplantation with stable graft function and
no episodes of rejection for at least 2 years that were then offered total immunosuppression withdrawal Fourteen
patients received UDCA (15 mgkg body weightday) and 12 received placebo Rejection occurred in 43 and
75 of patients respectively (no significant difference) None developed chronic rejection After follow-up two
patients were free of immunosuppression 80 were steroid free and 50 were able to reduce their dose of
cyclosporine
Clavien 1996 Case series Fifty consecutive liver-transplanted patients were treated with a standard cyclosporine immunosup-
pressive regimen Twenty three of the 43 survivors developed an episode of rejection and UDCA (10 mgkg
weightday) was initiated Only one patient had a second episode of rejection
Friman 1992 Observational study Thirty-three liver-transplanted patients received 10 mg UDCAkg body weightday for
median of 10 months (range four to 21 months) Eight historical liver-transplanted patients served as control
group The rejection incidence was significantly lower in the patients who received the treatment with UDCA
Biochemistry one month after transplantation demonstrated significantly lower average values of aminotrans-
ferases and alkaline phosphatases in patients treated with UDCA than in the control group
30Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
Heathcote 1999 Observational study From 1987 to 1996 37 UDCA treated and 53 placebo treated patients with primary biliary
cirrhosis were referred for transplantation Posttransplantation survival rates at one month were 939 in the
UDCA group and 884 in the placebo group and one year survival rates were 903 and 784 respectively
(no significant differences) However rejection (type not defined - a secondary outcome measure) occurred
significantly less often in the UDCA group (429) than in placebo group (688)
Henriksson 1991 Observational study All patients in this study were given sequential quadruple immunosuppression with anti-
lymphocyte globulin azathioprine steroids and cyclosporine All patients with primary graft function (n = 11)
were treated with 10 mg UDCAkg body weightday starting during the first postoperative week Patients who
received liver transplantation in the first 6 months of 1989 (n = 8) served as controls In the control group one
patient died after 9 months with chronic graft dysfunction and six patients had rejection episodes during the
first postoperative month All patients in the UDCA group were alive without rejection episodes
Persson 1990 Observational study All 11 adult patients transplanted between August 1989 and January 1990 with primary
graft function were treated with 10 mg UDCA kg body weightday Eight patients transplanted during the first
half of 1989 served as control UDCA was started during the first postoperative week and the treatment was
continued for six months All patients in the UDCA treated group survived with satisfactory graft function In
the control group six patients had at least one rejection episode needing treatment during the first postoperative
month
Rafael 1995 Observational study Seventeen patients who underwent liver transplantation between February 1990 and April
1993 and developed biliary complications after transplantation were retrospectively analysed regarding treatment
with UDCA UDCA was given in a dose of 500 to 1000 mgday Ten patients were treated for at least one year while
seven patients were treated for 14 to 250 days UDCA significantly improved gammaglutamyl transpeptidase in
liver graft recipients with biliary complications There was also a trend towards improvement in serum bilirubin
and alanine transaminase values
Sama 1998 Observational study Thirty-four patients who underwent liver transplantation between January 1995 and June
1996 were included in the study Seventeen were treated with UDCA 10 mgkg body weightday during 6
months while 17 served as controls on the basis of having undergone liver transplantation closest to UDCA
patients A significant decrease in serum bilirubin levels was observed in UDCA patients There was a significantly
higher incidence of recurrent hepatitis in the control group
UDCA ursodeoxycholic acid
31Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
D A T A A N D A N A L Y S E S
Comparison 1 Bile acids for liver-transplanted patients
Outcome or subgroup titleNo of
studies
No of
participants Statistical method Effect size
1 All-cause mortality at maximum
follow-up
5 257 Risk Ratio (M-H Fixed 95 CI) 085 [053 136]
11 UDCA versus placebo or
no treatment
4 224 Risk Ratio (M-H Fixed 95 CI) 080 [049 130]
12 TUDCA versus no
treatment
1 33 Risk Ratio (M-H Fixed 95 CI) 159 [030 833]
2 All-cause mortality worst-best
case and best-worst case
scenarios
5 Risk Ratio (M-H Fixed 95 CI) Subtotals only
21 Worst-best case scenario 5 257 Risk Ratio (M-H Fixed 95 CI) 130 [086 196]
22 Best-worst case scenario 5 257 Risk Ratio (M-H Fixed 95 CI) 058 [038 090]
3 Subgroup analyses all-cause
mortality at maximum
follow-up according to time of
start of bile acids
5 257 Risk Ratio (M-H Fixed 95 CI) 085 [053 136]
31 Less than three days after
transplantation
1 102 Risk Ratio (M-H Fixed 95 CI) 124 [061 254]
32 Three days or more after
transplantation
4 155 Risk Ratio (M-H Fixed 95 CI) 063 [033 120]
4 Subgroup analyses all cause
mortality at maximum
follow-up according to
treatment duration
5 257 Risk Ratio (M-H Fixed 95 CI) 085 [053 136]
41 Less than six months 3 184 Risk Ratio (M-H Fixed 95 CI) 078 [045 138]
42 Six months or more 2 73 Risk Ratio (M-H Fixed 95 CI) 102 [043 240]
5 Number of deaths related
to rejection at maximum
follow-up
1 102 Risk Ratio (M-H Fixed 95 CI) 030 [001 712]
51 UDCA versus placebo 1 102 Risk Ratio (M-H Fixed 95 CI) 030 [001 712]
6 Number of retransplantations at
maximum follow-up
2 132 Risk Ratio (M-H Fixed 95 CI) 076 [020 286]
7 Number of patients with acute
cellular rejection at maximum
follow-up
7 339 Risk Ratio (M-H Fixed 95 CI) 089 [074 106]
71 UDCA versus placebo or
no treatment
6 306 Risk Ratio (M-H Fixed 95 CI) 089 [074 108]
72 TUDCA versus no
treatment
1 33 Risk Ratio (M-H Fixed 95 CI) 085 [045 160]
8 Subgroup analysis number of
patients with acute cellular
rejection according to time of
start of bile acid
7 339 Risk Ratio (M-H Fixed 95 CI) 089 [074 106]
32Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
81 Less than three days after
transplantation
2 134 Risk Ratio (M-H Fixed 95 CI) 084 [063 111]
82 Three days or more after
liver transplantation
5 205 Risk Ratio (M-H Fixed 95 CI) 092 [072 117]
9 Subgroup analysis number
of patients with acute
cellular rejection according to
treatment duration
7 339 Risk Ratio (M-H Fixed 95 CI) 089 [074 106]
91 Less than six months 5 266 Risk Ratio (M-H Fixed 95 CI) 087 [071 107]
92 Six months or more 2 73 Risk Ratio (M-H Fixed 95 CI) 094 [065 136]
10 Number of patients with
chronic rejection at maximum
follow-up
3 184 Risk Ratio (M-H Fixed 95 CI) 028 [008 095]
11 Number of patients with
steroid-resistant rejection at
maximum follow-up
4 234 Risk Ratio (M-H Fixed 95 CI) 077 [047 127]
12 Serum bilirubin (mgdl) at the
end of treatment
1 30 Mean Difference (IV Fixed 95 CI) 26 [-096 616]
13 Number of days of
hospitalisation after liver
transplantation
1 52 Mean Difference (IV Fixed 95 CI) -85 [-1667 -033]
14 Adverse events 3 187 Risk Ratio (M-H Fixed 95 CI) 088 [030 260]
Analysis 11 Comparison 1 Bile acids for liver-transplanted patients Outcome 1 All-cause mortality at
maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 1 All-cause mortality at maximum follow-up
Study or subgroup Favours bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 UDCA versus placebo or no treatment
Barnes 1997 228 724 253 024 [ 006 107 ]
Fleckenstein 1998 214 416 125 057 [ 012 266 ]
Keiding 1997 1454 1048 355 124 [ 061 254 ]
Sama 1991 520 620 201 083 [ 030 229 ]
Subtotal (95 CI) 116 108 935 080 [ 049 130 ]
Total events 23 (Favours bile acids) 27 (Control)
Heterogeneity Chi2 = 416 df = 3 (P = 025) I2 =28
Test for overall effect Z = 091 (P = 036)
01 02 05 1 2 5 10
Favours bile acids Favours control
(Continued )
33Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Favours bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
2 TUDCA versus no treatment
Angelico 1999 316 217 65 159 [ 030 833 ]
Subtotal (95 CI) 16 17 65 159 [ 030 833 ]
Total events 3 (Favours bile acids) 2 (Control)
Heterogeneity not applicable
Test for overall effect Z = 055 (P = 058)
Total (95 CI) 132 125 1000 085 [ 053 136 ]
Total events 26 (Favours bile acids) 29 (Control)
Heterogeneity Chi2 = 466 df = 4 (P = 032) I2 =14
Test for overall effect Z = 069 (P = 049)
01 02 05 1 2 5 10
Favours bile acids Favours control
Analysis 12 Comparison 1 Bile acids for liver-transplanted patients Outcome 2 All-cause mortality worst-
best case and best-worst case scenarios
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 2 All-cause mortality worst-best case and best-worst case scenarios
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 Worst-best case scenario
Angelico 1999 516 217 65 266 [ 060 1180 ]
Barnes 1997 828 724 253 098 [ 042 230 ]
Fleckenstein 1998 314 416 125 086 [ 023 319 ]
Keiding 1997 1954 1048 355 169 [ 087 327 ]
Sama 1991 520 620 201 083 [ 030 229 ]
Subtotal (95 CI) 132 125 1000 130 [ 086 196 ]
Total events 40 (Bile acids) 29 (Control)
Heterogeneity Chi2 = 303 df = 4 (P = 055) I2 =00
Test for overall effect Z = 123 (P = 022)
2 Best-worst case scenario
005 02 1 5 20
Favours bile acids Favours control
(Continued )
34Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Angelico 1999 316 417 90 080 [ 021 302 ]
Barnes 1997 228 1124 274 016 [ 004 063 ]
Fleckenstein 1998 214 616 130 038 [ 009 159 ]
Keiding 1997 1454 1548 368 083 [ 045 154 ]
Sama 1991 520 620 139 083 [ 030 229 ]
Subtotal (95 CI) 132 125 1000 058 [ 038 090 ]
Total events 26 (Bile acids) 42 (Control)
Heterogeneity Chi2 = 567 df = 4 (P = 023) I2 =29
Test for overall effect Z = 247 (P = 0014)
005 02 1 5 20
Favours bile acids Favours control
Analysis 13 Comparison 1 Bile acids for liver-transplanted patients Outcome 3 Subgroup analyses all-
cause mortality at maximum follow-up according to time of start of bile acids
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 3 Subgroup analyses all-cause mortality at maximum follow-up according to time of start of bile acids
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 Less than three days after transplantation
Keiding 1997 1454 1048 355 124 [ 061 254 ]
Subtotal (95 CI) 54 48 355 124 [ 061 254 ]
Total events 14 (Bile acids) 10 (Control)
Heterogeneity not applicable
Test for overall effect Z = 060 (P = 055)
2 Three days or more after transplantation
Angelico 1999 316 217 65 159 [ 030 833 ]
Barnes 1997 228 724 253 024 [ 006 107 ]
Fleckenstein 1998 214 416 125 057 [ 012 266 ]
Sama 1991 520 620 201 083 [ 030 229 ]
005 02 1 5 20
Favours bile acids Favours control
(Continued )
35Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Subtotal (95 CI) 78 77 645 063 [ 033 120 ]
Total events 12 (Bile acids) 19 (Control)
Heterogeneity Chi2 = 310 df = 3 (P = 038) I2 =3
Test for overall effect Z = 141 (P = 016)
Total (95 CI) 132 125 1000 085 [ 053 136 ]
Total events 26 (Bile acids) 29 (Control)
Heterogeneity Chi2 = 466 df = 4 (P = 032) I2 =14
Test for overall effect Z = 069 (P = 049)
005 02 1 5 20
Favours bile acids Favours control
Analysis 14 Comparison 1 Bile acids for liver-transplanted patients Outcome 4 Subgroup analyses all
cause mortality at maximum follow-up according to treatment duration
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 4 Subgroup analyses all cause mortality at maximum follow-up according to treatment duration
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 Less than six months
Barnes 1997 228 724 253 024 [ 006 107 ]
Fleckenstein 1998 214 416 125 057 [ 012 266 ]
Keiding 1997 1454 1048 355 124 [ 061 254 ]
Subtotal (95 CI) 96 88 734 078 [ 045 138 ]
Total events 18 (Bile acids) 21 (Control)
Heterogeneity Chi2 = 417 df = 2 (P = 012) I2 =52
Test for overall effect Z = 084 (P = 040)
2 Six months or more
Angelico 1999 316 217 65 159 [ 030 833 ]
Sama 1991 520 620 201 083 [ 030 229 ]
Subtotal (95 CI) 36 37 266 102 [ 043 240 ]
Total events 8 (Bile acids) 8 (Control)
Heterogeneity Chi2 = 043 df = 1 (P = 051) I2 =00
005 02 1 5 20
Favours bile acids Favours control
(Continued )
36Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Test for overall effect Z = 004 (P = 097)
Total (95 CI) 132 125 1000 085 [ 053 136 ]
Total events 26 (Bile acids) 29 (Control)
Heterogeneity Chi2 = 466 df = 4 (P = 032) I2 =14
Test for overall effect Z = 069 (P = 049)
005 02 1 5 20
Favours bile acids Favours control
Analysis 15 Comparison 1 Bile acids for liver-transplanted patients Outcome 5 Number of deaths related
to rejection at maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 5 Number of deaths related to rejection at maximum follow-up
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 UDCA versus placebo
Keiding 1997 054 148 1000 030 [ 001 712 ]
Total (95 CI) 54 48 1000 030 [ 001 712 ]
Total events 0 (Bile acids) 1 (Control)
Heterogeneity not applicable
Test for overall effect Z = 075 (P = 045)
0001 001 01 1 10 100 1000
Favours bile acids Favours control
37Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 16 Comparison 1 Bile acids for liver-transplanted patients Outcome 6 Number of
retransplantations at maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 6 Number of retransplantations at maximum follow-up
Study or subgroup Bile acids Placebo Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Fleckenstein 1998 214 016 100 567 [ 029 10891 ]
Keiding 1997 154 448 900 022 [ 003 192 ]
Total (95 CI) 68 64 1000 076 [ 020 286 ]
Total events 3 (Bile acids) 4 (Placebo)
Heterogeneity Chi2 = 303 df = 1 (P = 008) I2 =67
Test for overall effect Z = 040 (P = 069)
0001 001 01 1 10 100 1000
Favours bile acids Favours placebo
Analysis 17 Comparison 1 Bile acids for liver-transplanted patients Outcome 7 Number of patients with
acute cellular rejection at maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 7 Number of patients with acute cellular rejection at maximum follow-up
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 UDCA versus placebo or no treatment
Barnes 1997 1728 1724 180 086 [ 058 127 ]
Fleckenstein 1998 814 916 83 102 [ 054 190 ]
Keiding 1997 3554 3248 333 097 [ 073 129 ]
Koneru 1993 316 916 89 033 [ 011 101 ]
Pageaux 1995 926 924 92 092 [ 044 193 ]
Sama 1991 1320 1320 128 100 [ 063 158 ]
Subtotal (95 CI) 158 148 905 089 [ 074 108 ]
01 02 05 1 2 5 10
Favours bile acids Favours control
(Continued )
38Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Total events 85 (Bile acids) 89 (Control)
Heterogeneity Chi2 = 387 df = 5 (P = 057) I2 =00
Test for overall effect Z = 120 (P = 023)
2 TUDCA versus no treatment
Angelico 1999 816 1017 95 085 [ 045 160 ]
Subtotal (95 CI) 16 17 95 085 [ 045 160 ]
Total events 8 (Bile acids) 10 (Control)
Heterogeneity not applicable
Test for overall effect Z = 050 (P = 061)
Total (95 CI) 174 165 1000 089 [ 074 106 ]
Total events 93 (Bile acids) 99 (Control)
Heterogeneity Chi2 = 392 df = 6 (P = 069) I2 =00
Test for overall effect Z = 130 (P = 019)
01 02 05 1 2 5 10
Favours bile acids Favours control
Analysis 18 Comparison 1 Bile acids for liver-transplanted patients Outcome 8 Subgroup analysis
number of patients with acute cellular rejection according to time of start of bile acid
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 8 Subgroup analysis number of patients with acute cellular rejection according to time of start of bile acid
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 Less than three days after transplantation
Keiding 1997 3554 3248 333 097 [ 073 129 ]
Koneru 1993 316 916 89 033 [ 011 101 ]
Subtotal (95 CI) 70 64 422 084 [ 063 111 ]
Total events 38 (Bile acids) 41 (Control)
Heterogeneity Chi2 = 374 df = 1 (P = 005) I2 =73
Test for overall effect Z = 124 (P = 022)
2 Three days or more after liver transplantation
Angelico 1999 816 1017 95 085 [ 045 160 ]
01 02 05 1 2 5 10
Favours bile acids Favours control
(Continued )
39Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Barnes 1997 1728 1724 180 086 [ 058 127 ]
Fleckenstein 1998 814 916 83 102 [ 054 190 ]
Pageaux 1995 926 924 92 092 [ 044 193 ]
Sama 1991 1320 1320 128 100 [ 063 158 ]
Subtotal (95 CI) 104 101 578 092 [ 072 117 ]
Total events 55 (Bile acids) 58 (Control)
Heterogeneity Chi2 = 041 df = 4 (P = 098) I2 =00
Test for overall effect Z = 067 (P = 050)
Total (95 CI) 174 165 1000 089 [ 074 106 ]
Total events 93 (Bile acids) 99 (Control)
Heterogeneity Chi2 = 392 df = 6 (P = 069) I2 =00
Test for overall effect Z = 130 (P = 019)
01 02 05 1 2 5 10
Favours bile acids Favours control
40Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 19 Comparison 1 Bile acids for liver-transplanted patients Outcome 9 Subgroup analysis
number of patients with acute cellular rejection according to treatment duration
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 9 Subgroup analysis number of patients with acute cellular rejection according to treatment duration
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 Less than six months
Barnes 1997 1728 1724 180 086 [ 058 127 ]
Fleckenstein 1998 814 916 83 102 [ 054 190 ]
Keiding 1997 3554 3248 333 097 [ 073 129 ]
Koneru 1993 316 916 89 033 [ 011 101 ]
Pageaux 1995 926 924 92 092 [ 044 193 ]
Subtotal (95 CI) 138 128 777 087 [ 071 107 ]
Total events 72 (Bile acids) 76 (Control)
Heterogeneity Chi2 = 374 df = 4 (P = 044) I2 =00
Test for overall effect Z = 129 (P = 020)
2 Six months or more
Angelico 1999 816 1017 95 085 [ 045 160 ]
Sama 1991 1320 1320 128 100 [ 063 158 ]
Subtotal (95 CI) 36 37 223 094 [ 065 136 ]
Total events 21 (Bile acids) 23 (Control)
Heterogeneity Chi2 = 017 df = 1 (P = 068) I2 =00
Test for overall effect Z = 035 (P = 073)
Total (95 CI) 174 165 1000 089 [ 074 106 ]
Total events 93 (Bile acids) 99 (Control)
Heterogeneity Chi2 = 392 df = 6 (P = 069) I2 =00
Test for overall effect Z = 130 (P = 019)
01 02 05 1 2 5 10
Favours bile acids Favours control
41Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 110 Comparison 1 Bile acids for liver-transplanted patients Outcome 10 Number of patients
with chronic rejection at maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 10 Number of patients with chronic rejection at maximum follow-up
Study or subgroup Bile acids Placebo Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Barnes 1997 128 624 611 014 [ 002 110 ]
Fleckenstein 1998 114 116 88 114 [ 008 1663 ]
Keiding 1997 154 348 300 030 [ 003 275 ]
Total (95 CI) 96 88 1000 028 [ 008 095 ]
Total events 3 (Bile acids) 10 (Placebo)
Heterogeneity Chi2 = 148 df = 2 (P = 048) I2 =00
Test for overall effect Z = 204 (P = 0041)
0001 001 01 1 10 100 1000
Favours bile acids Favours placebo
Analysis 111 Comparison 1 Bile acids for liver-transplanted patients Outcome 11 Number of patients
with steroid-resistant rejection at maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 11 Number of patients with steroid-resistant rejection at maximum follow-up
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Barnes 1997 328 724 277 037 [ 011 127 ]
Fleckenstein 1998 314 316 103 114 [ 027 478 ]
Keiding 1997 1454 1548 583 083 [ 045 154 ]
Pageaux 1995 226 124 38 185 [ 018 1908 ]
Total (95 CI) 122 112 1000 077 [ 047 127 ]
Total events 22 (Bile acids) 26 (Control)
Heterogeneity Chi2 = 226 df = 3 (P = 052) I2 =00
Test for overall effect Z = 102 (P = 031)
001 01 1 10 100
Favours bile acids Favours placebo
42Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 112 Comparison 1 Bile acids for liver-transplanted patients Outcome 12 Serum bilirubin (mgdl)
at the end of treatment
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 12 Serum bilirubin (mgdl) at the end of treatment
Study or subgroup Bile acids Placebo Mean Difference Weight Mean Difference
N Mean(SD) N Mean(SD) IVFixed95 CI IVFixed95 CI
Fleckenstein 1998 14 319 (68) 16 059 (022) 1000 260 [ -096 616 ]
Total (95 CI) 14 16 1000 260 [ -096 616 ]
Heterogeneity not applicable
Test for overall effect Z = 143 (P = 015)
-10 -5 0 5 10
Favours bile acids Favours placebo
Analysis 113 Comparison 1 Bile acids for liver-transplanted patients Outcome 13 Number of days of
hospitalisation after liver transplantation
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 13 Number of days of hospitalisation after liver transplantation
Study or subgroup Bile acids Placebo Mean Difference Weight Mean Difference
N Mean(SD) N Mean(SD) IVFixed95 CI IVFixed95 CI
Barnes 1997 28 25 (17) 24 335 (13) 1000 -850 [ -1667 -033 ]
Total (95 CI) 28 24 1000 -850 [ -1667 -033 ]
Heterogeneity not applicable
Test for overall effect Z = 204 (P = 0041)
-100 -50 0 50 100
Favours bile acids Favours placebo
43Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 114 Comparison 1 Bile acids for liver-transplanted patients Outcome 14 Adverse events
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 14 Adverse events
Study or subgroup Bile acids Placebo Risk Ratio Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Angelico 1999 016 017 00 [ 00 00 ]
Barnes 1997 128 124 086 [ 006 1298 ]
Keiding 1997 554 548 089 [ 027 288 ]
Total (95 CI) 98 89 088 [ 030 260 ]
Total events 6 (Bile acids) 6 (Placebo)
Heterogeneity Chi2 = 000 df = 1 (P = 098) I2 =00
Test for overall effect Z = 022 (P = 082)
001 01 1 10 100
Favours bile acids Favours placebo
A P P E N D I C E S
Appendix 1 Search strategies
Data Base Date of Search Search Strategy
The Cochrane Hepato-Biliary Group Con-
trolled Trials Register
September 2009 1 rsquoliver transplantationrsquo and rsquochenodeoxy-
cholicrsquo
2 rsquoliver transplantationrsquo and rsquocholicrsquo
3 rsquoliver transplantationrsquo and rsquodeoxycholicrsquo
4 rsquoliver transplantationrsquo and rsquoglycochen-
odeoxycholicrsquo
5 rsquoliver transplantationrsquo and rsquoglycocholicrsquo
6 rsquoliver transplantationrsquo and rsquoglycodeoxy-
cholicrsquo
7 rsquoliver transplantationrsquo and rsquoglycolitho-
cholicrsquo
8 rsquoliver transplantationrsquo and rsquohyodeoxy-
cholicrsquo
9 rsquoliver transplantationrsquo and rsquolithocholicrsquo
10 rsquoliver transplantationrsquo and rsquotaurochen-
odeoxycholicrsquo
44Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
11 rsquoliver transplantationrsquo and rsquotauro-
cholicrsquo
12 rsquoliver transplantationrsquo and rsquotaurodehy-
drocholicrsquo
13 rsquoliver transplantationrsquo and rsquotau-
rodeoxycholicrsquo
14 rsquoliver transplantationrsquo and rsquotauroglyco-
cholicrsquo
15 rsquoliver transplantationrsquo and rsquotaurolitho-
cholicrsquo
16 rsquoliver transplantationrsquo and rsquotaurosel-
cholicrsquo
17 rsquoliver transplantationrsquo and rsquotaurourso-
cholicrsquo
18 rsquoliver transplantationrsquo and rsquotaurour-
sodeoxycholicrsquo
19 rsquoliver transplantationrsquo and rsquoursocholicrsquo
20 rsquoliver transplantationrsquo and rsquoursodeoxy-
cholicrsquo
The Cochrane Central Register of Con-
trolled Trials in The Cochrane Library
Issue 3 2009 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
6 3 or 4
7 5 and 6
MEDLINE September 2009 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
45Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
6 3 or 4
7 5 and 6
8 RANDOMIZED-CONTROLLED-
TRIAL ME
9 RANDOM
10 8 or 9
11 7 and 10
EMBASE September 2009 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
6 3 or 4
7 5 and 6
8 RANDOMIZED-CONTROLLED-
TRIAL ME
9 RANDOM
10 8 or 9
11 7 and 10
46Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
Science Citation Index Expanded September 2009 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
6 3 or 4
7 5 and 6
8 RANDOMIZED-CONTROLLED-
TRIAL ME
9 RANDOM
10 8 or 9
11 7 and 10
The Chinese Biomedical Database Searched from January 1980 to April 2002 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
47Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
6 3 or 4
7 5 and 6
8 RANDOMIZED-CONTROLLED-
TRIAL ME
9 RANDOM
10 8 or 9
11 7 and 10
W H A T rsquo S N E W
Last assessed as up-to-date 8 February 2010
18 September 2009 New citation required but conclusions have not
changed
This review is an updated version of a review that was
published for the first time in Issue 3 2005 of TheCochrane Library by Chen 2003b
18 September 2009 New search has been performed No new studies fulfilled the inclusion criteria
H I S T O R Y
Protocol first published Issue 3 2003
Review first published Issue 3 2005
C O N T R I B U T I O N S O F A U T H O R S
GP and VG independently performed searches of relevant databases GP validated the search selected trials for inclusion contacted
the authors of the trials performed data extraction and data analysis and drafted the systematic review VG revised the review update
CG and DS revised the review update solved discrepancies of data extraction validated data analyses and provided consultation
D E C L A R A T I O N S O F I N T E R E S T
None known
48Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
S O U R C E S O F S U P P O R T
Internal sources
bull Copenhagen Trial Unit Denmark
External sources
bull Danish Medical Research Councilrsquos Grant on Getting Research into Practice (GRIP) Denmark
D I F F E R E N C E S B E T W E E N P R O T O C O L A N D R E V I E W
We assessed the risk of bias in the included studies for another four domains that were added to the review protocol (incomplete
outcome data selective outcome reporting baseline imbalance and early stopping of trial) In general the text of the risk of bias
domains were updated following Higgins 2008 Trials were considered at low risk of bias when judged as adequate in all domains
Quasi-randomised studies observational and case-control studies were included for the report of adverse events
We performed trial sequential analysis for outcomes demonstrating a statistically significant result
I N D E X T E R M S
Medical Subject Headings (MeSH)
lowastLiver Transplantation Cholagogues and Choleretics [lowasttherapeutic use] Graft Rejection [lowastprevention amp control] Randomized Con-
trolled Trials as Topic Taurochenodeoxycholic Acid [lowasttherapeutic use] Ursodeoxycholic Acid [lowasttherapeutic use]
MeSH check words
Humans
49Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
antigens by CD4+ T cells (Vierling 1992) Moreover the inhibi-
tion of the production of interleukin-2 by peripheral blood lym-
phocytes with UDCA (Heuman 1993) might be negated by the
immunosuppressive treatment after liver transplantation (van den
Berg 1998) so that UDCA is unable to demonstrate effects on
graft rejection In a recent study by Assy 2007 a significant re-
duction in the mean dose of immunosuppressive medications was
achieved in stable liver graft recipients treated with UDCA indi-
cating a possible influence of UDCA on rejection mechanisms
In accordance with previous systematic reviews (Chen 2003a
Chen 2007 Gong 2008) bile acids were not associated with the
occurrence of serious adverse events or any major occurrence of
adverse events
In summary our results do not support or refute the use of bile
acids (UDCA and TUDCA) additional to standard immunosup-
pressive treatment in liver-transplanted patients
A U T H O R S rsquo C O N C L U S I O N SImplications for practice
There seems to be no evidence to support or refute the use of bile
acids for liver-transplanted patients receiving standard immuno-
suppressive treatment
Implications for research
We need more randomised placebo-controlled clinical trials with
enough statistical power and low risk of bias to explore the poten-
tial effects of bile acids on chronic rejection and mortality in liver-
transplanted patients Such trials should also consider evaluation
of quality of life and length of hospitalisation Such trials may
consider starting bile acid and placebo interventions before liver
transplantation we were not able to identify any randomised trials
addressing this regimen Such trials ought to be reported accord-
ing to the CONSORT statement (wwwconsort-statementorg)
However before embarking on such trials the effects of bile acids
in other patient groups should be scrutinised as they may have
small or negative effects
A C K N O W L E D G E M E N T S
We thank all the patients and investigators who were involved in
the clinical trials mentioned in this review We thank Wendong
Chen for his work and contribution on the previous version of this
review We thank the staff of The Cochrane Hepato-Biliary Group
Editorial Team especially Dimitrinka Nikolova and Sarah Louise
Klingenberg for excellent collaboration and assistance during the
update of this review
Peer Reviewers Carlo Merkel Italy M Tomikawa Japan
Contact Editor Bodil Als-Nielsen Denmark
R E F E R E N C E S
References to studies included in this review
Angelico 1999 published data only
Angelico M Tisone G Baiocchi L Palmieri G Pisani F Negrini S
et alOne-year pilot study on tauroursodeoxycholic acid as an
adjuvant treatment after liver transplantation Italian Journal of
Gastroenterology and Hepatology 199931(6)462ndash8 [MEDLINE
10575563]
Barnes 1997 published data onlylowast Barnes D Talenti D Cammell G Goormastic M Farquhar L
Henderson M et alA randomized clinical trial of ursodeoxycholic
acid as adjuvant treatment to prevent liver transplant rejection
Hepatology 199726(4)853ndash7 [MEDLINE 9328304]
Barnes D Talenti D Goormastic M Farquhar L Cammell G
Henderson M et alUrsodeoxycholic acid (UDCA) reduces hepatic
allograft rejection after orthotopic liver transplantation (OLT) - a
prospective randomized placebo-controlled double-blind trial
Hepatology 199522149A
Fleckenstein 1998 published data only
Fleckenstein JF Paredes M Thuluvath PJ A prospective
randomized double-blind trial evaluating the efficacy of
ursodeoxycholic acid in prevention of liver transplant rejection
Liver Transplantation and Surgery 19984(4)276ndash9 [MEDLINE
9649640]
Keiding 1997 published data only
Keiding S Hockerstedt K Bjoro K Bondesen S Hjortrup A
Isoniemi H et alThe Nordic multicenter double-blind randomized
controlled trial of prophylactic ursodeoxycholic acid in liver
transplant patients Transplantation 199763(11)1591ndash4
[MEDLINE 9197351]
Koneru 1993 published data only
Koneru B Tint GS Wilson DJ Leevy CB Salen F Randomised
prospective trial of ursodeoxycholic acid in liver transplant
recipients Hepatology 199318336A
Pageaux 1995 published data only
Pageaux GP Blanc P Perrigault PF Navarro F Fabre JM Souche B
et alFailure of ursodeoxycholic acid to prevent acute cellular
rejection after liver transplantation Journal of Hepatology 199523
(2)119ndash22 [MEDLINE 7499781]
Sama 1991 published data only
Sama C Mazziotti A Grigioni W Morselli AM Chianura A
Stefanini GF et alUrsodeoxycholic acid administration does not
14Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
prevent rejection after OLT Journal of Hepatology 199113(Suppl
2)68
References to studies excluded from this review
Assy 2007 published data only
Assy N Adams PC Myers P Simon V Minuk GY Wall W et
alRandomized controlled trial of total immunosuppression
withdrawal in liver transplant recipients role of ursodeoxycholic
acid Transplantation 200783(12)1571ndash6 [MEDLINE
17589339]
Clavien 1996 published data only
Clavien PA Sharara AI Camargo CA Jr Harland RC Fitz JG
Evidence that ursodeoxycholic acid prevents steroid-resistant
rejection in adult liver transplantation Clinical Transplantation
199610(6 Pt 2)658ndash62 [MEDLINE 8996761]
Friman 1992 published data only
Friman S Persson H Schersten T Svanvik J Karlberg I Adjuvant
treatment with ursodeoxycholic acid reduces acute rejection after
liver transplantation Transplantation Proceedings 199224(1)
389ndash90 [MEDLINE 1539328]
Heathcote 1999 published data onlylowast Heathcote EJ Stone J Cauch-Dudek K Poupon R Chazouilleres
O Lindor KD et alEffect of pretransplantation ursodeoxycholic
acid therapy on the outcome of liver transplantation in patients
with primary biliary cirrhosis Liver Transplantation and Surgery
19995(4)269ndash74 [MEDLINE 10388499]
Henriksson 1991 published data only
Henriksson BA Persson H Friman S Wangberg B Svanvik J
Karlberg I Adjuvant ursodeoxycholic acid prevents acute rejection
in liver transplant recipients Transplantation Proceedings 199123
(3)1971 [MEDLINE 2063453]
Persson 1990 published data only
Persson H Friman S Schersten T Svanvik J Karlberg I
Ursodeoxycholic acid for prevention of acute rejection in liver
transplant recipients Lancet 1990336(8706)52ndash3 [MEDLINE
1973232]
Rafael 1995 published data only
Rafael E Duraj F Rudstrom H Wilczek H Ericzon B Effect of
ursodeoxycholic acid treatment for cholestasis in liver transplant
recipients Transplantation Proceedings 199527(6)3501ndash2
[MEDLINE 8540069]
Sama 1998 published data only
Sama C Morselli-Labate AM Grazi GL Mastroianni A Danesi G
Pianta P et alUrsodeoxycholic acid in liver transplantation effect
on cholestasis and rejection Gastroenterology 1998114(4 Suppl)
A1332
Additional references
Adams 1990
Adams DH Neuberger JM Patterns of graft rejection following
liver transplantation Journal of Hepatology 199010(1)113ndash9
[MEDLINE 2407770]
Al-Quaiz 1994
Al-Quaiz M OrsquoGrady J Tredger J Williams R Variable effect of
ursodeoxycholic acid on cyclosporin absorption after orthotopic
liver transplantation Transplant International 19947(3)190ndash4
[MEDLINE 8060468]
Armstrong 1982
Armstrong MJ Carey MC The hydrophobic-hydrophilic balance
of bile salt Inverse correlation between reverse phase high
performance liquid chromatographic mobilities and micellar
cholesterol-solubilizing capacities Journal of Lipid Research 1982
23(1)70ndash80 [MEDLINE 7057113]
Ascher 1988
Ascher NL Stock PG Baumgardner GL Payne WD Najarian JS
Infection and rejection of primary hepatic transplant in 93
consecutive patients treated with triple immunosuppressive therapy
Surgery Gynecology amp Obstetrics 1988167(6)474ndash84
[MEDLINE 3055368]
Brok 2008
Brok J Thorlund K Gluud C Wetterslev J Trial sequential
analysis reveals insufficient information size and potentially false
positive results in many meta-analyses Journal of Clinical
Epidemiology 200861(8)763ndash9 [MEDLINE 18411040]
Brok 2009
Brok J Thorlund K Wetterslev J Gluud C Apparently conclusive
meta-analysis may be inconclusive - Trial sequential analysis
adjustment of random error risk due to repetitive testing of
accumulating data in apparently conclusive neonatal meta-analysis
International Journal of Epidemiology 200938(1)298ndash303
[MEDLINE 18824466]
Calmus 1990
Calmus Y Gane P Rouger P Poupon R Hepatic expression of class
I and class II major histocompatibility complex molecules in
primary biliary cirrhosis effect of ursodeoxycholic acid Hepatology
199011(1)12ndash5 [MEDLINE 2403961]
Calmus 1992
Calmus Y Arvieux C Gane P Boucher E Nordlinger B Rouger P
et alCholestasis induces major histocompatibility complex class I
expression in hepatocytes Gastroenterology 1992102(4 Pt 1)
1371ndash7 [MEDLINE 1551542]
Chen 2003a
Chen W Gluud C Bile acids for primary sclerosing cholangitis
Cochrane Database of Systematic Reviews 2003 Issue 2 [DOI
10100214651858CD003626]
Chen 2007
Chen W Liu J Gluud C Bile acids for viral hepatitis Cochrane
Database of Systematic Reviews 2007 Issue 4 [DOI 101002
14651858CD003181pub2]
Cheng 2002
Cheng K Ashby D Smyth R Ursodeoxycholic acid for cystic
fibrosis-related liver disease Cochrane Database of Systematic
Reviews 2002 Issue 2 [DOI 10100214651858CD000222]
Corbani 2008
Corbani A Burroughs AK Intrahepatic cholestasis after liver
transplantation Clinics in Liver Disease 200812(1)111ndash29
[MEDLINE 18242500]
DeMets 1987
DeMets DL Methods for combining randomised clinical trials
strengths and limitations Statistics in Medicine 19876(3)341ndash50
[MEDLINE 3616287]
15Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
DerSimonian 1986
DerSimonian R Laird N Meta-analysis in clinical trials Controlled
Clinical Trials 19867(3)177ndash88 [MEDLINE 3802833]
Egger 1997
Egger M Davey Smith G Schneider M Minder C Bias in meta-
analysis detected by a simple graphical test BMJ (Clinical Research
Ed) 1997315(7109)629ndash34 [MEDLINE 9310563]
Ericzon 1990
Ericzon BG Eusufzai S Kubota K Einarsson K Angelin B
Characteristics of biliary lipid metabolism after liver
transplantation Hepatology 199012(5)1222ndash8 [MEDLINE
2227822]
FK506 1994
The US Multicenter FK506 Liver Study Group A comparison of
tacrolimus (FK506) and cyclosporine for immunosuppression in
liver transplantation New England Journal of Medicine 1994331
(17)1110ndash5 [MEDLINE 7523946]
Friman 1994
Friman S Svanvik J A possible role of ursodeoxycholic acid in liver
transplantation Scandinavian Journal of Gastroenterology 1994204
62ndash4 [MEDLINE 7824880]
Fuchs 1999
Fuchs M Stange EF Metabolism of bile acids In Johannes
Bircher Jean-Pierre Benhamou Neil McIntyre Mario Rizzetto
Juan Rodes editor(s) Oxford Textbook of Clinical Hepatology 2
Vol 1 Oxford Oxford University Press 1999223ndash56
Fusai 2006
Fusai G Dhaliwal P Rolando N Sabin CA Patch D Davidson BR
et alIncidence and risk factors for the development of prolonged
and severe intrahepatic cholestasis after liver transplantation Liver
Transplantation 200612(11)1626ndash33 [DOI 101002lt20870]
Gluud 2001
Gluud C Alcoholic hepatitis no glucocorticosteroids In
Leuschner U James OFW Dancygier H editor(s) Steatohepatitis
(NASH and ASH) Falk Symposium 121 Lancaster Kluwer
Academic Publisher 2001322ndash42
Gluud 2010
Gluud C Nikolova D Klingenberg SL Alexakis N Als-Nielsen B
Colli A et alCochrane Hepato-Biliary Group About The
Cochrane Collaboration (Cochrane Review Groups (CRGs))
2010 Issue 1 Art No LIVER
Gong 2008
Gong Y Huang ZB Christiansen E Gluud C Ursodeoxycholic
acid for primary biliary cirrhosis Cochrane Database of Systematic
Reviews 2008 Issue 3 [DOI 101002
14651858CD000551pub2]
Haddad 2006
Haddad EM McAlister VC Renouf E Malthaner R Kjaer MS
Gluud LL Cyclosporin versus tacrolimus for liver transplanted
patients Cochrane Database of Systematic Reviews 2006 Issue 4
[DOI 10100214651858CD005161pub2]
Heuman 1993
Heuman DM Hepatoprotective properties of ursodeoxycholic acid
Gastroenterology 1993104(6)1865ndash9 [MEDLINE 8500748]
Higgins 2008
Higgins PTJ Green S editors Cochrane Handbook for Systematic
Reviews of Interventions West Sussex England Wiley-Blackwell
2008
Hirschfield 2009
Hirschfield GM Gibbs P Griffiths WJH Adult liver
transplantation what non-specialists need to know BMJ (Clinical
Research Ed) 2009338(b1670)1321ndash7 [DOI 101136
bmjb1670]
Hussain 2002
Hussain HK Nghiem HV Imaging of hepatic transplantation
Clinics in Liver Disease 20026(1)247ndash70 [MEDLINE
11933592]
ICH-GCP 1997
International Conference on Harmonisation Expert Working
Group Code of Federal Regulations amp International Conference on
Harmonization Guidelines Media Parexel Barnett 1997
Ioannidis 2001
Ioannidis JPA Lau J Evolution of treatment effects over time
Empirical insight from recursive cumulative meta analyses
Proceedings of the National Academy of Sciences 200198(3)831ndash6
IWP 1995
International Working Party Terminology for hepatic allograft
rejection Hepatology 199522(2)648ndash54 [MEDLINE 7635435]
Kjaergard 2001
Kjaergard LL Villumsen J Gluud C Reported methodological
quality and discrepancies between large and small randomised trials
in meta-analyses Annals of Internal Medicine 2001135(11)982ndash9
[MEDLINE 11730399]
Klintmalm 1989
Klintmalm GB Nery JR Husberg BS Gonwa TA Tillery GW
Rejection in liver transplantation Hepatology 198910(6)978ndash85
[MEDLINE 2583691]
Knechtle 2009
Knechtle SJ Kwun J Unique aspects of rejection and tolerance in
liver transplantation Seminars in Liver Disease 200929(1)91ndash101
[MEDLINE 19235662]
Krams 1993
Krams SM Ascher NL Martinez OM New immunologic insights
into mechanisms of allograft rejection Gastroenterology Clinics of
North America 199318(2)374ndash7 [MEDLINE 8509176]
Lan 1983
Lan KKG DeMets DL Discrete sequential boundaries for clinical
trials Biometrika 198370659ndash63
Merion 1989
Merion RM Gorski DH Burtch GD Turcotte JG Colletti LM
Campbell DA Jr Bile refeeding after liver transplantation and
avoidance of intravenous cyclosporine Surgery 1989106(4)
604ndash9 [MEDLINE 2799635]
Moher 1998
Moher D Pham B Jones A Cook DJ Jadad AR Moher M et
alDoes quality of reports of randomised trials affect estimates of
intervention efficacy reported in meta-analyses Lancet 1998352
(9128)609ndash13 [MEDLINE 9746022]
16Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Neuberger 1999
Neuberger J Incidence timing and risk factors for acute and
chronic rejection Liver Transplantation and Surgery 19995(4 Suppl
1)S30ndashS36 [MEDLINE 10431015]
Okolicsanyi 1986
Okolicsanyi L Lirussi F Strazzabosco M Jemmolo RM Orlando R
Nassuato G et alThe effect of drugs on bile flow and composition
An overview Drugs 198631(5)430ndash48 [MEDLINE 2872047]
Palmer 1972
Palmer RH Bile acids liver injury and liver disease Archives of
Internal Medicine 1972130(4)606ndash17 [MEDLINE 4627840]
Perez 2009
Perez MJ Briz O Bile-acid-induced cell injury and protection
World Journal of Gastroenterology 200915(14)1677ndash89
[MEDLINE 19360911]
Pogue 1997
Pogue JM Yusuf S Cumulating evidence from randomized trials
Utilizing sequential monitoring boundaries for cumulative meta-
analysis Controlled Clinical Trials 199718(6)580ndash93
[MEDLINE 9408720]
Pogue 1998
Pogue J Yusuf S Overcoming the limitations of current meta-
analysis of randomised controlled trials Lancet 1998351(9095)
45ndash52 [MEDLINE 9433436]
RevMan 2008
The Nordic Cochrane Centre The Cochrane Collaboration
Review Manager (RevMan) 50 Copenhagen The Nordic
Cochrane Centre The Cochrane Collaboration 2008
Royle 2003
Royle P Milne R Literature searching for randomized controlled
trials used in Cochrane reviews rapid versus exhaustive searches
International Journal of Technology Assessment in Health Care 2003
19(4)591ndash603
Schulz 1995
Schulz KF Chalmers I Hayer R Altman D Empirical evidence of
bias JAMA 1995273(5)408ndash12 [MEDLINE 7823387]
Sharara 1995
Sharara AI Camargo CA Clavien PA Ursodeoxycholic acid
prevents steroid resistant rejection in liver transplant recipients
Gastroenterology 1995108A1168
Sholmerich 1984
Sholmerich J Becher MS Schmidt KH Schubert R Kremer B
Felhaus S et alInfluence of hydroxylation and conjugation of bile
salts on their membrane damaging properties Hepatology 19844
(4)661ndash7 [MEDLINE 6745854]
Soderdahl 1998
Soderdahl G Nowak G Duraj F Wang FH Einarsson C Ericzon
BG Ursodeoxycholic acid increased bile flow and affects bile
composition in the early postoperative phase following liver
transplantation Transplantation International 199811(Suppl 1)
S231ndashS238 [MEDLINE 9664985]
Terasaki 1991
Terasaki S Nakanuma Y Ogino H Unoura M Kobayashi K
Hepatocellular and biliary expression of HLA antigens in primary
biliary cirrhosis before and after ursodeoxycholic acid therapy
American Journal of Gastroenterology 199186(9)1194ndash9
[MEDLINE 1882800]
Thalheimer 2002
Thalheimer U Capra F Liver transplantation making the best out
of what we have Digestive Diseases and Sciences 200247(5)
945ndash53 [MEDLINE 12018919]
Thorlund 2009
Thorlund K Devereaux PJ Wetterslev J Guyatt G Ioannidis JP
Thabane L et alCan trial sequential monitoring boundaries reduce
spurious inferences from meta-analyses International Journal of
Epidemiology 200938(1)276ndash86 [MEDLINE 18824467]
Thuluvath 2003
Thuluvath PJ Yoo HY Thompson RE A model to predict survival
at one month one year and five years after liver transplantation
based on pretransplant clinical characteristics Liver Transplantation
20039(5)527ndash32 [MEDLINE 12740799]
van den Berg 1998
van den Berg AP Twilhaar WN Mesander G van Son WJ van der
Bij W Klompmaker IJ et alQuantitation of immunosuppression
by flow cytometric measurement of the capacity of T cells for
interleukin-2 production Transplantation 199865(8)1066ndash71
[MEDLINE 9583867]
Vierling 1992
Vierling J Immunologic mechanisms of hepatic allograft rejection
Seminars in Liver Disease 199212(1)16ndash27 [MEDLINE
1570548]
Wetterslev 2008
Wetterslev J Thorlund K Brok J Gluud C Trial sequential
analysis may establish when firm evidence is reached in cumulative
meta-analysis Journal of Clinical Epidemiology 200861(1)64ndash75
[MEDLINE 18083463]
Wiesner 1992
Wiesner RH Acute cellular rejection following liver
transplantation incidence risk factors and outcome in the
NIDDK Liver Transplant Database (LTD) study Gastroenterology
1992102A910
Wood 2008
Wood L Egger M Gluud LL Schulz KF Juni P Altman DG et
alEmpirical evidence of bias in treatment effect estimates in
controlled trials with different interventions and outcomes meta-
epidemiological study BMJ (Clinical Research Ed) 2008336
(7644)601ndash5 [MEDLINE 18316340]
Yoshikawa 1998
Yoshikawa M Matsui Y Kawamoto H Toyohara M Matsumura
K Yamao J et alIntragastric administration of ursodeoxycholic
acid suppresses immunoglobulin secretion by lymphocytes from
liver but not from peripheral blood spleen or Peyerrsquos patches in
mice International Journal of Immunopharmacology 199820(1-3)
29ndash38 [MEDLINE 9717080]
References to other published versions of this review
17Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Chen 2003b
Chen W Gluud C Bile acids for liver transplanted patients
Cochrane Database of Systematic Reviews 2005 Issue 3 [DOI
10100214651858CD005442]lowast Indicates the major publication for the study
18Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
C H A R A C T E R I S T I C S O F S T U D I E S
Characteristics of included studies [ordered by study ID]
Angelico 1999
Methods Study design open-label randomised one-year pilot study
Participants Country Italy
Publication language English
Inclusion criteria
- patients who underwent liver transplantation from April 1994 to December 1994
Exclusion criteria
- not mentioned
Participants
Two patients in TUDCA group and two patients in control group were excluded from
the basic information of participants by the study due to withdrawal
- TUDCA group (n = 14)
Mean age (years +- SD)
467 +- 84
Ratio of sex (malefemale) 122
Origins of liver diseases
hepatitis C cirrhosis (9) hepatitis B cirrhosis (2) hepatitis B and C cirrhosis (1) cryp-
togenic cirrhosis (2) alcoholic cirrhosis (0) Wilson cirrhosis (0)
- Control group (n = 15)
Mean age (years +- SD)
474 +- 74
Ratio of sex (malefemale) 123
Origins of liver diseases
hepatitis C cirrhosis (7) hepatitis B cirrhosis (2) hepatitis B and C cirrhosis (2) cryp-
togenic cirrhosis (2) alcoholic cirrhosis (1) Wilson cirrhosis (1)
Interventions TUDCA group
- Dose 500 mgday in two divided doses
- Route orally
- Duration the treatment was started on day 5 after transplantation and continued for
one year
Control group
- no treatment
Co-interventions all patients received standard triple-drug regimens (steroids azathio-
prine and cyclosporine or tacrolimus)
Outcomes All cause mortality
Number of patients with rejection after liver transplantation
Notes Letter was sent to the authors in September 2009 A reply with additional information
was received shortly after
Risk of bias
19Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Angelico 1999 (Continued)
Item Authorsrsquo judgement Description
Adequate sequence generation Yes Computer generated table
Allocation concealment Unclear No information provided
Blinding No Not performed
Incomplete outcome data addressed
All outcomes
Yes Withdrawal two patients from the
TUDCA group and two patients from the
placebo group Three of them died due to
transplant non-function in the first postop-
erative week and one patient was regrafted
due to thrombosis of hepatic artery
Free of selective reporting Unclear Post-transplant cholestasis and liver bio-
chemistry specified as outcomes Differ-
ence reported as not significant but no ac-
tual data given
Sample size calculation No Not reported
Intention-to-treat analysis No Not stated and not used
Baseline imbalance Unclear Not enough information provided
Early stopping of trial Unclear Not enough information provided
Barnes 1997
Methods Study design randomised placebo-controlled double-blind trial
Participants Country United States
Publication language English
Inclusion criteria
- patients aged 18 years or older who underwent liver transplantation at the Cleveland
Clinic Foundation from April 1992 through June of 1994
Exclusion criteria
- patients who were found to have cancer at surgically resected margins of the biliary
tree
- patents who underwent retransplantation
Participants
- UDCA group (n = 28)
Mean age (years +- SD)
505 +- 116
Ratio of sex (malefemale) 1810
Child class A 7
20Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Barnes 1997 (Continued)
B 13
and C 8
Origins of liver diseases Laennecrsquos cirrhosis 4
PBC 3
cryptogenic cirrhosis 6
hepatitis Ccirrhosis 4
hepatitis Bcirrhosis 3
autoimmune hepatitis with cirrhosis 3
PSC 2
other 3
- Placebo group (n = 24)
Mean age (years +- SD)
507 +- 93
Ratio of sex (malefemale) 159
Child class A 6
B 14
and C 4
Origins of liver diseases Laennecrsquos cirrhosis 9
PBC 5
cryptogenic cirrhosis 1
hepatitis Ccirrhosis 1
hepatitis Bcirrhosis 1
autoimmune hepatitis with cirrhosis 1
PSC 2
other 4
Interventions UDCA group
- Dose 10-15 mgkg body weightday in divided doses
- Route orally
- Duration immediately after intestinal transit recovery usually between postoperative
days three and five and continue for three months
Placebo group
- identical-appearing capsules administered in the same quantity and manner
Co-interventions all patients received standard triple-drug regimens (steroids azathio-
prine and cyclosporine or tacrolimus)
Outcomes All cause mortality
Number of patients with acute cellular rejection
Number of patients with chronic rejection
Number of patients with steroid-resistant rejection
Number of days of hospitalisation
Adverse events
Notes Letter was sent to the authors in September 2009 A reply with additional information
was received shortly after
Risk of bias
Item Authorsrsquo judgement Description
21Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Barnes 1997 (Continued)
Adequate sequence generation Yes Computer generated table
Allocation concealment Unclear No information provided
Blinding Yes Quote ldquorandomised to receive either
UDCA or an identical placebo capsulerdquo
Incomplete outcome data addressed
All outcomes
Yes Mean follow-up time 18 months Ten pa-
tients withdrawn from study 6 in UDCA
group and 4 in placebo group Reasons
for withdrawal were reported Four patients
died in the placebo group
Free of selective reporting Yes All expected outcomes reported
Sample size calculation Unclear The trial reported the method of sample
size calculation but the actual number of
patients needed was not reported
Intention-to-treat analysis Yes Stated and used
Baseline imbalance Unclear Not enough information provided
Early stopping of trial Unclear The number of patients needed to gain the
actual power was not reported Whether
the trial was terminated early is not clear
Fleckenstein 1998
Methods Study design prospective randomised double-blind trial
Participants Country United States
Publication language English
Inclusion criteria
- patients who underwent liver transplantation at the Johns Hopkins Hospital
Exclusion criteria
- patients who were under 18 years old undergoing repeat transplantation had primary
graft nonfunction or refused consent
Participants
- UDCA group (n = 14)
Mean age (years +- SD)
443 +- 127
Ratio of sex (malefemale) 68
Origins of liver diseases hepatitis C 6
alcohol 2
autoimmune 1
PBC 2
22Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Fleckenstein 1998 (Continued)
PSC 1
autoimmune cholangiopathy 1
hepatitis B 1
- Placebo group (n = 16)
Mean age (years +- SD)
496 +- 109
Ratio of sex (malefemale) 124
Origins of liver diseases hepatitis C 3
alcohol 3
autoimmune 3
PBC 1
PSC 2
cryptogenic 2
hepatitis B 1
alpha1-antitrypsin deficiency 1
Interventions UDCA group
- Dose 15 mgkg body weightday in divided doses
- Route orally
- Duration immediately after intestinal transit recovery usually between postoperative
days three and five and continue for three months
Placebo group
- Identical-appearing capsules administered in the same quantity and manner
Co-interventions all patients received standard triple-drug regimens (steroids azathio-
prine and cyclosporine or tacrolimus)
Outcomes All cause mortality
Number with retransplantation
Number of patients with acute cellular rejection
Number of patients with chronic rejection
Serum bilirubin levels at the end of treatment
Notes Follow-up time nine months
Letter was sent to the authors in September 2009 No reply was received
Risk of bias
Item Authorsrsquo judgement Description
Adequate sequence generation Unclear No information provided
Allocation concealment Unclear No information provided
Blinding Yes Method of blinding not described but
probably adequate
Incomplete outcome data addressed
All outcomes
Yes Withdrawal one patient from the UDCA
group and two patients from the placebo
group because of capsule size
23Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Fleckenstein 1998 (Continued)
Free of selective reporting Unclear Outcomes were not completely described
Sample size calculation No Not reported
Intention-to-treat analysis Yes Quote ldquoThree patients withdrew after in-
clusionThey were included in the statis-
tical analysisrdquo
Baseline imbalance Unclear Not enough information provided
Early stopping of trial Unclear Not enough information provided
Keiding 1997
Methods Study design prospective randomised placebo-controlled multicenter study
Participants Country Denmark Finland Norway and Sweden
Publication language English
Inclusion criteria
- patients who underwent liver transplantation in Denmark Finland Norway and Swe-
den from September 1 1992 to May 31 1994
Exclusion criteria
- patients with malignant diseases
Participants
The age of the children ranged from 0 to 13 years (median 15) and the age of adults
ranged from 14 to 59 years old (median 44) MaleFemale ratio was 96 for children and
4344 for adults
- UDCA group (n = 54)
Origins of liver diseases
paracetamol intoxication 1 hepatitis B 1 autoimmune hepatitis 0 biliary atresia 2
metabolic diseases 7 neonatal hepatitis 2 PBC 13 post hepatitis cirrhosis 8 PSC 3
cryptogenic cirrhosis 7 alcoholic cirrhosis 2 other reasons 8
- Placebo group (n = 48)
Origins of liver diseases paracetamol intoxication 1 hepatitis B 0 autoimmune hepatitis
1 biliary atresia 3 metabolic diseases 11 neonatal hepatitis 0 PBC 7 post hepatitis
cirrhosis 5 PSC 7 cryptogenic cirrhosis 2 alcoholic cirrhosis 6 other reasons 5
Interventions UDCA group
- Dose 15 mgkg body weightday in two or three divided doses
- Route orally
- Duration immediately after intestinal transit recovery usually between postoperative
days three and five and continue for three months
Placebo group
- Identical-appearing capsules administered in the same quantity and manner
Co-interventions all patients received standard triple-drug regimens (steroids azathio-
prine and cyclosporine or tacrolimus)
24Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Keiding 1997 (Continued)
Outcomes All cause mortality
Number of deaths related to rejection
Number of patients with acute cellular rejection
Number of patients with chronic rejection
Number of patients with steroid-resistant rejection
Adverse events
Notes Letter was sent to the authors in September 2009 No reply was received
Risk of bias
Item Authorsrsquo judgement Description
Adequate sequence generation Unclear Patients were randomised at a ratio of 11
Allocation concealment Yes Quote ldquo The allocation was performed in
blocks of 10 patients using the sealed serial
envelope methodrdquo
Blinding Yes Quote ldquoThe UDCA and the placebo cap-
sules had identical appearance and tasterdquo
Incomplete outcome data addressed
All outcomes
Yes Follow-up time 12 months Five UDCA
patients and five placebo patients withdrew
from study Reasons were reported
Free of selective reporting Unclear Insufficient information
Sample size calculation Yes Performed and allowed for a difference in
the incidence of at least one episode of
acute rejection of 50 between the treat-
ment and placebo groups with 90 statisti-
cal power and a significance level of P value
less than 005 The calculated sample size
was 80 patients
Intention-to-treat analysis Yes Stated and used
Baseline imbalance Yes The study seems to be free of baseline im-
balance
Early stopping of trial Yes Study attained the pre-specified sample
size
25Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Koneru 1993
Methods Study design randomised controlled trial
Participants Country United States
Publication language English
Inclusion criteria
- patients who underwent liver transplantation
Exclusion criteria
- not mentioned
Participants
- UDCA group (n = 16)
Mean age (years +- SD)
no information
Ratio of sex (malefemale) no information
Origins of liver diseases
no information
- Control group (n = 16)
Mean age (years +- SD)
no information
Ratio of sex (malefemale) no information
Origins of liver diseases
no information
Interventions UDCA group
- Dose 900 mgday
- Route orally
- Duration immediately after intestinal transit recovery usually between postoperative
days three and five and continue for three months
Control group
- no treatment
Co-interventions all patients received standard triple-drug regimens (steroids azathio-
prine and cyclosporine)
Outcomes Number of patients with retransplantation due to rejection
Number of patients with rejection episodes
Notes Abstract
Letter was sent to the authors in September 2009 No reply was received
Risk of bias
Item Authorsrsquo judgement Description
Adequate sequence generation Unclear No information provided
Allocation concealment Unclear No information provided
Blinding No Not performed
26Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Koneru 1993 (Continued)
Incomplete outcome data addressed
All outcomes
Unclear The study gives the impression that there
were no withdrawals but this was not ex-
plicitly stated
Free of selective reporting Unclear Insufficient information provided
Sample size calculation No Not performed
Intention-to-treat analysis Unclear No information provided
Baseline imbalance Unclear Not enough information provided
Early stopping of trial Unclear Not enough information provided
Pageaux 1995
Methods Study design double-blind randomised study
Participants Country France
Publication language English
Inclusion criteria
- patients who underwent liver transplantation
Exclusion criteria
- not mentioned
Participants
- UDCA group (n=26)
Mean age (years +- SD)
47 +- 10
Ratio of sex (malefemale) 179
Origins of liver diseases alcoholic cirrhosis 14
post-hepatic B cirrhosis 2
post-hepatitis C cirrhosis 4
PBC 2
liver cancer 2
fulminant hepatitis 1
miscellaneous 1
- Placebo group (n = 24)
Mean age (years +- SD)
51+- 9
Ratio of sex (malefemale) 159
Origins of liver diseases alcoholic cirrhosis 10
post-hepatic B cirrhosis 0
post-hepatic C cirrhosis 6
PBC 3
liver cancer 4
fulminant hepatitis 0
miscellaneous 1
27Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Pageaux 1995 (Continued)
Interventions UDCA group
- Dose 600 mgday in three divided doses
- Route orally
- Duration immediately after intestinal transit recovery usually between postoperative
days three and five and continue for two months
Placebo group
- identical-appearing capsules administered in the same quantity and manner
Co-interventions all patients received standard triple-drug regimens (steroids azathio-
prine and cyclosporine or tacrolimus)
Outcomes Number of patients with acute cellular rejection
Number of patients with steroid-resistant rejection
Notes Letter was sent to the authors in September 2009 No reply was received
Risk of bias
Item Authorsrsquo judgement Description
Adequate sequence generation Unclear No information provided
Allocation concealment Unclear No information provided
Blinding Unclear Method of blinding not described
Incomplete outcome data addressed
All outcomes
Yes Five patients died from non-immunologi-
cal causes before the end of the first month
and were excluded from the study Reasons
were reported
Free of selective reporting Unclear Not enough information provided
Sample size calculation No Not performed
Intention-to-treat analysis No Not stated and not used
Baseline imbalance Unclear Not enough information provided
Early stopping of trial Unclear Not enough information provided
Sama 1991
Methods Study design randomised controlled trial
Participants Country Italy
Publication language English
Inclusion criteria
28Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Sama 1991 (Continued)
- patients who underwent liver transplantation
Exclusion criteria
- not mentioned
Participants
- UDCA group (n = 20)
Mean age (years +- SD)
no information
Ratio of sex (malefemale) no information
Origins of liver diseases
no information
- Control group (n = 20)
Mean age (years +- SD)
no information
Ratio of sex (malefemale) no information
Origins of liver diseases
no information
Interventions UDCA group
- Dose 600 mgday in two divided doses
- Route orally
- Duration immediately after intestinal transit recovery usually between postoperative
day five and day seven and continue for six months
Control group
- no treatment
Co-interventions all patients received standard immunosuppressive treatment (steroids
and cyclosporine)
Outcomes All cause mortality
Number of patients with acute cellular rejection
Notes Abstract
Letter was sent to the authors in September 2009 No reply was received
Risk of bias
Item Authorsrsquo judgement Description
Adequate sequence generation Unclear A randomisation list was performed before
patients were admitted to the trial (infor-
mation from principal author)
Allocation concealment Unclear No information provided
Blinding Unclear The principle author provided information
that the study was made according to a
single-blind randomised protocol The pri-
mary outcome was the occurrence of biopsy
proven rejection episodes The pathologists
were blind but the patients were not
29Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Sama 1991 (Continued)
Incomplete outcome data addressed
All outcomes
Unclear Five patients from the UDCA group and
six patients from the placebo group were
excluded Reasons for exclusion were not
fully stated
Free of selective reporting No Data about survival of patients were not
adequately reported
Sample size calculation No Not performed
Intention-to-treat analysis No Not stated and not used
Baseline imbalance Unclear Basic characteristics of patients not re-
ported
Early stopping of trial Unclear Not enough information provided
UDCA = ursodeoxycholic acid
TUDCA = tauroursodeoxycholic acid
PBC = primary biliary cirrhosis
PSC = primary sclerosing cholangitis
OKT3 = anti-CD3 monoclonal antibody
Characteristics of excluded studies [ordered by study ID]
Assy 2007 A randomised controlled trial that included only recipients of liver transplantation with stable graft function and
no episodes of rejection for at least 2 years that were then offered total immunosuppression withdrawal Fourteen
patients received UDCA (15 mgkg body weightday) and 12 received placebo Rejection occurred in 43 and
75 of patients respectively (no significant difference) None developed chronic rejection After follow-up two
patients were free of immunosuppression 80 were steroid free and 50 were able to reduce their dose of
cyclosporine
Clavien 1996 Case series Fifty consecutive liver-transplanted patients were treated with a standard cyclosporine immunosup-
pressive regimen Twenty three of the 43 survivors developed an episode of rejection and UDCA (10 mgkg
weightday) was initiated Only one patient had a second episode of rejection
Friman 1992 Observational study Thirty-three liver-transplanted patients received 10 mg UDCAkg body weightday for
median of 10 months (range four to 21 months) Eight historical liver-transplanted patients served as control
group The rejection incidence was significantly lower in the patients who received the treatment with UDCA
Biochemistry one month after transplantation demonstrated significantly lower average values of aminotrans-
ferases and alkaline phosphatases in patients treated with UDCA than in the control group
30Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
Heathcote 1999 Observational study From 1987 to 1996 37 UDCA treated and 53 placebo treated patients with primary biliary
cirrhosis were referred for transplantation Posttransplantation survival rates at one month were 939 in the
UDCA group and 884 in the placebo group and one year survival rates were 903 and 784 respectively
(no significant differences) However rejection (type not defined - a secondary outcome measure) occurred
significantly less often in the UDCA group (429) than in placebo group (688)
Henriksson 1991 Observational study All patients in this study were given sequential quadruple immunosuppression with anti-
lymphocyte globulin azathioprine steroids and cyclosporine All patients with primary graft function (n = 11)
were treated with 10 mg UDCAkg body weightday starting during the first postoperative week Patients who
received liver transplantation in the first 6 months of 1989 (n = 8) served as controls In the control group one
patient died after 9 months with chronic graft dysfunction and six patients had rejection episodes during the
first postoperative month All patients in the UDCA group were alive without rejection episodes
Persson 1990 Observational study All 11 adult patients transplanted between August 1989 and January 1990 with primary
graft function were treated with 10 mg UDCA kg body weightday Eight patients transplanted during the first
half of 1989 served as control UDCA was started during the first postoperative week and the treatment was
continued for six months All patients in the UDCA treated group survived with satisfactory graft function In
the control group six patients had at least one rejection episode needing treatment during the first postoperative
month
Rafael 1995 Observational study Seventeen patients who underwent liver transplantation between February 1990 and April
1993 and developed biliary complications after transplantation were retrospectively analysed regarding treatment
with UDCA UDCA was given in a dose of 500 to 1000 mgday Ten patients were treated for at least one year while
seven patients were treated for 14 to 250 days UDCA significantly improved gammaglutamyl transpeptidase in
liver graft recipients with biliary complications There was also a trend towards improvement in serum bilirubin
and alanine transaminase values
Sama 1998 Observational study Thirty-four patients who underwent liver transplantation between January 1995 and June
1996 were included in the study Seventeen were treated with UDCA 10 mgkg body weightday during 6
months while 17 served as controls on the basis of having undergone liver transplantation closest to UDCA
patients A significant decrease in serum bilirubin levels was observed in UDCA patients There was a significantly
higher incidence of recurrent hepatitis in the control group
UDCA ursodeoxycholic acid
31Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
D A T A A N D A N A L Y S E S
Comparison 1 Bile acids for liver-transplanted patients
Outcome or subgroup titleNo of
studies
No of
participants Statistical method Effect size
1 All-cause mortality at maximum
follow-up
5 257 Risk Ratio (M-H Fixed 95 CI) 085 [053 136]
11 UDCA versus placebo or
no treatment
4 224 Risk Ratio (M-H Fixed 95 CI) 080 [049 130]
12 TUDCA versus no
treatment
1 33 Risk Ratio (M-H Fixed 95 CI) 159 [030 833]
2 All-cause mortality worst-best
case and best-worst case
scenarios
5 Risk Ratio (M-H Fixed 95 CI) Subtotals only
21 Worst-best case scenario 5 257 Risk Ratio (M-H Fixed 95 CI) 130 [086 196]
22 Best-worst case scenario 5 257 Risk Ratio (M-H Fixed 95 CI) 058 [038 090]
3 Subgroup analyses all-cause
mortality at maximum
follow-up according to time of
start of bile acids
5 257 Risk Ratio (M-H Fixed 95 CI) 085 [053 136]
31 Less than three days after
transplantation
1 102 Risk Ratio (M-H Fixed 95 CI) 124 [061 254]
32 Three days or more after
transplantation
4 155 Risk Ratio (M-H Fixed 95 CI) 063 [033 120]
4 Subgroup analyses all cause
mortality at maximum
follow-up according to
treatment duration
5 257 Risk Ratio (M-H Fixed 95 CI) 085 [053 136]
41 Less than six months 3 184 Risk Ratio (M-H Fixed 95 CI) 078 [045 138]
42 Six months or more 2 73 Risk Ratio (M-H Fixed 95 CI) 102 [043 240]
5 Number of deaths related
to rejection at maximum
follow-up
1 102 Risk Ratio (M-H Fixed 95 CI) 030 [001 712]
51 UDCA versus placebo 1 102 Risk Ratio (M-H Fixed 95 CI) 030 [001 712]
6 Number of retransplantations at
maximum follow-up
2 132 Risk Ratio (M-H Fixed 95 CI) 076 [020 286]
7 Number of patients with acute
cellular rejection at maximum
follow-up
7 339 Risk Ratio (M-H Fixed 95 CI) 089 [074 106]
71 UDCA versus placebo or
no treatment
6 306 Risk Ratio (M-H Fixed 95 CI) 089 [074 108]
72 TUDCA versus no
treatment
1 33 Risk Ratio (M-H Fixed 95 CI) 085 [045 160]
8 Subgroup analysis number of
patients with acute cellular
rejection according to time of
start of bile acid
7 339 Risk Ratio (M-H Fixed 95 CI) 089 [074 106]
32Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
81 Less than three days after
transplantation
2 134 Risk Ratio (M-H Fixed 95 CI) 084 [063 111]
82 Three days or more after
liver transplantation
5 205 Risk Ratio (M-H Fixed 95 CI) 092 [072 117]
9 Subgroup analysis number
of patients with acute
cellular rejection according to
treatment duration
7 339 Risk Ratio (M-H Fixed 95 CI) 089 [074 106]
91 Less than six months 5 266 Risk Ratio (M-H Fixed 95 CI) 087 [071 107]
92 Six months or more 2 73 Risk Ratio (M-H Fixed 95 CI) 094 [065 136]
10 Number of patients with
chronic rejection at maximum
follow-up
3 184 Risk Ratio (M-H Fixed 95 CI) 028 [008 095]
11 Number of patients with
steroid-resistant rejection at
maximum follow-up
4 234 Risk Ratio (M-H Fixed 95 CI) 077 [047 127]
12 Serum bilirubin (mgdl) at the
end of treatment
1 30 Mean Difference (IV Fixed 95 CI) 26 [-096 616]
13 Number of days of
hospitalisation after liver
transplantation
1 52 Mean Difference (IV Fixed 95 CI) -85 [-1667 -033]
14 Adverse events 3 187 Risk Ratio (M-H Fixed 95 CI) 088 [030 260]
Analysis 11 Comparison 1 Bile acids for liver-transplanted patients Outcome 1 All-cause mortality at
maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 1 All-cause mortality at maximum follow-up
Study or subgroup Favours bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 UDCA versus placebo or no treatment
Barnes 1997 228 724 253 024 [ 006 107 ]
Fleckenstein 1998 214 416 125 057 [ 012 266 ]
Keiding 1997 1454 1048 355 124 [ 061 254 ]
Sama 1991 520 620 201 083 [ 030 229 ]
Subtotal (95 CI) 116 108 935 080 [ 049 130 ]
Total events 23 (Favours bile acids) 27 (Control)
Heterogeneity Chi2 = 416 df = 3 (P = 025) I2 =28
Test for overall effect Z = 091 (P = 036)
01 02 05 1 2 5 10
Favours bile acids Favours control
(Continued )
33Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Favours bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
2 TUDCA versus no treatment
Angelico 1999 316 217 65 159 [ 030 833 ]
Subtotal (95 CI) 16 17 65 159 [ 030 833 ]
Total events 3 (Favours bile acids) 2 (Control)
Heterogeneity not applicable
Test for overall effect Z = 055 (P = 058)
Total (95 CI) 132 125 1000 085 [ 053 136 ]
Total events 26 (Favours bile acids) 29 (Control)
Heterogeneity Chi2 = 466 df = 4 (P = 032) I2 =14
Test for overall effect Z = 069 (P = 049)
01 02 05 1 2 5 10
Favours bile acids Favours control
Analysis 12 Comparison 1 Bile acids for liver-transplanted patients Outcome 2 All-cause mortality worst-
best case and best-worst case scenarios
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 2 All-cause mortality worst-best case and best-worst case scenarios
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 Worst-best case scenario
Angelico 1999 516 217 65 266 [ 060 1180 ]
Barnes 1997 828 724 253 098 [ 042 230 ]
Fleckenstein 1998 314 416 125 086 [ 023 319 ]
Keiding 1997 1954 1048 355 169 [ 087 327 ]
Sama 1991 520 620 201 083 [ 030 229 ]
Subtotal (95 CI) 132 125 1000 130 [ 086 196 ]
Total events 40 (Bile acids) 29 (Control)
Heterogeneity Chi2 = 303 df = 4 (P = 055) I2 =00
Test for overall effect Z = 123 (P = 022)
2 Best-worst case scenario
005 02 1 5 20
Favours bile acids Favours control
(Continued )
34Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Angelico 1999 316 417 90 080 [ 021 302 ]
Barnes 1997 228 1124 274 016 [ 004 063 ]
Fleckenstein 1998 214 616 130 038 [ 009 159 ]
Keiding 1997 1454 1548 368 083 [ 045 154 ]
Sama 1991 520 620 139 083 [ 030 229 ]
Subtotal (95 CI) 132 125 1000 058 [ 038 090 ]
Total events 26 (Bile acids) 42 (Control)
Heterogeneity Chi2 = 567 df = 4 (P = 023) I2 =29
Test for overall effect Z = 247 (P = 0014)
005 02 1 5 20
Favours bile acids Favours control
Analysis 13 Comparison 1 Bile acids for liver-transplanted patients Outcome 3 Subgroup analyses all-
cause mortality at maximum follow-up according to time of start of bile acids
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 3 Subgroup analyses all-cause mortality at maximum follow-up according to time of start of bile acids
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 Less than three days after transplantation
Keiding 1997 1454 1048 355 124 [ 061 254 ]
Subtotal (95 CI) 54 48 355 124 [ 061 254 ]
Total events 14 (Bile acids) 10 (Control)
Heterogeneity not applicable
Test for overall effect Z = 060 (P = 055)
2 Three days or more after transplantation
Angelico 1999 316 217 65 159 [ 030 833 ]
Barnes 1997 228 724 253 024 [ 006 107 ]
Fleckenstein 1998 214 416 125 057 [ 012 266 ]
Sama 1991 520 620 201 083 [ 030 229 ]
005 02 1 5 20
Favours bile acids Favours control
(Continued )
35Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Subtotal (95 CI) 78 77 645 063 [ 033 120 ]
Total events 12 (Bile acids) 19 (Control)
Heterogeneity Chi2 = 310 df = 3 (P = 038) I2 =3
Test for overall effect Z = 141 (P = 016)
Total (95 CI) 132 125 1000 085 [ 053 136 ]
Total events 26 (Bile acids) 29 (Control)
Heterogeneity Chi2 = 466 df = 4 (P = 032) I2 =14
Test for overall effect Z = 069 (P = 049)
005 02 1 5 20
Favours bile acids Favours control
Analysis 14 Comparison 1 Bile acids for liver-transplanted patients Outcome 4 Subgroup analyses all
cause mortality at maximum follow-up according to treatment duration
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 4 Subgroup analyses all cause mortality at maximum follow-up according to treatment duration
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 Less than six months
Barnes 1997 228 724 253 024 [ 006 107 ]
Fleckenstein 1998 214 416 125 057 [ 012 266 ]
Keiding 1997 1454 1048 355 124 [ 061 254 ]
Subtotal (95 CI) 96 88 734 078 [ 045 138 ]
Total events 18 (Bile acids) 21 (Control)
Heterogeneity Chi2 = 417 df = 2 (P = 012) I2 =52
Test for overall effect Z = 084 (P = 040)
2 Six months or more
Angelico 1999 316 217 65 159 [ 030 833 ]
Sama 1991 520 620 201 083 [ 030 229 ]
Subtotal (95 CI) 36 37 266 102 [ 043 240 ]
Total events 8 (Bile acids) 8 (Control)
Heterogeneity Chi2 = 043 df = 1 (P = 051) I2 =00
005 02 1 5 20
Favours bile acids Favours control
(Continued )
36Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Test for overall effect Z = 004 (P = 097)
Total (95 CI) 132 125 1000 085 [ 053 136 ]
Total events 26 (Bile acids) 29 (Control)
Heterogeneity Chi2 = 466 df = 4 (P = 032) I2 =14
Test for overall effect Z = 069 (P = 049)
005 02 1 5 20
Favours bile acids Favours control
Analysis 15 Comparison 1 Bile acids for liver-transplanted patients Outcome 5 Number of deaths related
to rejection at maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 5 Number of deaths related to rejection at maximum follow-up
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 UDCA versus placebo
Keiding 1997 054 148 1000 030 [ 001 712 ]
Total (95 CI) 54 48 1000 030 [ 001 712 ]
Total events 0 (Bile acids) 1 (Control)
Heterogeneity not applicable
Test for overall effect Z = 075 (P = 045)
0001 001 01 1 10 100 1000
Favours bile acids Favours control
37Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 16 Comparison 1 Bile acids for liver-transplanted patients Outcome 6 Number of
retransplantations at maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 6 Number of retransplantations at maximum follow-up
Study or subgroup Bile acids Placebo Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Fleckenstein 1998 214 016 100 567 [ 029 10891 ]
Keiding 1997 154 448 900 022 [ 003 192 ]
Total (95 CI) 68 64 1000 076 [ 020 286 ]
Total events 3 (Bile acids) 4 (Placebo)
Heterogeneity Chi2 = 303 df = 1 (P = 008) I2 =67
Test for overall effect Z = 040 (P = 069)
0001 001 01 1 10 100 1000
Favours bile acids Favours placebo
Analysis 17 Comparison 1 Bile acids for liver-transplanted patients Outcome 7 Number of patients with
acute cellular rejection at maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 7 Number of patients with acute cellular rejection at maximum follow-up
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 UDCA versus placebo or no treatment
Barnes 1997 1728 1724 180 086 [ 058 127 ]
Fleckenstein 1998 814 916 83 102 [ 054 190 ]
Keiding 1997 3554 3248 333 097 [ 073 129 ]
Koneru 1993 316 916 89 033 [ 011 101 ]
Pageaux 1995 926 924 92 092 [ 044 193 ]
Sama 1991 1320 1320 128 100 [ 063 158 ]
Subtotal (95 CI) 158 148 905 089 [ 074 108 ]
01 02 05 1 2 5 10
Favours bile acids Favours control
(Continued )
38Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Total events 85 (Bile acids) 89 (Control)
Heterogeneity Chi2 = 387 df = 5 (P = 057) I2 =00
Test for overall effect Z = 120 (P = 023)
2 TUDCA versus no treatment
Angelico 1999 816 1017 95 085 [ 045 160 ]
Subtotal (95 CI) 16 17 95 085 [ 045 160 ]
Total events 8 (Bile acids) 10 (Control)
Heterogeneity not applicable
Test for overall effect Z = 050 (P = 061)
Total (95 CI) 174 165 1000 089 [ 074 106 ]
Total events 93 (Bile acids) 99 (Control)
Heterogeneity Chi2 = 392 df = 6 (P = 069) I2 =00
Test for overall effect Z = 130 (P = 019)
01 02 05 1 2 5 10
Favours bile acids Favours control
Analysis 18 Comparison 1 Bile acids for liver-transplanted patients Outcome 8 Subgroup analysis
number of patients with acute cellular rejection according to time of start of bile acid
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 8 Subgroup analysis number of patients with acute cellular rejection according to time of start of bile acid
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 Less than three days after transplantation
Keiding 1997 3554 3248 333 097 [ 073 129 ]
Koneru 1993 316 916 89 033 [ 011 101 ]
Subtotal (95 CI) 70 64 422 084 [ 063 111 ]
Total events 38 (Bile acids) 41 (Control)
Heterogeneity Chi2 = 374 df = 1 (P = 005) I2 =73
Test for overall effect Z = 124 (P = 022)
2 Three days or more after liver transplantation
Angelico 1999 816 1017 95 085 [ 045 160 ]
01 02 05 1 2 5 10
Favours bile acids Favours control
(Continued )
39Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Barnes 1997 1728 1724 180 086 [ 058 127 ]
Fleckenstein 1998 814 916 83 102 [ 054 190 ]
Pageaux 1995 926 924 92 092 [ 044 193 ]
Sama 1991 1320 1320 128 100 [ 063 158 ]
Subtotal (95 CI) 104 101 578 092 [ 072 117 ]
Total events 55 (Bile acids) 58 (Control)
Heterogeneity Chi2 = 041 df = 4 (P = 098) I2 =00
Test for overall effect Z = 067 (P = 050)
Total (95 CI) 174 165 1000 089 [ 074 106 ]
Total events 93 (Bile acids) 99 (Control)
Heterogeneity Chi2 = 392 df = 6 (P = 069) I2 =00
Test for overall effect Z = 130 (P = 019)
01 02 05 1 2 5 10
Favours bile acids Favours control
40Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 19 Comparison 1 Bile acids for liver-transplanted patients Outcome 9 Subgroup analysis
number of patients with acute cellular rejection according to treatment duration
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 9 Subgroup analysis number of patients with acute cellular rejection according to treatment duration
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 Less than six months
Barnes 1997 1728 1724 180 086 [ 058 127 ]
Fleckenstein 1998 814 916 83 102 [ 054 190 ]
Keiding 1997 3554 3248 333 097 [ 073 129 ]
Koneru 1993 316 916 89 033 [ 011 101 ]
Pageaux 1995 926 924 92 092 [ 044 193 ]
Subtotal (95 CI) 138 128 777 087 [ 071 107 ]
Total events 72 (Bile acids) 76 (Control)
Heterogeneity Chi2 = 374 df = 4 (P = 044) I2 =00
Test for overall effect Z = 129 (P = 020)
2 Six months or more
Angelico 1999 816 1017 95 085 [ 045 160 ]
Sama 1991 1320 1320 128 100 [ 063 158 ]
Subtotal (95 CI) 36 37 223 094 [ 065 136 ]
Total events 21 (Bile acids) 23 (Control)
Heterogeneity Chi2 = 017 df = 1 (P = 068) I2 =00
Test for overall effect Z = 035 (P = 073)
Total (95 CI) 174 165 1000 089 [ 074 106 ]
Total events 93 (Bile acids) 99 (Control)
Heterogeneity Chi2 = 392 df = 6 (P = 069) I2 =00
Test for overall effect Z = 130 (P = 019)
01 02 05 1 2 5 10
Favours bile acids Favours control
41Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 110 Comparison 1 Bile acids for liver-transplanted patients Outcome 10 Number of patients
with chronic rejection at maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 10 Number of patients with chronic rejection at maximum follow-up
Study or subgroup Bile acids Placebo Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Barnes 1997 128 624 611 014 [ 002 110 ]
Fleckenstein 1998 114 116 88 114 [ 008 1663 ]
Keiding 1997 154 348 300 030 [ 003 275 ]
Total (95 CI) 96 88 1000 028 [ 008 095 ]
Total events 3 (Bile acids) 10 (Placebo)
Heterogeneity Chi2 = 148 df = 2 (P = 048) I2 =00
Test for overall effect Z = 204 (P = 0041)
0001 001 01 1 10 100 1000
Favours bile acids Favours placebo
Analysis 111 Comparison 1 Bile acids for liver-transplanted patients Outcome 11 Number of patients
with steroid-resistant rejection at maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 11 Number of patients with steroid-resistant rejection at maximum follow-up
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Barnes 1997 328 724 277 037 [ 011 127 ]
Fleckenstein 1998 314 316 103 114 [ 027 478 ]
Keiding 1997 1454 1548 583 083 [ 045 154 ]
Pageaux 1995 226 124 38 185 [ 018 1908 ]
Total (95 CI) 122 112 1000 077 [ 047 127 ]
Total events 22 (Bile acids) 26 (Control)
Heterogeneity Chi2 = 226 df = 3 (P = 052) I2 =00
Test for overall effect Z = 102 (P = 031)
001 01 1 10 100
Favours bile acids Favours placebo
42Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 112 Comparison 1 Bile acids for liver-transplanted patients Outcome 12 Serum bilirubin (mgdl)
at the end of treatment
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 12 Serum bilirubin (mgdl) at the end of treatment
Study or subgroup Bile acids Placebo Mean Difference Weight Mean Difference
N Mean(SD) N Mean(SD) IVFixed95 CI IVFixed95 CI
Fleckenstein 1998 14 319 (68) 16 059 (022) 1000 260 [ -096 616 ]
Total (95 CI) 14 16 1000 260 [ -096 616 ]
Heterogeneity not applicable
Test for overall effect Z = 143 (P = 015)
-10 -5 0 5 10
Favours bile acids Favours placebo
Analysis 113 Comparison 1 Bile acids for liver-transplanted patients Outcome 13 Number of days of
hospitalisation after liver transplantation
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 13 Number of days of hospitalisation after liver transplantation
Study or subgroup Bile acids Placebo Mean Difference Weight Mean Difference
N Mean(SD) N Mean(SD) IVFixed95 CI IVFixed95 CI
Barnes 1997 28 25 (17) 24 335 (13) 1000 -850 [ -1667 -033 ]
Total (95 CI) 28 24 1000 -850 [ -1667 -033 ]
Heterogeneity not applicable
Test for overall effect Z = 204 (P = 0041)
-100 -50 0 50 100
Favours bile acids Favours placebo
43Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 114 Comparison 1 Bile acids for liver-transplanted patients Outcome 14 Adverse events
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 14 Adverse events
Study or subgroup Bile acids Placebo Risk Ratio Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Angelico 1999 016 017 00 [ 00 00 ]
Barnes 1997 128 124 086 [ 006 1298 ]
Keiding 1997 554 548 089 [ 027 288 ]
Total (95 CI) 98 89 088 [ 030 260 ]
Total events 6 (Bile acids) 6 (Placebo)
Heterogeneity Chi2 = 000 df = 1 (P = 098) I2 =00
Test for overall effect Z = 022 (P = 082)
001 01 1 10 100
Favours bile acids Favours placebo
A P P E N D I C E S
Appendix 1 Search strategies
Data Base Date of Search Search Strategy
The Cochrane Hepato-Biliary Group Con-
trolled Trials Register
September 2009 1 rsquoliver transplantationrsquo and rsquochenodeoxy-
cholicrsquo
2 rsquoliver transplantationrsquo and rsquocholicrsquo
3 rsquoliver transplantationrsquo and rsquodeoxycholicrsquo
4 rsquoliver transplantationrsquo and rsquoglycochen-
odeoxycholicrsquo
5 rsquoliver transplantationrsquo and rsquoglycocholicrsquo
6 rsquoliver transplantationrsquo and rsquoglycodeoxy-
cholicrsquo
7 rsquoliver transplantationrsquo and rsquoglycolitho-
cholicrsquo
8 rsquoliver transplantationrsquo and rsquohyodeoxy-
cholicrsquo
9 rsquoliver transplantationrsquo and rsquolithocholicrsquo
10 rsquoliver transplantationrsquo and rsquotaurochen-
odeoxycholicrsquo
44Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
11 rsquoliver transplantationrsquo and rsquotauro-
cholicrsquo
12 rsquoliver transplantationrsquo and rsquotaurodehy-
drocholicrsquo
13 rsquoliver transplantationrsquo and rsquotau-
rodeoxycholicrsquo
14 rsquoliver transplantationrsquo and rsquotauroglyco-
cholicrsquo
15 rsquoliver transplantationrsquo and rsquotaurolitho-
cholicrsquo
16 rsquoliver transplantationrsquo and rsquotaurosel-
cholicrsquo
17 rsquoliver transplantationrsquo and rsquotaurourso-
cholicrsquo
18 rsquoliver transplantationrsquo and rsquotaurour-
sodeoxycholicrsquo
19 rsquoliver transplantationrsquo and rsquoursocholicrsquo
20 rsquoliver transplantationrsquo and rsquoursodeoxy-
cholicrsquo
The Cochrane Central Register of Con-
trolled Trials in The Cochrane Library
Issue 3 2009 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
6 3 or 4
7 5 and 6
MEDLINE September 2009 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
45Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
6 3 or 4
7 5 and 6
8 RANDOMIZED-CONTROLLED-
TRIAL ME
9 RANDOM
10 8 or 9
11 7 and 10
EMBASE September 2009 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
6 3 or 4
7 5 and 6
8 RANDOMIZED-CONTROLLED-
TRIAL ME
9 RANDOM
10 8 or 9
11 7 and 10
46Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
Science Citation Index Expanded September 2009 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
6 3 or 4
7 5 and 6
8 RANDOMIZED-CONTROLLED-
TRIAL ME
9 RANDOM
10 8 or 9
11 7 and 10
The Chinese Biomedical Database Searched from January 1980 to April 2002 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
47Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
6 3 or 4
7 5 and 6
8 RANDOMIZED-CONTROLLED-
TRIAL ME
9 RANDOM
10 8 or 9
11 7 and 10
W H A T rsquo S N E W
Last assessed as up-to-date 8 February 2010
18 September 2009 New citation required but conclusions have not
changed
This review is an updated version of a review that was
published for the first time in Issue 3 2005 of TheCochrane Library by Chen 2003b
18 September 2009 New search has been performed No new studies fulfilled the inclusion criteria
H I S T O R Y
Protocol first published Issue 3 2003
Review first published Issue 3 2005
C O N T R I B U T I O N S O F A U T H O R S
GP and VG independently performed searches of relevant databases GP validated the search selected trials for inclusion contacted
the authors of the trials performed data extraction and data analysis and drafted the systematic review VG revised the review update
CG and DS revised the review update solved discrepancies of data extraction validated data analyses and provided consultation
D E C L A R A T I O N S O F I N T E R E S T
None known
48Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
S O U R C E S O F S U P P O R T
Internal sources
bull Copenhagen Trial Unit Denmark
External sources
bull Danish Medical Research Councilrsquos Grant on Getting Research into Practice (GRIP) Denmark
D I F F E R E N C E S B E T W E E N P R O T O C O L A N D R E V I E W
We assessed the risk of bias in the included studies for another four domains that were added to the review protocol (incomplete
outcome data selective outcome reporting baseline imbalance and early stopping of trial) In general the text of the risk of bias
domains were updated following Higgins 2008 Trials were considered at low risk of bias when judged as adequate in all domains
Quasi-randomised studies observational and case-control studies were included for the report of adverse events
We performed trial sequential analysis for outcomes demonstrating a statistically significant result
I N D E X T E R M S
Medical Subject Headings (MeSH)
lowastLiver Transplantation Cholagogues and Choleretics [lowasttherapeutic use] Graft Rejection [lowastprevention amp control] Randomized Con-
trolled Trials as Topic Taurochenodeoxycholic Acid [lowasttherapeutic use] Ursodeoxycholic Acid [lowasttherapeutic use]
MeSH check words
Humans
49Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
prevent rejection after OLT Journal of Hepatology 199113(Suppl
2)68
References to studies excluded from this review
Assy 2007 published data only
Assy N Adams PC Myers P Simon V Minuk GY Wall W et
alRandomized controlled trial of total immunosuppression
withdrawal in liver transplant recipients role of ursodeoxycholic
acid Transplantation 200783(12)1571ndash6 [MEDLINE
17589339]
Clavien 1996 published data only
Clavien PA Sharara AI Camargo CA Jr Harland RC Fitz JG
Evidence that ursodeoxycholic acid prevents steroid-resistant
rejection in adult liver transplantation Clinical Transplantation
199610(6 Pt 2)658ndash62 [MEDLINE 8996761]
Friman 1992 published data only
Friman S Persson H Schersten T Svanvik J Karlberg I Adjuvant
treatment with ursodeoxycholic acid reduces acute rejection after
liver transplantation Transplantation Proceedings 199224(1)
389ndash90 [MEDLINE 1539328]
Heathcote 1999 published data onlylowast Heathcote EJ Stone J Cauch-Dudek K Poupon R Chazouilleres
O Lindor KD et alEffect of pretransplantation ursodeoxycholic
acid therapy on the outcome of liver transplantation in patients
with primary biliary cirrhosis Liver Transplantation and Surgery
19995(4)269ndash74 [MEDLINE 10388499]
Henriksson 1991 published data only
Henriksson BA Persson H Friman S Wangberg B Svanvik J
Karlberg I Adjuvant ursodeoxycholic acid prevents acute rejection
in liver transplant recipients Transplantation Proceedings 199123
(3)1971 [MEDLINE 2063453]
Persson 1990 published data only
Persson H Friman S Schersten T Svanvik J Karlberg I
Ursodeoxycholic acid for prevention of acute rejection in liver
transplant recipients Lancet 1990336(8706)52ndash3 [MEDLINE
1973232]
Rafael 1995 published data only
Rafael E Duraj F Rudstrom H Wilczek H Ericzon B Effect of
ursodeoxycholic acid treatment for cholestasis in liver transplant
recipients Transplantation Proceedings 199527(6)3501ndash2
[MEDLINE 8540069]
Sama 1998 published data only
Sama C Morselli-Labate AM Grazi GL Mastroianni A Danesi G
Pianta P et alUrsodeoxycholic acid in liver transplantation effect
on cholestasis and rejection Gastroenterology 1998114(4 Suppl)
A1332
Additional references
Adams 1990
Adams DH Neuberger JM Patterns of graft rejection following
liver transplantation Journal of Hepatology 199010(1)113ndash9
[MEDLINE 2407770]
Al-Quaiz 1994
Al-Quaiz M OrsquoGrady J Tredger J Williams R Variable effect of
ursodeoxycholic acid on cyclosporin absorption after orthotopic
liver transplantation Transplant International 19947(3)190ndash4
[MEDLINE 8060468]
Armstrong 1982
Armstrong MJ Carey MC The hydrophobic-hydrophilic balance
of bile salt Inverse correlation between reverse phase high
performance liquid chromatographic mobilities and micellar
cholesterol-solubilizing capacities Journal of Lipid Research 1982
23(1)70ndash80 [MEDLINE 7057113]
Ascher 1988
Ascher NL Stock PG Baumgardner GL Payne WD Najarian JS
Infection and rejection of primary hepatic transplant in 93
consecutive patients treated with triple immunosuppressive therapy
Surgery Gynecology amp Obstetrics 1988167(6)474ndash84
[MEDLINE 3055368]
Brok 2008
Brok J Thorlund K Gluud C Wetterslev J Trial sequential
analysis reveals insufficient information size and potentially false
positive results in many meta-analyses Journal of Clinical
Epidemiology 200861(8)763ndash9 [MEDLINE 18411040]
Brok 2009
Brok J Thorlund K Wetterslev J Gluud C Apparently conclusive
meta-analysis may be inconclusive - Trial sequential analysis
adjustment of random error risk due to repetitive testing of
accumulating data in apparently conclusive neonatal meta-analysis
International Journal of Epidemiology 200938(1)298ndash303
[MEDLINE 18824466]
Calmus 1990
Calmus Y Gane P Rouger P Poupon R Hepatic expression of class
I and class II major histocompatibility complex molecules in
primary biliary cirrhosis effect of ursodeoxycholic acid Hepatology
199011(1)12ndash5 [MEDLINE 2403961]
Calmus 1992
Calmus Y Arvieux C Gane P Boucher E Nordlinger B Rouger P
et alCholestasis induces major histocompatibility complex class I
expression in hepatocytes Gastroenterology 1992102(4 Pt 1)
1371ndash7 [MEDLINE 1551542]
Chen 2003a
Chen W Gluud C Bile acids for primary sclerosing cholangitis
Cochrane Database of Systematic Reviews 2003 Issue 2 [DOI
10100214651858CD003626]
Chen 2007
Chen W Liu J Gluud C Bile acids for viral hepatitis Cochrane
Database of Systematic Reviews 2007 Issue 4 [DOI 101002
14651858CD003181pub2]
Cheng 2002
Cheng K Ashby D Smyth R Ursodeoxycholic acid for cystic
fibrosis-related liver disease Cochrane Database of Systematic
Reviews 2002 Issue 2 [DOI 10100214651858CD000222]
Corbani 2008
Corbani A Burroughs AK Intrahepatic cholestasis after liver
transplantation Clinics in Liver Disease 200812(1)111ndash29
[MEDLINE 18242500]
DeMets 1987
DeMets DL Methods for combining randomised clinical trials
strengths and limitations Statistics in Medicine 19876(3)341ndash50
[MEDLINE 3616287]
15Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
DerSimonian 1986
DerSimonian R Laird N Meta-analysis in clinical trials Controlled
Clinical Trials 19867(3)177ndash88 [MEDLINE 3802833]
Egger 1997
Egger M Davey Smith G Schneider M Minder C Bias in meta-
analysis detected by a simple graphical test BMJ (Clinical Research
Ed) 1997315(7109)629ndash34 [MEDLINE 9310563]
Ericzon 1990
Ericzon BG Eusufzai S Kubota K Einarsson K Angelin B
Characteristics of biliary lipid metabolism after liver
transplantation Hepatology 199012(5)1222ndash8 [MEDLINE
2227822]
FK506 1994
The US Multicenter FK506 Liver Study Group A comparison of
tacrolimus (FK506) and cyclosporine for immunosuppression in
liver transplantation New England Journal of Medicine 1994331
(17)1110ndash5 [MEDLINE 7523946]
Friman 1994
Friman S Svanvik J A possible role of ursodeoxycholic acid in liver
transplantation Scandinavian Journal of Gastroenterology 1994204
62ndash4 [MEDLINE 7824880]
Fuchs 1999
Fuchs M Stange EF Metabolism of bile acids In Johannes
Bircher Jean-Pierre Benhamou Neil McIntyre Mario Rizzetto
Juan Rodes editor(s) Oxford Textbook of Clinical Hepatology 2
Vol 1 Oxford Oxford University Press 1999223ndash56
Fusai 2006
Fusai G Dhaliwal P Rolando N Sabin CA Patch D Davidson BR
et alIncidence and risk factors for the development of prolonged
and severe intrahepatic cholestasis after liver transplantation Liver
Transplantation 200612(11)1626ndash33 [DOI 101002lt20870]
Gluud 2001
Gluud C Alcoholic hepatitis no glucocorticosteroids In
Leuschner U James OFW Dancygier H editor(s) Steatohepatitis
(NASH and ASH) Falk Symposium 121 Lancaster Kluwer
Academic Publisher 2001322ndash42
Gluud 2010
Gluud C Nikolova D Klingenberg SL Alexakis N Als-Nielsen B
Colli A et alCochrane Hepato-Biliary Group About The
Cochrane Collaboration (Cochrane Review Groups (CRGs))
2010 Issue 1 Art No LIVER
Gong 2008
Gong Y Huang ZB Christiansen E Gluud C Ursodeoxycholic
acid for primary biliary cirrhosis Cochrane Database of Systematic
Reviews 2008 Issue 3 [DOI 101002
14651858CD000551pub2]
Haddad 2006
Haddad EM McAlister VC Renouf E Malthaner R Kjaer MS
Gluud LL Cyclosporin versus tacrolimus for liver transplanted
patients Cochrane Database of Systematic Reviews 2006 Issue 4
[DOI 10100214651858CD005161pub2]
Heuman 1993
Heuman DM Hepatoprotective properties of ursodeoxycholic acid
Gastroenterology 1993104(6)1865ndash9 [MEDLINE 8500748]
Higgins 2008
Higgins PTJ Green S editors Cochrane Handbook for Systematic
Reviews of Interventions West Sussex England Wiley-Blackwell
2008
Hirschfield 2009
Hirschfield GM Gibbs P Griffiths WJH Adult liver
transplantation what non-specialists need to know BMJ (Clinical
Research Ed) 2009338(b1670)1321ndash7 [DOI 101136
bmjb1670]
Hussain 2002
Hussain HK Nghiem HV Imaging of hepatic transplantation
Clinics in Liver Disease 20026(1)247ndash70 [MEDLINE
11933592]
ICH-GCP 1997
International Conference on Harmonisation Expert Working
Group Code of Federal Regulations amp International Conference on
Harmonization Guidelines Media Parexel Barnett 1997
Ioannidis 2001
Ioannidis JPA Lau J Evolution of treatment effects over time
Empirical insight from recursive cumulative meta analyses
Proceedings of the National Academy of Sciences 200198(3)831ndash6
IWP 1995
International Working Party Terminology for hepatic allograft
rejection Hepatology 199522(2)648ndash54 [MEDLINE 7635435]
Kjaergard 2001
Kjaergard LL Villumsen J Gluud C Reported methodological
quality and discrepancies between large and small randomised trials
in meta-analyses Annals of Internal Medicine 2001135(11)982ndash9
[MEDLINE 11730399]
Klintmalm 1989
Klintmalm GB Nery JR Husberg BS Gonwa TA Tillery GW
Rejection in liver transplantation Hepatology 198910(6)978ndash85
[MEDLINE 2583691]
Knechtle 2009
Knechtle SJ Kwun J Unique aspects of rejection and tolerance in
liver transplantation Seminars in Liver Disease 200929(1)91ndash101
[MEDLINE 19235662]
Krams 1993
Krams SM Ascher NL Martinez OM New immunologic insights
into mechanisms of allograft rejection Gastroenterology Clinics of
North America 199318(2)374ndash7 [MEDLINE 8509176]
Lan 1983
Lan KKG DeMets DL Discrete sequential boundaries for clinical
trials Biometrika 198370659ndash63
Merion 1989
Merion RM Gorski DH Burtch GD Turcotte JG Colletti LM
Campbell DA Jr Bile refeeding after liver transplantation and
avoidance of intravenous cyclosporine Surgery 1989106(4)
604ndash9 [MEDLINE 2799635]
Moher 1998
Moher D Pham B Jones A Cook DJ Jadad AR Moher M et
alDoes quality of reports of randomised trials affect estimates of
intervention efficacy reported in meta-analyses Lancet 1998352
(9128)609ndash13 [MEDLINE 9746022]
16Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Neuberger 1999
Neuberger J Incidence timing and risk factors for acute and
chronic rejection Liver Transplantation and Surgery 19995(4 Suppl
1)S30ndashS36 [MEDLINE 10431015]
Okolicsanyi 1986
Okolicsanyi L Lirussi F Strazzabosco M Jemmolo RM Orlando R
Nassuato G et alThe effect of drugs on bile flow and composition
An overview Drugs 198631(5)430ndash48 [MEDLINE 2872047]
Palmer 1972
Palmer RH Bile acids liver injury and liver disease Archives of
Internal Medicine 1972130(4)606ndash17 [MEDLINE 4627840]
Perez 2009
Perez MJ Briz O Bile-acid-induced cell injury and protection
World Journal of Gastroenterology 200915(14)1677ndash89
[MEDLINE 19360911]
Pogue 1997
Pogue JM Yusuf S Cumulating evidence from randomized trials
Utilizing sequential monitoring boundaries for cumulative meta-
analysis Controlled Clinical Trials 199718(6)580ndash93
[MEDLINE 9408720]
Pogue 1998
Pogue J Yusuf S Overcoming the limitations of current meta-
analysis of randomised controlled trials Lancet 1998351(9095)
45ndash52 [MEDLINE 9433436]
RevMan 2008
The Nordic Cochrane Centre The Cochrane Collaboration
Review Manager (RevMan) 50 Copenhagen The Nordic
Cochrane Centre The Cochrane Collaboration 2008
Royle 2003
Royle P Milne R Literature searching for randomized controlled
trials used in Cochrane reviews rapid versus exhaustive searches
International Journal of Technology Assessment in Health Care 2003
19(4)591ndash603
Schulz 1995
Schulz KF Chalmers I Hayer R Altman D Empirical evidence of
bias JAMA 1995273(5)408ndash12 [MEDLINE 7823387]
Sharara 1995
Sharara AI Camargo CA Clavien PA Ursodeoxycholic acid
prevents steroid resistant rejection in liver transplant recipients
Gastroenterology 1995108A1168
Sholmerich 1984
Sholmerich J Becher MS Schmidt KH Schubert R Kremer B
Felhaus S et alInfluence of hydroxylation and conjugation of bile
salts on their membrane damaging properties Hepatology 19844
(4)661ndash7 [MEDLINE 6745854]
Soderdahl 1998
Soderdahl G Nowak G Duraj F Wang FH Einarsson C Ericzon
BG Ursodeoxycholic acid increased bile flow and affects bile
composition in the early postoperative phase following liver
transplantation Transplantation International 199811(Suppl 1)
S231ndashS238 [MEDLINE 9664985]
Terasaki 1991
Terasaki S Nakanuma Y Ogino H Unoura M Kobayashi K
Hepatocellular and biliary expression of HLA antigens in primary
biliary cirrhosis before and after ursodeoxycholic acid therapy
American Journal of Gastroenterology 199186(9)1194ndash9
[MEDLINE 1882800]
Thalheimer 2002
Thalheimer U Capra F Liver transplantation making the best out
of what we have Digestive Diseases and Sciences 200247(5)
945ndash53 [MEDLINE 12018919]
Thorlund 2009
Thorlund K Devereaux PJ Wetterslev J Guyatt G Ioannidis JP
Thabane L et alCan trial sequential monitoring boundaries reduce
spurious inferences from meta-analyses International Journal of
Epidemiology 200938(1)276ndash86 [MEDLINE 18824467]
Thuluvath 2003
Thuluvath PJ Yoo HY Thompson RE A model to predict survival
at one month one year and five years after liver transplantation
based on pretransplant clinical characteristics Liver Transplantation
20039(5)527ndash32 [MEDLINE 12740799]
van den Berg 1998
van den Berg AP Twilhaar WN Mesander G van Son WJ van der
Bij W Klompmaker IJ et alQuantitation of immunosuppression
by flow cytometric measurement of the capacity of T cells for
interleukin-2 production Transplantation 199865(8)1066ndash71
[MEDLINE 9583867]
Vierling 1992
Vierling J Immunologic mechanisms of hepatic allograft rejection
Seminars in Liver Disease 199212(1)16ndash27 [MEDLINE
1570548]
Wetterslev 2008
Wetterslev J Thorlund K Brok J Gluud C Trial sequential
analysis may establish when firm evidence is reached in cumulative
meta-analysis Journal of Clinical Epidemiology 200861(1)64ndash75
[MEDLINE 18083463]
Wiesner 1992
Wiesner RH Acute cellular rejection following liver
transplantation incidence risk factors and outcome in the
NIDDK Liver Transplant Database (LTD) study Gastroenterology
1992102A910
Wood 2008
Wood L Egger M Gluud LL Schulz KF Juni P Altman DG et
alEmpirical evidence of bias in treatment effect estimates in
controlled trials with different interventions and outcomes meta-
epidemiological study BMJ (Clinical Research Ed) 2008336
(7644)601ndash5 [MEDLINE 18316340]
Yoshikawa 1998
Yoshikawa M Matsui Y Kawamoto H Toyohara M Matsumura
K Yamao J et alIntragastric administration of ursodeoxycholic
acid suppresses immunoglobulin secretion by lymphocytes from
liver but not from peripheral blood spleen or Peyerrsquos patches in
mice International Journal of Immunopharmacology 199820(1-3)
29ndash38 [MEDLINE 9717080]
References to other published versions of this review
17Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Chen 2003b
Chen W Gluud C Bile acids for liver transplanted patients
Cochrane Database of Systematic Reviews 2005 Issue 3 [DOI
10100214651858CD005442]lowast Indicates the major publication for the study
18Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
C H A R A C T E R I S T I C S O F S T U D I E S
Characteristics of included studies [ordered by study ID]
Angelico 1999
Methods Study design open-label randomised one-year pilot study
Participants Country Italy
Publication language English
Inclusion criteria
- patients who underwent liver transplantation from April 1994 to December 1994
Exclusion criteria
- not mentioned
Participants
Two patients in TUDCA group and two patients in control group were excluded from
the basic information of participants by the study due to withdrawal
- TUDCA group (n = 14)
Mean age (years +- SD)
467 +- 84
Ratio of sex (malefemale) 122
Origins of liver diseases
hepatitis C cirrhosis (9) hepatitis B cirrhosis (2) hepatitis B and C cirrhosis (1) cryp-
togenic cirrhosis (2) alcoholic cirrhosis (0) Wilson cirrhosis (0)
- Control group (n = 15)
Mean age (years +- SD)
474 +- 74
Ratio of sex (malefemale) 123
Origins of liver diseases
hepatitis C cirrhosis (7) hepatitis B cirrhosis (2) hepatitis B and C cirrhosis (2) cryp-
togenic cirrhosis (2) alcoholic cirrhosis (1) Wilson cirrhosis (1)
Interventions TUDCA group
- Dose 500 mgday in two divided doses
- Route orally
- Duration the treatment was started on day 5 after transplantation and continued for
one year
Control group
- no treatment
Co-interventions all patients received standard triple-drug regimens (steroids azathio-
prine and cyclosporine or tacrolimus)
Outcomes All cause mortality
Number of patients with rejection after liver transplantation
Notes Letter was sent to the authors in September 2009 A reply with additional information
was received shortly after
Risk of bias
19Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Angelico 1999 (Continued)
Item Authorsrsquo judgement Description
Adequate sequence generation Yes Computer generated table
Allocation concealment Unclear No information provided
Blinding No Not performed
Incomplete outcome data addressed
All outcomes
Yes Withdrawal two patients from the
TUDCA group and two patients from the
placebo group Three of them died due to
transplant non-function in the first postop-
erative week and one patient was regrafted
due to thrombosis of hepatic artery
Free of selective reporting Unclear Post-transplant cholestasis and liver bio-
chemistry specified as outcomes Differ-
ence reported as not significant but no ac-
tual data given
Sample size calculation No Not reported
Intention-to-treat analysis No Not stated and not used
Baseline imbalance Unclear Not enough information provided
Early stopping of trial Unclear Not enough information provided
Barnes 1997
Methods Study design randomised placebo-controlled double-blind trial
Participants Country United States
Publication language English
Inclusion criteria
- patients aged 18 years or older who underwent liver transplantation at the Cleveland
Clinic Foundation from April 1992 through June of 1994
Exclusion criteria
- patients who were found to have cancer at surgically resected margins of the biliary
tree
- patents who underwent retransplantation
Participants
- UDCA group (n = 28)
Mean age (years +- SD)
505 +- 116
Ratio of sex (malefemale) 1810
Child class A 7
20Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Barnes 1997 (Continued)
B 13
and C 8
Origins of liver diseases Laennecrsquos cirrhosis 4
PBC 3
cryptogenic cirrhosis 6
hepatitis Ccirrhosis 4
hepatitis Bcirrhosis 3
autoimmune hepatitis with cirrhosis 3
PSC 2
other 3
- Placebo group (n = 24)
Mean age (years +- SD)
507 +- 93
Ratio of sex (malefemale) 159
Child class A 6
B 14
and C 4
Origins of liver diseases Laennecrsquos cirrhosis 9
PBC 5
cryptogenic cirrhosis 1
hepatitis Ccirrhosis 1
hepatitis Bcirrhosis 1
autoimmune hepatitis with cirrhosis 1
PSC 2
other 4
Interventions UDCA group
- Dose 10-15 mgkg body weightday in divided doses
- Route orally
- Duration immediately after intestinal transit recovery usually between postoperative
days three and five and continue for three months
Placebo group
- identical-appearing capsules administered in the same quantity and manner
Co-interventions all patients received standard triple-drug regimens (steroids azathio-
prine and cyclosporine or tacrolimus)
Outcomes All cause mortality
Number of patients with acute cellular rejection
Number of patients with chronic rejection
Number of patients with steroid-resistant rejection
Number of days of hospitalisation
Adverse events
Notes Letter was sent to the authors in September 2009 A reply with additional information
was received shortly after
Risk of bias
Item Authorsrsquo judgement Description
21Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Barnes 1997 (Continued)
Adequate sequence generation Yes Computer generated table
Allocation concealment Unclear No information provided
Blinding Yes Quote ldquorandomised to receive either
UDCA or an identical placebo capsulerdquo
Incomplete outcome data addressed
All outcomes
Yes Mean follow-up time 18 months Ten pa-
tients withdrawn from study 6 in UDCA
group and 4 in placebo group Reasons
for withdrawal were reported Four patients
died in the placebo group
Free of selective reporting Yes All expected outcomes reported
Sample size calculation Unclear The trial reported the method of sample
size calculation but the actual number of
patients needed was not reported
Intention-to-treat analysis Yes Stated and used
Baseline imbalance Unclear Not enough information provided
Early stopping of trial Unclear The number of patients needed to gain the
actual power was not reported Whether
the trial was terminated early is not clear
Fleckenstein 1998
Methods Study design prospective randomised double-blind trial
Participants Country United States
Publication language English
Inclusion criteria
- patients who underwent liver transplantation at the Johns Hopkins Hospital
Exclusion criteria
- patients who were under 18 years old undergoing repeat transplantation had primary
graft nonfunction or refused consent
Participants
- UDCA group (n = 14)
Mean age (years +- SD)
443 +- 127
Ratio of sex (malefemale) 68
Origins of liver diseases hepatitis C 6
alcohol 2
autoimmune 1
PBC 2
22Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Fleckenstein 1998 (Continued)
PSC 1
autoimmune cholangiopathy 1
hepatitis B 1
- Placebo group (n = 16)
Mean age (years +- SD)
496 +- 109
Ratio of sex (malefemale) 124
Origins of liver diseases hepatitis C 3
alcohol 3
autoimmune 3
PBC 1
PSC 2
cryptogenic 2
hepatitis B 1
alpha1-antitrypsin deficiency 1
Interventions UDCA group
- Dose 15 mgkg body weightday in divided doses
- Route orally
- Duration immediately after intestinal transit recovery usually between postoperative
days three and five and continue for three months
Placebo group
- Identical-appearing capsules administered in the same quantity and manner
Co-interventions all patients received standard triple-drug regimens (steroids azathio-
prine and cyclosporine or tacrolimus)
Outcomes All cause mortality
Number with retransplantation
Number of patients with acute cellular rejection
Number of patients with chronic rejection
Serum bilirubin levels at the end of treatment
Notes Follow-up time nine months
Letter was sent to the authors in September 2009 No reply was received
Risk of bias
Item Authorsrsquo judgement Description
Adequate sequence generation Unclear No information provided
Allocation concealment Unclear No information provided
Blinding Yes Method of blinding not described but
probably adequate
Incomplete outcome data addressed
All outcomes
Yes Withdrawal one patient from the UDCA
group and two patients from the placebo
group because of capsule size
23Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Fleckenstein 1998 (Continued)
Free of selective reporting Unclear Outcomes were not completely described
Sample size calculation No Not reported
Intention-to-treat analysis Yes Quote ldquoThree patients withdrew after in-
clusionThey were included in the statis-
tical analysisrdquo
Baseline imbalance Unclear Not enough information provided
Early stopping of trial Unclear Not enough information provided
Keiding 1997
Methods Study design prospective randomised placebo-controlled multicenter study
Participants Country Denmark Finland Norway and Sweden
Publication language English
Inclusion criteria
- patients who underwent liver transplantation in Denmark Finland Norway and Swe-
den from September 1 1992 to May 31 1994
Exclusion criteria
- patients with malignant diseases
Participants
The age of the children ranged from 0 to 13 years (median 15) and the age of adults
ranged from 14 to 59 years old (median 44) MaleFemale ratio was 96 for children and
4344 for adults
- UDCA group (n = 54)
Origins of liver diseases
paracetamol intoxication 1 hepatitis B 1 autoimmune hepatitis 0 biliary atresia 2
metabolic diseases 7 neonatal hepatitis 2 PBC 13 post hepatitis cirrhosis 8 PSC 3
cryptogenic cirrhosis 7 alcoholic cirrhosis 2 other reasons 8
- Placebo group (n = 48)
Origins of liver diseases paracetamol intoxication 1 hepatitis B 0 autoimmune hepatitis
1 biliary atresia 3 metabolic diseases 11 neonatal hepatitis 0 PBC 7 post hepatitis
cirrhosis 5 PSC 7 cryptogenic cirrhosis 2 alcoholic cirrhosis 6 other reasons 5
Interventions UDCA group
- Dose 15 mgkg body weightday in two or three divided doses
- Route orally
- Duration immediately after intestinal transit recovery usually between postoperative
days three and five and continue for three months
Placebo group
- Identical-appearing capsules administered in the same quantity and manner
Co-interventions all patients received standard triple-drug regimens (steroids azathio-
prine and cyclosporine or tacrolimus)
24Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Keiding 1997 (Continued)
Outcomes All cause mortality
Number of deaths related to rejection
Number of patients with acute cellular rejection
Number of patients with chronic rejection
Number of patients with steroid-resistant rejection
Adverse events
Notes Letter was sent to the authors in September 2009 No reply was received
Risk of bias
Item Authorsrsquo judgement Description
Adequate sequence generation Unclear Patients were randomised at a ratio of 11
Allocation concealment Yes Quote ldquo The allocation was performed in
blocks of 10 patients using the sealed serial
envelope methodrdquo
Blinding Yes Quote ldquoThe UDCA and the placebo cap-
sules had identical appearance and tasterdquo
Incomplete outcome data addressed
All outcomes
Yes Follow-up time 12 months Five UDCA
patients and five placebo patients withdrew
from study Reasons were reported
Free of selective reporting Unclear Insufficient information
Sample size calculation Yes Performed and allowed for a difference in
the incidence of at least one episode of
acute rejection of 50 between the treat-
ment and placebo groups with 90 statisti-
cal power and a significance level of P value
less than 005 The calculated sample size
was 80 patients
Intention-to-treat analysis Yes Stated and used
Baseline imbalance Yes The study seems to be free of baseline im-
balance
Early stopping of trial Yes Study attained the pre-specified sample
size
25Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Koneru 1993
Methods Study design randomised controlled trial
Participants Country United States
Publication language English
Inclusion criteria
- patients who underwent liver transplantation
Exclusion criteria
- not mentioned
Participants
- UDCA group (n = 16)
Mean age (years +- SD)
no information
Ratio of sex (malefemale) no information
Origins of liver diseases
no information
- Control group (n = 16)
Mean age (years +- SD)
no information
Ratio of sex (malefemale) no information
Origins of liver diseases
no information
Interventions UDCA group
- Dose 900 mgday
- Route orally
- Duration immediately after intestinal transit recovery usually between postoperative
days three and five and continue for three months
Control group
- no treatment
Co-interventions all patients received standard triple-drug regimens (steroids azathio-
prine and cyclosporine)
Outcomes Number of patients with retransplantation due to rejection
Number of patients with rejection episodes
Notes Abstract
Letter was sent to the authors in September 2009 No reply was received
Risk of bias
Item Authorsrsquo judgement Description
Adequate sequence generation Unclear No information provided
Allocation concealment Unclear No information provided
Blinding No Not performed
26Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Koneru 1993 (Continued)
Incomplete outcome data addressed
All outcomes
Unclear The study gives the impression that there
were no withdrawals but this was not ex-
plicitly stated
Free of selective reporting Unclear Insufficient information provided
Sample size calculation No Not performed
Intention-to-treat analysis Unclear No information provided
Baseline imbalance Unclear Not enough information provided
Early stopping of trial Unclear Not enough information provided
Pageaux 1995
Methods Study design double-blind randomised study
Participants Country France
Publication language English
Inclusion criteria
- patients who underwent liver transplantation
Exclusion criteria
- not mentioned
Participants
- UDCA group (n=26)
Mean age (years +- SD)
47 +- 10
Ratio of sex (malefemale) 179
Origins of liver diseases alcoholic cirrhosis 14
post-hepatic B cirrhosis 2
post-hepatitis C cirrhosis 4
PBC 2
liver cancer 2
fulminant hepatitis 1
miscellaneous 1
- Placebo group (n = 24)
Mean age (years +- SD)
51+- 9
Ratio of sex (malefemale) 159
Origins of liver diseases alcoholic cirrhosis 10
post-hepatic B cirrhosis 0
post-hepatic C cirrhosis 6
PBC 3
liver cancer 4
fulminant hepatitis 0
miscellaneous 1
27Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Pageaux 1995 (Continued)
Interventions UDCA group
- Dose 600 mgday in three divided doses
- Route orally
- Duration immediately after intestinal transit recovery usually between postoperative
days three and five and continue for two months
Placebo group
- identical-appearing capsules administered in the same quantity and manner
Co-interventions all patients received standard triple-drug regimens (steroids azathio-
prine and cyclosporine or tacrolimus)
Outcomes Number of patients with acute cellular rejection
Number of patients with steroid-resistant rejection
Notes Letter was sent to the authors in September 2009 No reply was received
Risk of bias
Item Authorsrsquo judgement Description
Adequate sequence generation Unclear No information provided
Allocation concealment Unclear No information provided
Blinding Unclear Method of blinding not described
Incomplete outcome data addressed
All outcomes
Yes Five patients died from non-immunologi-
cal causes before the end of the first month
and were excluded from the study Reasons
were reported
Free of selective reporting Unclear Not enough information provided
Sample size calculation No Not performed
Intention-to-treat analysis No Not stated and not used
Baseline imbalance Unclear Not enough information provided
Early stopping of trial Unclear Not enough information provided
Sama 1991
Methods Study design randomised controlled trial
Participants Country Italy
Publication language English
Inclusion criteria
28Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Sama 1991 (Continued)
- patients who underwent liver transplantation
Exclusion criteria
- not mentioned
Participants
- UDCA group (n = 20)
Mean age (years +- SD)
no information
Ratio of sex (malefemale) no information
Origins of liver diseases
no information
- Control group (n = 20)
Mean age (years +- SD)
no information
Ratio of sex (malefemale) no information
Origins of liver diseases
no information
Interventions UDCA group
- Dose 600 mgday in two divided doses
- Route orally
- Duration immediately after intestinal transit recovery usually between postoperative
day five and day seven and continue for six months
Control group
- no treatment
Co-interventions all patients received standard immunosuppressive treatment (steroids
and cyclosporine)
Outcomes All cause mortality
Number of patients with acute cellular rejection
Notes Abstract
Letter was sent to the authors in September 2009 No reply was received
Risk of bias
Item Authorsrsquo judgement Description
Adequate sequence generation Unclear A randomisation list was performed before
patients were admitted to the trial (infor-
mation from principal author)
Allocation concealment Unclear No information provided
Blinding Unclear The principle author provided information
that the study was made according to a
single-blind randomised protocol The pri-
mary outcome was the occurrence of biopsy
proven rejection episodes The pathologists
were blind but the patients were not
29Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Sama 1991 (Continued)
Incomplete outcome data addressed
All outcomes
Unclear Five patients from the UDCA group and
six patients from the placebo group were
excluded Reasons for exclusion were not
fully stated
Free of selective reporting No Data about survival of patients were not
adequately reported
Sample size calculation No Not performed
Intention-to-treat analysis No Not stated and not used
Baseline imbalance Unclear Basic characteristics of patients not re-
ported
Early stopping of trial Unclear Not enough information provided
UDCA = ursodeoxycholic acid
TUDCA = tauroursodeoxycholic acid
PBC = primary biliary cirrhosis
PSC = primary sclerosing cholangitis
OKT3 = anti-CD3 monoclonal antibody
Characteristics of excluded studies [ordered by study ID]
Assy 2007 A randomised controlled trial that included only recipients of liver transplantation with stable graft function and
no episodes of rejection for at least 2 years that were then offered total immunosuppression withdrawal Fourteen
patients received UDCA (15 mgkg body weightday) and 12 received placebo Rejection occurred in 43 and
75 of patients respectively (no significant difference) None developed chronic rejection After follow-up two
patients were free of immunosuppression 80 were steroid free and 50 were able to reduce their dose of
cyclosporine
Clavien 1996 Case series Fifty consecutive liver-transplanted patients were treated with a standard cyclosporine immunosup-
pressive regimen Twenty three of the 43 survivors developed an episode of rejection and UDCA (10 mgkg
weightday) was initiated Only one patient had a second episode of rejection
Friman 1992 Observational study Thirty-three liver-transplanted patients received 10 mg UDCAkg body weightday for
median of 10 months (range four to 21 months) Eight historical liver-transplanted patients served as control
group The rejection incidence was significantly lower in the patients who received the treatment with UDCA
Biochemistry one month after transplantation demonstrated significantly lower average values of aminotrans-
ferases and alkaline phosphatases in patients treated with UDCA than in the control group
30Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
Heathcote 1999 Observational study From 1987 to 1996 37 UDCA treated and 53 placebo treated patients with primary biliary
cirrhosis were referred for transplantation Posttransplantation survival rates at one month were 939 in the
UDCA group and 884 in the placebo group and one year survival rates were 903 and 784 respectively
(no significant differences) However rejection (type not defined - a secondary outcome measure) occurred
significantly less often in the UDCA group (429) than in placebo group (688)
Henriksson 1991 Observational study All patients in this study were given sequential quadruple immunosuppression with anti-
lymphocyte globulin azathioprine steroids and cyclosporine All patients with primary graft function (n = 11)
were treated with 10 mg UDCAkg body weightday starting during the first postoperative week Patients who
received liver transplantation in the first 6 months of 1989 (n = 8) served as controls In the control group one
patient died after 9 months with chronic graft dysfunction and six patients had rejection episodes during the
first postoperative month All patients in the UDCA group were alive without rejection episodes
Persson 1990 Observational study All 11 adult patients transplanted between August 1989 and January 1990 with primary
graft function were treated with 10 mg UDCA kg body weightday Eight patients transplanted during the first
half of 1989 served as control UDCA was started during the first postoperative week and the treatment was
continued for six months All patients in the UDCA treated group survived with satisfactory graft function In
the control group six patients had at least one rejection episode needing treatment during the first postoperative
month
Rafael 1995 Observational study Seventeen patients who underwent liver transplantation between February 1990 and April
1993 and developed biliary complications after transplantation were retrospectively analysed regarding treatment
with UDCA UDCA was given in a dose of 500 to 1000 mgday Ten patients were treated for at least one year while
seven patients were treated for 14 to 250 days UDCA significantly improved gammaglutamyl transpeptidase in
liver graft recipients with biliary complications There was also a trend towards improvement in serum bilirubin
and alanine transaminase values
Sama 1998 Observational study Thirty-four patients who underwent liver transplantation between January 1995 and June
1996 were included in the study Seventeen were treated with UDCA 10 mgkg body weightday during 6
months while 17 served as controls on the basis of having undergone liver transplantation closest to UDCA
patients A significant decrease in serum bilirubin levels was observed in UDCA patients There was a significantly
higher incidence of recurrent hepatitis in the control group
UDCA ursodeoxycholic acid
31Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
D A T A A N D A N A L Y S E S
Comparison 1 Bile acids for liver-transplanted patients
Outcome or subgroup titleNo of
studies
No of
participants Statistical method Effect size
1 All-cause mortality at maximum
follow-up
5 257 Risk Ratio (M-H Fixed 95 CI) 085 [053 136]
11 UDCA versus placebo or
no treatment
4 224 Risk Ratio (M-H Fixed 95 CI) 080 [049 130]
12 TUDCA versus no
treatment
1 33 Risk Ratio (M-H Fixed 95 CI) 159 [030 833]
2 All-cause mortality worst-best
case and best-worst case
scenarios
5 Risk Ratio (M-H Fixed 95 CI) Subtotals only
21 Worst-best case scenario 5 257 Risk Ratio (M-H Fixed 95 CI) 130 [086 196]
22 Best-worst case scenario 5 257 Risk Ratio (M-H Fixed 95 CI) 058 [038 090]
3 Subgroup analyses all-cause
mortality at maximum
follow-up according to time of
start of bile acids
5 257 Risk Ratio (M-H Fixed 95 CI) 085 [053 136]
31 Less than three days after
transplantation
1 102 Risk Ratio (M-H Fixed 95 CI) 124 [061 254]
32 Three days or more after
transplantation
4 155 Risk Ratio (M-H Fixed 95 CI) 063 [033 120]
4 Subgroup analyses all cause
mortality at maximum
follow-up according to
treatment duration
5 257 Risk Ratio (M-H Fixed 95 CI) 085 [053 136]
41 Less than six months 3 184 Risk Ratio (M-H Fixed 95 CI) 078 [045 138]
42 Six months or more 2 73 Risk Ratio (M-H Fixed 95 CI) 102 [043 240]
5 Number of deaths related
to rejection at maximum
follow-up
1 102 Risk Ratio (M-H Fixed 95 CI) 030 [001 712]
51 UDCA versus placebo 1 102 Risk Ratio (M-H Fixed 95 CI) 030 [001 712]
6 Number of retransplantations at
maximum follow-up
2 132 Risk Ratio (M-H Fixed 95 CI) 076 [020 286]
7 Number of patients with acute
cellular rejection at maximum
follow-up
7 339 Risk Ratio (M-H Fixed 95 CI) 089 [074 106]
71 UDCA versus placebo or
no treatment
6 306 Risk Ratio (M-H Fixed 95 CI) 089 [074 108]
72 TUDCA versus no
treatment
1 33 Risk Ratio (M-H Fixed 95 CI) 085 [045 160]
8 Subgroup analysis number of
patients with acute cellular
rejection according to time of
start of bile acid
7 339 Risk Ratio (M-H Fixed 95 CI) 089 [074 106]
32Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
81 Less than three days after
transplantation
2 134 Risk Ratio (M-H Fixed 95 CI) 084 [063 111]
82 Three days or more after
liver transplantation
5 205 Risk Ratio (M-H Fixed 95 CI) 092 [072 117]
9 Subgroup analysis number
of patients with acute
cellular rejection according to
treatment duration
7 339 Risk Ratio (M-H Fixed 95 CI) 089 [074 106]
91 Less than six months 5 266 Risk Ratio (M-H Fixed 95 CI) 087 [071 107]
92 Six months or more 2 73 Risk Ratio (M-H Fixed 95 CI) 094 [065 136]
10 Number of patients with
chronic rejection at maximum
follow-up
3 184 Risk Ratio (M-H Fixed 95 CI) 028 [008 095]
11 Number of patients with
steroid-resistant rejection at
maximum follow-up
4 234 Risk Ratio (M-H Fixed 95 CI) 077 [047 127]
12 Serum bilirubin (mgdl) at the
end of treatment
1 30 Mean Difference (IV Fixed 95 CI) 26 [-096 616]
13 Number of days of
hospitalisation after liver
transplantation
1 52 Mean Difference (IV Fixed 95 CI) -85 [-1667 -033]
14 Adverse events 3 187 Risk Ratio (M-H Fixed 95 CI) 088 [030 260]
Analysis 11 Comparison 1 Bile acids for liver-transplanted patients Outcome 1 All-cause mortality at
maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 1 All-cause mortality at maximum follow-up
Study or subgroup Favours bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 UDCA versus placebo or no treatment
Barnes 1997 228 724 253 024 [ 006 107 ]
Fleckenstein 1998 214 416 125 057 [ 012 266 ]
Keiding 1997 1454 1048 355 124 [ 061 254 ]
Sama 1991 520 620 201 083 [ 030 229 ]
Subtotal (95 CI) 116 108 935 080 [ 049 130 ]
Total events 23 (Favours bile acids) 27 (Control)
Heterogeneity Chi2 = 416 df = 3 (P = 025) I2 =28
Test for overall effect Z = 091 (P = 036)
01 02 05 1 2 5 10
Favours bile acids Favours control
(Continued )
33Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Favours bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
2 TUDCA versus no treatment
Angelico 1999 316 217 65 159 [ 030 833 ]
Subtotal (95 CI) 16 17 65 159 [ 030 833 ]
Total events 3 (Favours bile acids) 2 (Control)
Heterogeneity not applicable
Test for overall effect Z = 055 (P = 058)
Total (95 CI) 132 125 1000 085 [ 053 136 ]
Total events 26 (Favours bile acids) 29 (Control)
Heterogeneity Chi2 = 466 df = 4 (P = 032) I2 =14
Test for overall effect Z = 069 (P = 049)
01 02 05 1 2 5 10
Favours bile acids Favours control
Analysis 12 Comparison 1 Bile acids for liver-transplanted patients Outcome 2 All-cause mortality worst-
best case and best-worst case scenarios
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 2 All-cause mortality worst-best case and best-worst case scenarios
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 Worst-best case scenario
Angelico 1999 516 217 65 266 [ 060 1180 ]
Barnes 1997 828 724 253 098 [ 042 230 ]
Fleckenstein 1998 314 416 125 086 [ 023 319 ]
Keiding 1997 1954 1048 355 169 [ 087 327 ]
Sama 1991 520 620 201 083 [ 030 229 ]
Subtotal (95 CI) 132 125 1000 130 [ 086 196 ]
Total events 40 (Bile acids) 29 (Control)
Heterogeneity Chi2 = 303 df = 4 (P = 055) I2 =00
Test for overall effect Z = 123 (P = 022)
2 Best-worst case scenario
005 02 1 5 20
Favours bile acids Favours control
(Continued )
34Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Angelico 1999 316 417 90 080 [ 021 302 ]
Barnes 1997 228 1124 274 016 [ 004 063 ]
Fleckenstein 1998 214 616 130 038 [ 009 159 ]
Keiding 1997 1454 1548 368 083 [ 045 154 ]
Sama 1991 520 620 139 083 [ 030 229 ]
Subtotal (95 CI) 132 125 1000 058 [ 038 090 ]
Total events 26 (Bile acids) 42 (Control)
Heterogeneity Chi2 = 567 df = 4 (P = 023) I2 =29
Test for overall effect Z = 247 (P = 0014)
005 02 1 5 20
Favours bile acids Favours control
Analysis 13 Comparison 1 Bile acids for liver-transplanted patients Outcome 3 Subgroup analyses all-
cause mortality at maximum follow-up according to time of start of bile acids
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 3 Subgroup analyses all-cause mortality at maximum follow-up according to time of start of bile acids
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 Less than three days after transplantation
Keiding 1997 1454 1048 355 124 [ 061 254 ]
Subtotal (95 CI) 54 48 355 124 [ 061 254 ]
Total events 14 (Bile acids) 10 (Control)
Heterogeneity not applicable
Test for overall effect Z = 060 (P = 055)
2 Three days or more after transplantation
Angelico 1999 316 217 65 159 [ 030 833 ]
Barnes 1997 228 724 253 024 [ 006 107 ]
Fleckenstein 1998 214 416 125 057 [ 012 266 ]
Sama 1991 520 620 201 083 [ 030 229 ]
005 02 1 5 20
Favours bile acids Favours control
(Continued )
35Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Subtotal (95 CI) 78 77 645 063 [ 033 120 ]
Total events 12 (Bile acids) 19 (Control)
Heterogeneity Chi2 = 310 df = 3 (P = 038) I2 =3
Test for overall effect Z = 141 (P = 016)
Total (95 CI) 132 125 1000 085 [ 053 136 ]
Total events 26 (Bile acids) 29 (Control)
Heterogeneity Chi2 = 466 df = 4 (P = 032) I2 =14
Test for overall effect Z = 069 (P = 049)
005 02 1 5 20
Favours bile acids Favours control
Analysis 14 Comparison 1 Bile acids for liver-transplanted patients Outcome 4 Subgroup analyses all
cause mortality at maximum follow-up according to treatment duration
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 4 Subgroup analyses all cause mortality at maximum follow-up according to treatment duration
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 Less than six months
Barnes 1997 228 724 253 024 [ 006 107 ]
Fleckenstein 1998 214 416 125 057 [ 012 266 ]
Keiding 1997 1454 1048 355 124 [ 061 254 ]
Subtotal (95 CI) 96 88 734 078 [ 045 138 ]
Total events 18 (Bile acids) 21 (Control)
Heterogeneity Chi2 = 417 df = 2 (P = 012) I2 =52
Test for overall effect Z = 084 (P = 040)
2 Six months or more
Angelico 1999 316 217 65 159 [ 030 833 ]
Sama 1991 520 620 201 083 [ 030 229 ]
Subtotal (95 CI) 36 37 266 102 [ 043 240 ]
Total events 8 (Bile acids) 8 (Control)
Heterogeneity Chi2 = 043 df = 1 (P = 051) I2 =00
005 02 1 5 20
Favours bile acids Favours control
(Continued )
36Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Test for overall effect Z = 004 (P = 097)
Total (95 CI) 132 125 1000 085 [ 053 136 ]
Total events 26 (Bile acids) 29 (Control)
Heterogeneity Chi2 = 466 df = 4 (P = 032) I2 =14
Test for overall effect Z = 069 (P = 049)
005 02 1 5 20
Favours bile acids Favours control
Analysis 15 Comparison 1 Bile acids for liver-transplanted patients Outcome 5 Number of deaths related
to rejection at maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 5 Number of deaths related to rejection at maximum follow-up
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 UDCA versus placebo
Keiding 1997 054 148 1000 030 [ 001 712 ]
Total (95 CI) 54 48 1000 030 [ 001 712 ]
Total events 0 (Bile acids) 1 (Control)
Heterogeneity not applicable
Test for overall effect Z = 075 (P = 045)
0001 001 01 1 10 100 1000
Favours bile acids Favours control
37Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 16 Comparison 1 Bile acids for liver-transplanted patients Outcome 6 Number of
retransplantations at maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 6 Number of retransplantations at maximum follow-up
Study or subgroup Bile acids Placebo Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Fleckenstein 1998 214 016 100 567 [ 029 10891 ]
Keiding 1997 154 448 900 022 [ 003 192 ]
Total (95 CI) 68 64 1000 076 [ 020 286 ]
Total events 3 (Bile acids) 4 (Placebo)
Heterogeneity Chi2 = 303 df = 1 (P = 008) I2 =67
Test for overall effect Z = 040 (P = 069)
0001 001 01 1 10 100 1000
Favours bile acids Favours placebo
Analysis 17 Comparison 1 Bile acids for liver-transplanted patients Outcome 7 Number of patients with
acute cellular rejection at maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 7 Number of patients with acute cellular rejection at maximum follow-up
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 UDCA versus placebo or no treatment
Barnes 1997 1728 1724 180 086 [ 058 127 ]
Fleckenstein 1998 814 916 83 102 [ 054 190 ]
Keiding 1997 3554 3248 333 097 [ 073 129 ]
Koneru 1993 316 916 89 033 [ 011 101 ]
Pageaux 1995 926 924 92 092 [ 044 193 ]
Sama 1991 1320 1320 128 100 [ 063 158 ]
Subtotal (95 CI) 158 148 905 089 [ 074 108 ]
01 02 05 1 2 5 10
Favours bile acids Favours control
(Continued )
38Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Total events 85 (Bile acids) 89 (Control)
Heterogeneity Chi2 = 387 df = 5 (P = 057) I2 =00
Test for overall effect Z = 120 (P = 023)
2 TUDCA versus no treatment
Angelico 1999 816 1017 95 085 [ 045 160 ]
Subtotal (95 CI) 16 17 95 085 [ 045 160 ]
Total events 8 (Bile acids) 10 (Control)
Heterogeneity not applicable
Test for overall effect Z = 050 (P = 061)
Total (95 CI) 174 165 1000 089 [ 074 106 ]
Total events 93 (Bile acids) 99 (Control)
Heterogeneity Chi2 = 392 df = 6 (P = 069) I2 =00
Test for overall effect Z = 130 (P = 019)
01 02 05 1 2 5 10
Favours bile acids Favours control
Analysis 18 Comparison 1 Bile acids for liver-transplanted patients Outcome 8 Subgroup analysis
number of patients with acute cellular rejection according to time of start of bile acid
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 8 Subgroup analysis number of patients with acute cellular rejection according to time of start of bile acid
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 Less than three days after transplantation
Keiding 1997 3554 3248 333 097 [ 073 129 ]
Koneru 1993 316 916 89 033 [ 011 101 ]
Subtotal (95 CI) 70 64 422 084 [ 063 111 ]
Total events 38 (Bile acids) 41 (Control)
Heterogeneity Chi2 = 374 df = 1 (P = 005) I2 =73
Test for overall effect Z = 124 (P = 022)
2 Three days or more after liver transplantation
Angelico 1999 816 1017 95 085 [ 045 160 ]
01 02 05 1 2 5 10
Favours bile acids Favours control
(Continued )
39Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Barnes 1997 1728 1724 180 086 [ 058 127 ]
Fleckenstein 1998 814 916 83 102 [ 054 190 ]
Pageaux 1995 926 924 92 092 [ 044 193 ]
Sama 1991 1320 1320 128 100 [ 063 158 ]
Subtotal (95 CI) 104 101 578 092 [ 072 117 ]
Total events 55 (Bile acids) 58 (Control)
Heterogeneity Chi2 = 041 df = 4 (P = 098) I2 =00
Test for overall effect Z = 067 (P = 050)
Total (95 CI) 174 165 1000 089 [ 074 106 ]
Total events 93 (Bile acids) 99 (Control)
Heterogeneity Chi2 = 392 df = 6 (P = 069) I2 =00
Test for overall effect Z = 130 (P = 019)
01 02 05 1 2 5 10
Favours bile acids Favours control
40Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 19 Comparison 1 Bile acids for liver-transplanted patients Outcome 9 Subgroup analysis
number of patients with acute cellular rejection according to treatment duration
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 9 Subgroup analysis number of patients with acute cellular rejection according to treatment duration
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 Less than six months
Barnes 1997 1728 1724 180 086 [ 058 127 ]
Fleckenstein 1998 814 916 83 102 [ 054 190 ]
Keiding 1997 3554 3248 333 097 [ 073 129 ]
Koneru 1993 316 916 89 033 [ 011 101 ]
Pageaux 1995 926 924 92 092 [ 044 193 ]
Subtotal (95 CI) 138 128 777 087 [ 071 107 ]
Total events 72 (Bile acids) 76 (Control)
Heterogeneity Chi2 = 374 df = 4 (P = 044) I2 =00
Test for overall effect Z = 129 (P = 020)
2 Six months or more
Angelico 1999 816 1017 95 085 [ 045 160 ]
Sama 1991 1320 1320 128 100 [ 063 158 ]
Subtotal (95 CI) 36 37 223 094 [ 065 136 ]
Total events 21 (Bile acids) 23 (Control)
Heterogeneity Chi2 = 017 df = 1 (P = 068) I2 =00
Test for overall effect Z = 035 (P = 073)
Total (95 CI) 174 165 1000 089 [ 074 106 ]
Total events 93 (Bile acids) 99 (Control)
Heterogeneity Chi2 = 392 df = 6 (P = 069) I2 =00
Test for overall effect Z = 130 (P = 019)
01 02 05 1 2 5 10
Favours bile acids Favours control
41Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 110 Comparison 1 Bile acids for liver-transplanted patients Outcome 10 Number of patients
with chronic rejection at maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 10 Number of patients with chronic rejection at maximum follow-up
Study or subgroup Bile acids Placebo Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Barnes 1997 128 624 611 014 [ 002 110 ]
Fleckenstein 1998 114 116 88 114 [ 008 1663 ]
Keiding 1997 154 348 300 030 [ 003 275 ]
Total (95 CI) 96 88 1000 028 [ 008 095 ]
Total events 3 (Bile acids) 10 (Placebo)
Heterogeneity Chi2 = 148 df = 2 (P = 048) I2 =00
Test for overall effect Z = 204 (P = 0041)
0001 001 01 1 10 100 1000
Favours bile acids Favours placebo
Analysis 111 Comparison 1 Bile acids for liver-transplanted patients Outcome 11 Number of patients
with steroid-resistant rejection at maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 11 Number of patients with steroid-resistant rejection at maximum follow-up
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Barnes 1997 328 724 277 037 [ 011 127 ]
Fleckenstein 1998 314 316 103 114 [ 027 478 ]
Keiding 1997 1454 1548 583 083 [ 045 154 ]
Pageaux 1995 226 124 38 185 [ 018 1908 ]
Total (95 CI) 122 112 1000 077 [ 047 127 ]
Total events 22 (Bile acids) 26 (Control)
Heterogeneity Chi2 = 226 df = 3 (P = 052) I2 =00
Test for overall effect Z = 102 (P = 031)
001 01 1 10 100
Favours bile acids Favours placebo
42Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 112 Comparison 1 Bile acids for liver-transplanted patients Outcome 12 Serum bilirubin (mgdl)
at the end of treatment
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 12 Serum bilirubin (mgdl) at the end of treatment
Study or subgroup Bile acids Placebo Mean Difference Weight Mean Difference
N Mean(SD) N Mean(SD) IVFixed95 CI IVFixed95 CI
Fleckenstein 1998 14 319 (68) 16 059 (022) 1000 260 [ -096 616 ]
Total (95 CI) 14 16 1000 260 [ -096 616 ]
Heterogeneity not applicable
Test for overall effect Z = 143 (P = 015)
-10 -5 0 5 10
Favours bile acids Favours placebo
Analysis 113 Comparison 1 Bile acids for liver-transplanted patients Outcome 13 Number of days of
hospitalisation after liver transplantation
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 13 Number of days of hospitalisation after liver transplantation
Study or subgroup Bile acids Placebo Mean Difference Weight Mean Difference
N Mean(SD) N Mean(SD) IVFixed95 CI IVFixed95 CI
Barnes 1997 28 25 (17) 24 335 (13) 1000 -850 [ -1667 -033 ]
Total (95 CI) 28 24 1000 -850 [ -1667 -033 ]
Heterogeneity not applicable
Test for overall effect Z = 204 (P = 0041)
-100 -50 0 50 100
Favours bile acids Favours placebo
43Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 114 Comparison 1 Bile acids for liver-transplanted patients Outcome 14 Adverse events
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 14 Adverse events
Study or subgroup Bile acids Placebo Risk Ratio Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Angelico 1999 016 017 00 [ 00 00 ]
Barnes 1997 128 124 086 [ 006 1298 ]
Keiding 1997 554 548 089 [ 027 288 ]
Total (95 CI) 98 89 088 [ 030 260 ]
Total events 6 (Bile acids) 6 (Placebo)
Heterogeneity Chi2 = 000 df = 1 (P = 098) I2 =00
Test for overall effect Z = 022 (P = 082)
001 01 1 10 100
Favours bile acids Favours placebo
A P P E N D I C E S
Appendix 1 Search strategies
Data Base Date of Search Search Strategy
The Cochrane Hepato-Biliary Group Con-
trolled Trials Register
September 2009 1 rsquoliver transplantationrsquo and rsquochenodeoxy-
cholicrsquo
2 rsquoliver transplantationrsquo and rsquocholicrsquo
3 rsquoliver transplantationrsquo and rsquodeoxycholicrsquo
4 rsquoliver transplantationrsquo and rsquoglycochen-
odeoxycholicrsquo
5 rsquoliver transplantationrsquo and rsquoglycocholicrsquo
6 rsquoliver transplantationrsquo and rsquoglycodeoxy-
cholicrsquo
7 rsquoliver transplantationrsquo and rsquoglycolitho-
cholicrsquo
8 rsquoliver transplantationrsquo and rsquohyodeoxy-
cholicrsquo
9 rsquoliver transplantationrsquo and rsquolithocholicrsquo
10 rsquoliver transplantationrsquo and rsquotaurochen-
odeoxycholicrsquo
44Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
11 rsquoliver transplantationrsquo and rsquotauro-
cholicrsquo
12 rsquoliver transplantationrsquo and rsquotaurodehy-
drocholicrsquo
13 rsquoliver transplantationrsquo and rsquotau-
rodeoxycholicrsquo
14 rsquoliver transplantationrsquo and rsquotauroglyco-
cholicrsquo
15 rsquoliver transplantationrsquo and rsquotaurolitho-
cholicrsquo
16 rsquoliver transplantationrsquo and rsquotaurosel-
cholicrsquo
17 rsquoliver transplantationrsquo and rsquotaurourso-
cholicrsquo
18 rsquoliver transplantationrsquo and rsquotaurour-
sodeoxycholicrsquo
19 rsquoliver transplantationrsquo and rsquoursocholicrsquo
20 rsquoliver transplantationrsquo and rsquoursodeoxy-
cholicrsquo
The Cochrane Central Register of Con-
trolled Trials in The Cochrane Library
Issue 3 2009 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
6 3 or 4
7 5 and 6
MEDLINE September 2009 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
45Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
6 3 or 4
7 5 and 6
8 RANDOMIZED-CONTROLLED-
TRIAL ME
9 RANDOM
10 8 or 9
11 7 and 10
EMBASE September 2009 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
6 3 or 4
7 5 and 6
8 RANDOMIZED-CONTROLLED-
TRIAL ME
9 RANDOM
10 8 or 9
11 7 and 10
46Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
Science Citation Index Expanded September 2009 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
6 3 or 4
7 5 and 6
8 RANDOMIZED-CONTROLLED-
TRIAL ME
9 RANDOM
10 8 or 9
11 7 and 10
The Chinese Biomedical Database Searched from January 1980 to April 2002 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
47Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
6 3 or 4
7 5 and 6
8 RANDOMIZED-CONTROLLED-
TRIAL ME
9 RANDOM
10 8 or 9
11 7 and 10
W H A T rsquo S N E W
Last assessed as up-to-date 8 February 2010
18 September 2009 New citation required but conclusions have not
changed
This review is an updated version of a review that was
published for the first time in Issue 3 2005 of TheCochrane Library by Chen 2003b
18 September 2009 New search has been performed No new studies fulfilled the inclusion criteria
H I S T O R Y
Protocol first published Issue 3 2003
Review first published Issue 3 2005
C O N T R I B U T I O N S O F A U T H O R S
GP and VG independently performed searches of relevant databases GP validated the search selected trials for inclusion contacted
the authors of the trials performed data extraction and data analysis and drafted the systematic review VG revised the review update
CG and DS revised the review update solved discrepancies of data extraction validated data analyses and provided consultation
D E C L A R A T I O N S O F I N T E R E S T
None known
48Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
S O U R C E S O F S U P P O R T
Internal sources
bull Copenhagen Trial Unit Denmark
External sources
bull Danish Medical Research Councilrsquos Grant on Getting Research into Practice (GRIP) Denmark
D I F F E R E N C E S B E T W E E N P R O T O C O L A N D R E V I E W
We assessed the risk of bias in the included studies for another four domains that were added to the review protocol (incomplete
outcome data selective outcome reporting baseline imbalance and early stopping of trial) In general the text of the risk of bias
domains were updated following Higgins 2008 Trials were considered at low risk of bias when judged as adequate in all domains
Quasi-randomised studies observational and case-control studies were included for the report of adverse events
We performed trial sequential analysis for outcomes demonstrating a statistically significant result
I N D E X T E R M S
Medical Subject Headings (MeSH)
lowastLiver Transplantation Cholagogues and Choleretics [lowasttherapeutic use] Graft Rejection [lowastprevention amp control] Randomized Con-
trolled Trials as Topic Taurochenodeoxycholic Acid [lowasttherapeutic use] Ursodeoxycholic Acid [lowasttherapeutic use]
MeSH check words
Humans
49Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
DerSimonian 1986
DerSimonian R Laird N Meta-analysis in clinical trials Controlled
Clinical Trials 19867(3)177ndash88 [MEDLINE 3802833]
Egger 1997
Egger M Davey Smith G Schneider M Minder C Bias in meta-
analysis detected by a simple graphical test BMJ (Clinical Research
Ed) 1997315(7109)629ndash34 [MEDLINE 9310563]
Ericzon 1990
Ericzon BG Eusufzai S Kubota K Einarsson K Angelin B
Characteristics of biliary lipid metabolism after liver
transplantation Hepatology 199012(5)1222ndash8 [MEDLINE
2227822]
FK506 1994
The US Multicenter FK506 Liver Study Group A comparison of
tacrolimus (FK506) and cyclosporine for immunosuppression in
liver transplantation New England Journal of Medicine 1994331
(17)1110ndash5 [MEDLINE 7523946]
Friman 1994
Friman S Svanvik J A possible role of ursodeoxycholic acid in liver
transplantation Scandinavian Journal of Gastroenterology 1994204
62ndash4 [MEDLINE 7824880]
Fuchs 1999
Fuchs M Stange EF Metabolism of bile acids In Johannes
Bircher Jean-Pierre Benhamou Neil McIntyre Mario Rizzetto
Juan Rodes editor(s) Oxford Textbook of Clinical Hepatology 2
Vol 1 Oxford Oxford University Press 1999223ndash56
Fusai 2006
Fusai G Dhaliwal P Rolando N Sabin CA Patch D Davidson BR
et alIncidence and risk factors for the development of prolonged
and severe intrahepatic cholestasis after liver transplantation Liver
Transplantation 200612(11)1626ndash33 [DOI 101002lt20870]
Gluud 2001
Gluud C Alcoholic hepatitis no glucocorticosteroids In
Leuschner U James OFW Dancygier H editor(s) Steatohepatitis
(NASH and ASH) Falk Symposium 121 Lancaster Kluwer
Academic Publisher 2001322ndash42
Gluud 2010
Gluud C Nikolova D Klingenberg SL Alexakis N Als-Nielsen B
Colli A et alCochrane Hepato-Biliary Group About The
Cochrane Collaboration (Cochrane Review Groups (CRGs))
2010 Issue 1 Art No LIVER
Gong 2008
Gong Y Huang ZB Christiansen E Gluud C Ursodeoxycholic
acid for primary biliary cirrhosis Cochrane Database of Systematic
Reviews 2008 Issue 3 [DOI 101002
14651858CD000551pub2]
Haddad 2006
Haddad EM McAlister VC Renouf E Malthaner R Kjaer MS
Gluud LL Cyclosporin versus tacrolimus for liver transplanted
patients Cochrane Database of Systematic Reviews 2006 Issue 4
[DOI 10100214651858CD005161pub2]
Heuman 1993
Heuman DM Hepatoprotective properties of ursodeoxycholic acid
Gastroenterology 1993104(6)1865ndash9 [MEDLINE 8500748]
Higgins 2008
Higgins PTJ Green S editors Cochrane Handbook for Systematic
Reviews of Interventions West Sussex England Wiley-Blackwell
2008
Hirschfield 2009
Hirschfield GM Gibbs P Griffiths WJH Adult liver
transplantation what non-specialists need to know BMJ (Clinical
Research Ed) 2009338(b1670)1321ndash7 [DOI 101136
bmjb1670]
Hussain 2002
Hussain HK Nghiem HV Imaging of hepatic transplantation
Clinics in Liver Disease 20026(1)247ndash70 [MEDLINE
11933592]
ICH-GCP 1997
International Conference on Harmonisation Expert Working
Group Code of Federal Regulations amp International Conference on
Harmonization Guidelines Media Parexel Barnett 1997
Ioannidis 2001
Ioannidis JPA Lau J Evolution of treatment effects over time
Empirical insight from recursive cumulative meta analyses
Proceedings of the National Academy of Sciences 200198(3)831ndash6
IWP 1995
International Working Party Terminology for hepatic allograft
rejection Hepatology 199522(2)648ndash54 [MEDLINE 7635435]
Kjaergard 2001
Kjaergard LL Villumsen J Gluud C Reported methodological
quality and discrepancies between large and small randomised trials
in meta-analyses Annals of Internal Medicine 2001135(11)982ndash9
[MEDLINE 11730399]
Klintmalm 1989
Klintmalm GB Nery JR Husberg BS Gonwa TA Tillery GW
Rejection in liver transplantation Hepatology 198910(6)978ndash85
[MEDLINE 2583691]
Knechtle 2009
Knechtle SJ Kwun J Unique aspects of rejection and tolerance in
liver transplantation Seminars in Liver Disease 200929(1)91ndash101
[MEDLINE 19235662]
Krams 1993
Krams SM Ascher NL Martinez OM New immunologic insights
into mechanisms of allograft rejection Gastroenterology Clinics of
North America 199318(2)374ndash7 [MEDLINE 8509176]
Lan 1983
Lan KKG DeMets DL Discrete sequential boundaries for clinical
trials Biometrika 198370659ndash63
Merion 1989
Merion RM Gorski DH Burtch GD Turcotte JG Colletti LM
Campbell DA Jr Bile refeeding after liver transplantation and
avoidance of intravenous cyclosporine Surgery 1989106(4)
604ndash9 [MEDLINE 2799635]
Moher 1998
Moher D Pham B Jones A Cook DJ Jadad AR Moher M et
alDoes quality of reports of randomised trials affect estimates of
intervention efficacy reported in meta-analyses Lancet 1998352
(9128)609ndash13 [MEDLINE 9746022]
16Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Neuberger 1999
Neuberger J Incidence timing and risk factors for acute and
chronic rejection Liver Transplantation and Surgery 19995(4 Suppl
1)S30ndashS36 [MEDLINE 10431015]
Okolicsanyi 1986
Okolicsanyi L Lirussi F Strazzabosco M Jemmolo RM Orlando R
Nassuato G et alThe effect of drugs on bile flow and composition
An overview Drugs 198631(5)430ndash48 [MEDLINE 2872047]
Palmer 1972
Palmer RH Bile acids liver injury and liver disease Archives of
Internal Medicine 1972130(4)606ndash17 [MEDLINE 4627840]
Perez 2009
Perez MJ Briz O Bile-acid-induced cell injury and protection
World Journal of Gastroenterology 200915(14)1677ndash89
[MEDLINE 19360911]
Pogue 1997
Pogue JM Yusuf S Cumulating evidence from randomized trials
Utilizing sequential monitoring boundaries for cumulative meta-
analysis Controlled Clinical Trials 199718(6)580ndash93
[MEDLINE 9408720]
Pogue 1998
Pogue J Yusuf S Overcoming the limitations of current meta-
analysis of randomised controlled trials Lancet 1998351(9095)
45ndash52 [MEDLINE 9433436]
RevMan 2008
The Nordic Cochrane Centre The Cochrane Collaboration
Review Manager (RevMan) 50 Copenhagen The Nordic
Cochrane Centre The Cochrane Collaboration 2008
Royle 2003
Royle P Milne R Literature searching for randomized controlled
trials used in Cochrane reviews rapid versus exhaustive searches
International Journal of Technology Assessment in Health Care 2003
19(4)591ndash603
Schulz 1995
Schulz KF Chalmers I Hayer R Altman D Empirical evidence of
bias JAMA 1995273(5)408ndash12 [MEDLINE 7823387]
Sharara 1995
Sharara AI Camargo CA Clavien PA Ursodeoxycholic acid
prevents steroid resistant rejection in liver transplant recipients
Gastroenterology 1995108A1168
Sholmerich 1984
Sholmerich J Becher MS Schmidt KH Schubert R Kremer B
Felhaus S et alInfluence of hydroxylation and conjugation of bile
salts on their membrane damaging properties Hepatology 19844
(4)661ndash7 [MEDLINE 6745854]
Soderdahl 1998
Soderdahl G Nowak G Duraj F Wang FH Einarsson C Ericzon
BG Ursodeoxycholic acid increased bile flow and affects bile
composition in the early postoperative phase following liver
transplantation Transplantation International 199811(Suppl 1)
S231ndashS238 [MEDLINE 9664985]
Terasaki 1991
Terasaki S Nakanuma Y Ogino H Unoura M Kobayashi K
Hepatocellular and biliary expression of HLA antigens in primary
biliary cirrhosis before and after ursodeoxycholic acid therapy
American Journal of Gastroenterology 199186(9)1194ndash9
[MEDLINE 1882800]
Thalheimer 2002
Thalheimer U Capra F Liver transplantation making the best out
of what we have Digestive Diseases and Sciences 200247(5)
945ndash53 [MEDLINE 12018919]
Thorlund 2009
Thorlund K Devereaux PJ Wetterslev J Guyatt G Ioannidis JP
Thabane L et alCan trial sequential monitoring boundaries reduce
spurious inferences from meta-analyses International Journal of
Epidemiology 200938(1)276ndash86 [MEDLINE 18824467]
Thuluvath 2003
Thuluvath PJ Yoo HY Thompson RE A model to predict survival
at one month one year and five years after liver transplantation
based on pretransplant clinical characteristics Liver Transplantation
20039(5)527ndash32 [MEDLINE 12740799]
van den Berg 1998
van den Berg AP Twilhaar WN Mesander G van Son WJ van der
Bij W Klompmaker IJ et alQuantitation of immunosuppression
by flow cytometric measurement of the capacity of T cells for
interleukin-2 production Transplantation 199865(8)1066ndash71
[MEDLINE 9583867]
Vierling 1992
Vierling J Immunologic mechanisms of hepatic allograft rejection
Seminars in Liver Disease 199212(1)16ndash27 [MEDLINE
1570548]
Wetterslev 2008
Wetterslev J Thorlund K Brok J Gluud C Trial sequential
analysis may establish when firm evidence is reached in cumulative
meta-analysis Journal of Clinical Epidemiology 200861(1)64ndash75
[MEDLINE 18083463]
Wiesner 1992
Wiesner RH Acute cellular rejection following liver
transplantation incidence risk factors and outcome in the
NIDDK Liver Transplant Database (LTD) study Gastroenterology
1992102A910
Wood 2008
Wood L Egger M Gluud LL Schulz KF Juni P Altman DG et
alEmpirical evidence of bias in treatment effect estimates in
controlled trials with different interventions and outcomes meta-
epidemiological study BMJ (Clinical Research Ed) 2008336
(7644)601ndash5 [MEDLINE 18316340]
Yoshikawa 1998
Yoshikawa M Matsui Y Kawamoto H Toyohara M Matsumura
K Yamao J et alIntragastric administration of ursodeoxycholic
acid suppresses immunoglobulin secretion by lymphocytes from
liver but not from peripheral blood spleen or Peyerrsquos patches in
mice International Journal of Immunopharmacology 199820(1-3)
29ndash38 [MEDLINE 9717080]
References to other published versions of this review
17Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Chen 2003b
Chen W Gluud C Bile acids for liver transplanted patients
Cochrane Database of Systematic Reviews 2005 Issue 3 [DOI
10100214651858CD005442]lowast Indicates the major publication for the study
18Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
C H A R A C T E R I S T I C S O F S T U D I E S
Characteristics of included studies [ordered by study ID]
Angelico 1999
Methods Study design open-label randomised one-year pilot study
Participants Country Italy
Publication language English
Inclusion criteria
- patients who underwent liver transplantation from April 1994 to December 1994
Exclusion criteria
- not mentioned
Participants
Two patients in TUDCA group and two patients in control group were excluded from
the basic information of participants by the study due to withdrawal
- TUDCA group (n = 14)
Mean age (years +- SD)
467 +- 84
Ratio of sex (malefemale) 122
Origins of liver diseases
hepatitis C cirrhosis (9) hepatitis B cirrhosis (2) hepatitis B and C cirrhosis (1) cryp-
togenic cirrhosis (2) alcoholic cirrhosis (0) Wilson cirrhosis (0)
- Control group (n = 15)
Mean age (years +- SD)
474 +- 74
Ratio of sex (malefemale) 123
Origins of liver diseases
hepatitis C cirrhosis (7) hepatitis B cirrhosis (2) hepatitis B and C cirrhosis (2) cryp-
togenic cirrhosis (2) alcoholic cirrhosis (1) Wilson cirrhosis (1)
Interventions TUDCA group
- Dose 500 mgday in two divided doses
- Route orally
- Duration the treatment was started on day 5 after transplantation and continued for
one year
Control group
- no treatment
Co-interventions all patients received standard triple-drug regimens (steroids azathio-
prine and cyclosporine or tacrolimus)
Outcomes All cause mortality
Number of patients with rejection after liver transplantation
Notes Letter was sent to the authors in September 2009 A reply with additional information
was received shortly after
Risk of bias
19Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Angelico 1999 (Continued)
Item Authorsrsquo judgement Description
Adequate sequence generation Yes Computer generated table
Allocation concealment Unclear No information provided
Blinding No Not performed
Incomplete outcome data addressed
All outcomes
Yes Withdrawal two patients from the
TUDCA group and two patients from the
placebo group Three of them died due to
transplant non-function in the first postop-
erative week and one patient was regrafted
due to thrombosis of hepatic artery
Free of selective reporting Unclear Post-transplant cholestasis and liver bio-
chemistry specified as outcomes Differ-
ence reported as not significant but no ac-
tual data given
Sample size calculation No Not reported
Intention-to-treat analysis No Not stated and not used
Baseline imbalance Unclear Not enough information provided
Early stopping of trial Unclear Not enough information provided
Barnes 1997
Methods Study design randomised placebo-controlled double-blind trial
Participants Country United States
Publication language English
Inclusion criteria
- patients aged 18 years or older who underwent liver transplantation at the Cleveland
Clinic Foundation from April 1992 through June of 1994
Exclusion criteria
- patients who were found to have cancer at surgically resected margins of the biliary
tree
- patents who underwent retransplantation
Participants
- UDCA group (n = 28)
Mean age (years +- SD)
505 +- 116
Ratio of sex (malefemale) 1810
Child class A 7
20Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Barnes 1997 (Continued)
B 13
and C 8
Origins of liver diseases Laennecrsquos cirrhosis 4
PBC 3
cryptogenic cirrhosis 6
hepatitis Ccirrhosis 4
hepatitis Bcirrhosis 3
autoimmune hepatitis with cirrhosis 3
PSC 2
other 3
- Placebo group (n = 24)
Mean age (years +- SD)
507 +- 93
Ratio of sex (malefemale) 159
Child class A 6
B 14
and C 4
Origins of liver diseases Laennecrsquos cirrhosis 9
PBC 5
cryptogenic cirrhosis 1
hepatitis Ccirrhosis 1
hepatitis Bcirrhosis 1
autoimmune hepatitis with cirrhosis 1
PSC 2
other 4
Interventions UDCA group
- Dose 10-15 mgkg body weightday in divided doses
- Route orally
- Duration immediately after intestinal transit recovery usually between postoperative
days three and five and continue for three months
Placebo group
- identical-appearing capsules administered in the same quantity and manner
Co-interventions all patients received standard triple-drug regimens (steroids azathio-
prine and cyclosporine or tacrolimus)
Outcomes All cause mortality
Number of patients with acute cellular rejection
Number of patients with chronic rejection
Number of patients with steroid-resistant rejection
Number of days of hospitalisation
Adverse events
Notes Letter was sent to the authors in September 2009 A reply with additional information
was received shortly after
Risk of bias
Item Authorsrsquo judgement Description
21Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Barnes 1997 (Continued)
Adequate sequence generation Yes Computer generated table
Allocation concealment Unclear No information provided
Blinding Yes Quote ldquorandomised to receive either
UDCA or an identical placebo capsulerdquo
Incomplete outcome data addressed
All outcomes
Yes Mean follow-up time 18 months Ten pa-
tients withdrawn from study 6 in UDCA
group and 4 in placebo group Reasons
for withdrawal were reported Four patients
died in the placebo group
Free of selective reporting Yes All expected outcomes reported
Sample size calculation Unclear The trial reported the method of sample
size calculation but the actual number of
patients needed was not reported
Intention-to-treat analysis Yes Stated and used
Baseline imbalance Unclear Not enough information provided
Early stopping of trial Unclear The number of patients needed to gain the
actual power was not reported Whether
the trial was terminated early is not clear
Fleckenstein 1998
Methods Study design prospective randomised double-blind trial
Participants Country United States
Publication language English
Inclusion criteria
- patients who underwent liver transplantation at the Johns Hopkins Hospital
Exclusion criteria
- patients who were under 18 years old undergoing repeat transplantation had primary
graft nonfunction or refused consent
Participants
- UDCA group (n = 14)
Mean age (years +- SD)
443 +- 127
Ratio of sex (malefemale) 68
Origins of liver diseases hepatitis C 6
alcohol 2
autoimmune 1
PBC 2
22Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Fleckenstein 1998 (Continued)
PSC 1
autoimmune cholangiopathy 1
hepatitis B 1
- Placebo group (n = 16)
Mean age (years +- SD)
496 +- 109
Ratio of sex (malefemale) 124
Origins of liver diseases hepatitis C 3
alcohol 3
autoimmune 3
PBC 1
PSC 2
cryptogenic 2
hepatitis B 1
alpha1-antitrypsin deficiency 1
Interventions UDCA group
- Dose 15 mgkg body weightday in divided doses
- Route orally
- Duration immediately after intestinal transit recovery usually between postoperative
days three and five and continue for three months
Placebo group
- Identical-appearing capsules administered in the same quantity and manner
Co-interventions all patients received standard triple-drug regimens (steroids azathio-
prine and cyclosporine or tacrolimus)
Outcomes All cause mortality
Number with retransplantation
Number of patients with acute cellular rejection
Number of patients with chronic rejection
Serum bilirubin levels at the end of treatment
Notes Follow-up time nine months
Letter was sent to the authors in September 2009 No reply was received
Risk of bias
Item Authorsrsquo judgement Description
Adequate sequence generation Unclear No information provided
Allocation concealment Unclear No information provided
Blinding Yes Method of blinding not described but
probably adequate
Incomplete outcome data addressed
All outcomes
Yes Withdrawal one patient from the UDCA
group and two patients from the placebo
group because of capsule size
23Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Fleckenstein 1998 (Continued)
Free of selective reporting Unclear Outcomes were not completely described
Sample size calculation No Not reported
Intention-to-treat analysis Yes Quote ldquoThree patients withdrew after in-
clusionThey were included in the statis-
tical analysisrdquo
Baseline imbalance Unclear Not enough information provided
Early stopping of trial Unclear Not enough information provided
Keiding 1997
Methods Study design prospective randomised placebo-controlled multicenter study
Participants Country Denmark Finland Norway and Sweden
Publication language English
Inclusion criteria
- patients who underwent liver transplantation in Denmark Finland Norway and Swe-
den from September 1 1992 to May 31 1994
Exclusion criteria
- patients with malignant diseases
Participants
The age of the children ranged from 0 to 13 years (median 15) and the age of adults
ranged from 14 to 59 years old (median 44) MaleFemale ratio was 96 for children and
4344 for adults
- UDCA group (n = 54)
Origins of liver diseases
paracetamol intoxication 1 hepatitis B 1 autoimmune hepatitis 0 biliary atresia 2
metabolic diseases 7 neonatal hepatitis 2 PBC 13 post hepatitis cirrhosis 8 PSC 3
cryptogenic cirrhosis 7 alcoholic cirrhosis 2 other reasons 8
- Placebo group (n = 48)
Origins of liver diseases paracetamol intoxication 1 hepatitis B 0 autoimmune hepatitis
1 biliary atresia 3 metabolic diseases 11 neonatal hepatitis 0 PBC 7 post hepatitis
cirrhosis 5 PSC 7 cryptogenic cirrhosis 2 alcoholic cirrhosis 6 other reasons 5
Interventions UDCA group
- Dose 15 mgkg body weightday in two or three divided doses
- Route orally
- Duration immediately after intestinal transit recovery usually between postoperative
days three and five and continue for three months
Placebo group
- Identical-appearing capsules administered in the same quantity and manner
Co-interventions all patients received standard triple-drug regimens (steroids azathio-
prine and cyclosporine or tacrolimus)
24Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Keiding 1997 (Continued)
Outcomes All cause mortality
Number of deaths related to rejection
Number of patients with acute cellular rejection
Number of patients with chronic rejection
Number of patients with steroid-resistant rejection
Adverse events
Notes Letter was sent to the authors in September 2009 No reply was received
Risk of bias
Item Authorsrsquo judgement Description
Adequate sequence generation Unclear Patients were randomised at a ratio of 11
Allocation concealment Yes Quote ldquo The allocation was performed in
blocks of 10 patients using the sealed serial
envelope methodrdquo
Blinding Yes Quote ldquoThe UDCA and the placebo cap-
sules had identical appearance and tasterdquo
Incomplete outcome data addressed
All outcomes
Yes Follow-up time 12 months Five UDCA
patients and five placebo patients withdrew
from study Reasons were reported
Free of selective reporting Unclear Insufficient information
Sample size calculation Yes Performed and allowed for a difference in
the incidence of at least one episode of
acute rejection of 50 between the treat-
ment and placebo groups with 90 statisti-
cal power and a significance level of P value
less than 005 The calculated sample size
was 80 patients
Intention-to-treat analysis Yes Stated and used
Baseline imbalance Yes The study seems to be free of baseline im-
balance
Early stopping of trial Yes Study attained the pre-specified sample
size
25Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Koneru 1993
Methods Study design randomised controlled trial
Participants Country United States
Publication language English
Inclusion criteria
- patients who underwent liver transplantation
Exclusion criteria
- not mentioned
Participants
- UDCA group (n = 16)
Mean age (years +- SD)
no information
Ratio of sex (malefemale) no information
Origins of liver diseases
no information
- Control group (n = 16)
Mean age (years +- SD)
no information
Ratio of sex (malefemale) no information
Origins of liver diseases
no information
Interventions UDCA group
- Dose 900 mgday
- Route orally
- Duration immediately after intestinal transit recovery usually between postoperative
days three and five and continue for three months
Control group
- no treatment
Co-interventions all patients received standard triple-drug regimens (steroids azathio-
prine and cyclosporine)
Outcomes Number of patients with retransplantation due to rejection
Number of patients with rejection episodes
Notes Abstract
Letter was sent to the authors in September 2009 No reply was received
Risk of bias
Item Authorsrsquo judgement Description
Adequate sequence generation Unclear No information provided
Allocation concealment Unclear No information provided
Blinding No Not performed
26Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Koneru 1993 (Continued)
Incomplete outcome data addressed
All outcomes
Unclear The study gives the impression that there
were no withdrawals but this was not ex-
plicitly stated
Free of selective reporting Unclear Insufficient information provided
Sample size calculation No Not performed
Intention-to-treat analysis Unclear No information provided
Baseline imbalance Unclear Not enough information provided
Early stopping of trial Unclear Not enough information provided
Pageaux 1995
Methods Study design double-blind randomised study
Participants Country France
Publication language English
Inclusion criteria
- patients who underwent liver transplantation
Exclusion criteria
- not mentioned
Participants
- UDCA group (n=26)
Mean age (years +- SD)
47 +- 10
Ratio of sex (malefemale) 179
Origins of liver diseases alcoholic cirrhosis 14
post-hepatic B cirrhosis 2
post-hepatitis C cirrhosis 4
PBC 2
liver cancer 2
fulminant hepatitis 1
miscellaneous 1
- Placebo group (n = 24)
Mean age (years +- SD)
51+- 9
Ratio of sex (malefemale) 159
Origins of liver diseases alcoholic cirrhosis 10
post-hepatic B cirrhosis 0
post-hepatic C cirrhosis 6
PBC 3
liver cancer 4
fulminant hepatitis 0
miscellaneous 1
27Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Pageaux 1995 (Continued)
Interventions UDCA group
- Dose 600 mgday in three divided doses
- Route orally
- Duration immediately after intestinal transit recovery usually between postoperative
days three and five and continue for two months
Placebo group
- identical-appearing capsules administered in the same quantity and manner
Co-interventions all patients received standard triple-drug regimens (steroids azathio-
prine and cyclosporine or tacrolimus)
Outcomes Number of patients with acute cellular rejection
Number of patients with steroid-resistant rejection
Notes Letter was sent to the authors in September 2009 No reply was received
Risk of bias
Item Authorsrsquo judgement Description
Adequate sequence generation Unclear No information provided
Allocation concealment Unclear No information provided
Blinding Unclear Method of blinding not described
Incomplete outcome data addressed
All outcomes
Yes Five patients died from non-immunologi-
cal causes before the end of the first month
and were excluded from the study Reasons
were reported
Free of selective reporting Unclear Not enough information provided
Sample size calculation No Not performed
Intention-to-treat analysis No Not stated and not used
Baseline imbalance Unclear Not enough information provided
Early stopping of trial Unclear Not enough information provided
Sama 1991
Methods Study design randomised controlled trial
Participants Country Italy
Publication language English
Inclusion criteria
28Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Sama 1991 (Continued)
- patients who underwent liver transplantation
Exclusion criteria
- not mentioned
Participants
- UDCA group (n = 20)
Mean age (years +- SD)
no information
Ratio of sex (malefemale) no information
Origins of liver diseases
no information
- Control group (n = 20)
Mean age (years +- SD)
no information
Ratio of sex (malefemale) no information
Origins of liver diseases
no information
Interventions UDCA group
- Dose 600 mgday in two divided doses
- Route orally
- Duration immediately after intestinal transit recovery usually between postoperative
day five and day seven and continue for six months
Control group
- no treatment
Co-interventions all patients received standard immunosuppressive treatment (steroids
and cyclosporine)
Outcomes All cause mortality
Number of patients with acute cellular rejection
Notes Abstract
Letter was sent to the authors in September 2009 No reply was received
Risk of bias
Item Authorsrsquo judgement Description
Adequate sequence generation Unclear A randomisation list was performed before
patients were admitted to the trial (infor-
mation from principal author)
Allocation concealment Unclear No information provided
Blinding Unclear The principle author provided information
that the study was made according to a
single-blind randomised protocol The pri-
mary outcome was the occurrence of biopsy
proven rejection episodes The pathologists
were blind but the patients were not
29Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Sama 1991 (Continued)
Incomplete outcome data addressed
All outcomes
Unclear Five patients from the UDCA group and
six patients from the placebo group were
excluded Reasons for exclusion were not
fully stated
Free of selective reporting No Data about survival of patients were not
adequately reported
Sample size calculation No Not performed
Intention-to-treat analysis No Not stated and not used
Baseline imbalance Unclear Basic characteristics of patients not re-
ported
Early stopping of trial Unclear Not enough information provided
UDCA = ursodeoxycholic acid
TUDCA = tauroursodeoxycholic acid
PBC = primary biliary cirrhosis
PSC = primary sclerosing cholangitis
OKT3 = anti-CD3 monoclonal antibody
Characteristics of excluded studies [ordered by study ID]
Assy 2007 A randomised controlled trial that included only recipients of liver transplantation with stable graft function and
no episodes of rejection for at least 2 years that were then offered total immunosuppression withdrawal Fourteen
patients received UDCA (15 mgkg body weightday) and 12 received placebo Rejection occurred in 43 and
75 of patients respectively (no significant difference) None developed chronic rejection After follow-up two
patients were free of immunosuppression 80 were steroid free and 50 were able to reduce their dose of
cyclosporine
Clavien 1996 Case series Fifty consecutive liver-transplanted patients were treated with a standard cyclosporine immunosup-
pressive regimen Twenty three of the 43 survivors developed an episode of rejection and UDCA (10 mgkg
weightday) was initiated Only one patient had a second episode of rejection
Friman 1992 Observational study Thirty-three liver-transplanted patients received 10 mg UDCAkg body weightday for
median of 10 months (range four to 21 months) Eight historical liver-transplanted patients served as control
group The rejection incidence was significantly lower in the patients who received the treatment with UDCA
Biochemistry one month after transplantation demonstrated significantly lower average values of aminotrans-
ferases and alkaline phosphatases in patients treated with UDCA than in the control group
30Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
Heathcote 1999 Observational study From 1987 to 1996 37 UDCA treated and 53 placebo treated patients with primary biliary
cirrhosis were referred for transplantation Posttransplantation survival rates at one month were 939 in the
UDCA group and 884 in the placebo group and one year survival rates were 903 and 784 respectively
(no significant differences) However rejection (type not defined - a secondary outcome measure) occurred
significantly less often in the UDCA group (429) than in placebo group (688)
Henriksson 1991 Observational study All patients in this study were given sequential quadruple immunosuppression with anti-
lymphocyte globulin azathioprine steroids and cyclosporine All patients with primary graft function (n = 11)
were treated with 10 mg UDCAkg body weightday starting during the first postoperative week Patients who
received liver transplantation in the first 6 months of 1989 (n = 8) served as controls In the control group one
patient died after 9 months with chronic graft dysfunction and six patients had rejection episodes during the
first postoperative month All patients in the UDCA group were alive without rejection episodes
Persson 1990 Observational study All 11 adult patients transplanted between August 1989 and January 1990 with primary
graft function were treated with 10 mg UDCA kg body weightday Eight patients transplanted during the first
half of 1989 served as control UDCA was started during the first postoperative week and the treatment was
continued for six months All patients in the UDCA treated group survived with satisfactory graft function In
the control group six patients had at least one rejection episode needing treatment during the first postoperative
month
Rafael 1995 Observational study Seventeen patients who underwent liver transplantation between February 1990 and April
1993 and developed biliary complications after transplantation were retrospectively analysed regarding treatment
with UDCA UDCA was given in a dose of 500 to 1000 mgday Ten patients were treated for at least one year while
seven patients were treated for 14 to 250 days UDCA significantly improved gammaglutamyl transpeptidase in
liver graft recipients with biliary complications There was also a trend towards improvement in serum bilirubin
and alanine transaminase values
Sama 1998 Observational study Thirty-four patients who underwent liver transplantation between January 1995 and June
1996 were included in the study Seventeen were treated with UDCA 10 mgkg body weightday during 6
months while 17 served as controls on the basis of having undergone liver transplantation closest to UDCA
patients A significant decrease in serum bilirubin levels was observed in UDCA patients There was a significantly
higher incidence of recurrent hepatitis in the control group
UDCA ursodeoxycholic acid
31Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
D A T A A N D A N A L Y S E S
Comparison 1 Bile acids for liver-transplanted patients
Outcome or subgroup titleNo of
studies
No of
participants Statistical method Effect size
1 All-cause mortality at maximum
follow-up
5 257 Risk Ratio (M-H Fixed 95 CI) 085 [053 136]
11 UDCA versus placebo or
no treatment
4 224 Risk Ratio (M-H Fixed 95 CI) 080 [049 130]
12 TUDCA versus no
treatment
1 33 Risk Ratio (M-H Fixed 95 CI) 159 [030 833]
2 All-cause mortality worst-best
case and best-worst case
scenarios
5 Risk Ratio (M-H Fixed 95 CI) Subtotals only
21 Worst-best case scenario 5 257 Risk Ratio (M-H Fixed 95 CI) 130 [086 196]
22 Best-worst case scenario 5 257 Risk Ratio (M-H Fixed 95 CI) 058 [038 090]
3 Subgroup analyses all-cause
mortality at maximum
follow-up according to time of
start of bile acids
5 257 Risk Ratio (M-H Fixed 95 CI) 085 [053 136]
31 Less than three days after
transplantation
1 102 Risk Ratio (M-H Fixed 95 CI) 124 [061 254]
32 Three days or more after
transplantation
4 155 Risk Ratio (M-H Fixed 95 CI) 063 [033 120]
4 Subgroup analyses all cause
mortality at maximum
follow-up according to
treatment duration
5 257 Risk Ratio (M-H Fixed 95 CI) 085 [053 136]
41 Less than six months 3 184 Risk Ratio (M-H Fixed 95 CI) 078 [045 138]
42 Six months or more 2 73 Risk Ratio (M-H Fixed 95 CI) 102 [043 240]
5 Number of deaths related
to rejection at maximum
follow-up
1 102 Risk Ratio (M-H Fixed 95 CI) 030 [001 712]
51 UDCA versus placebo 1 102 Risk Ratio (M-H Fixed 95 CI) 030 [001 712]
6 Number of retransplantations at
maximum follow-up
2 132 Risk Ratio (M-H Fixed 95 CI) 076 [020 286]
7 Number of patients with acute
cellular rejection at maximum
follow-up
7 339 Risk Ratio (M-H Fixed 95 CI) 089 [074 106]
71 UDCA versus placebo or
no treatment
6 306 Risk Ratio (M-H Fixed 95 CI) 089 [074 108]
72 TUDCA versus no
treatment
1 33 Risk Ratio (M-H Fixed 95 CI) 085 [045 160]
8 Subgroup analysis number of
patients with acute cellular
rejection according to time of
start of bile acid
7 339 Risk Ratio (M-H Fixed 95 CI) 089 [074 106]
32Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
81 Less than three days after
transplantation
2 134 Risk Ratio (M-H Fixed 95 CI) 084 [063 111]
82 Three days or more after
liver transplantation
5 205 Risk Ratio (M-H Fixed 95 CI) 092 [072 117]
9 Subgroup analysis number
of patients with acute
cellular rejection according to
treatment duration
7 339 Risk Ratio (M-H Fixed 95 CI) 089 [074 106]
91 Less than six months 5 266 Risk Ratio (M-H Fixed 95 CI) 087 [071 107]
92 Six months or more 2 73 Risk Ratio (M-H Fixed 95 CI) 094 [065 136]
10 Number of patients with
chronic rejection at maximum
follow-up
3 184 Risk Ratio (M-H Fixed 95 CI) 028 [008 095]
11 Number of patients with
steroid-resistant rejection at
maximum follow-up
4 234 Risk Ratio (M-H Fixed 95 CI) 077 [047 127]
12 Serum bilirubin (mgdl) at the
end of treatment
1 30 Mean Difference (IV Fixed 95 CI) 26 [-096 616]
13 Number of days of
hospitalisation after liver
transplantation
1 52 Mean Difference (IV Fixed 95 CI) -85 [-1667 -033]
14 Adverse events 3 187 Risk Ratio (M-H Fixed 95 CI) 088 [030 260]
Analysis 11 Comparison 1 Bile acids for liver-transplanted patients Outcome 1 All-cause mortality at
maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 1 All-cause mortality at maximum follow-up
Study or subgroup Favours bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 UDCA versus placebo or no treatment
Barnes 1997 228 724 253 024 [ 006 107 ]
Fleckenstein 1998 214 416 125 057 [ 012 266 ]
Keiding 1997 1454 1048 355 124 [ 061 254 ]
Sama 1991 520 620 201 083 [ 030 229 ]
Subtotal (95 CI) 116 108 935 080 [ 049 130 ]
Total events 23 (Favours bile acids) 27 (Control)
Heterogeneity Chi2 = 416 df = 3 (P = 025) I2 =28
Test for overall effect Z = 091 (P = 036)
01 02 05 1 2 5 10
Favours bile acids Favours control
(Continued )
33Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Favours bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
2 TUDCA versus no treatment
Angelico 1999 316 217 65 159 [ 030 833 ]
Subtotal (95 CI) 16 17 65 159 [ 030 833 ]
Total events 3 (Favours bile acids) 2 (Control)
Heterogeneity not applicable
Test for overall effect Z = 055 (P = 058)
Total (95 CI) 132 125 1000 085 [ 053 136 ]
Total events 26 (Favours bile acids) 29 (Control)
Heterogeneity Chi2 = 466 df = 4 (P = 032) I2 =14
Test for overall effect Z = 069 (P = 049)
01 02 05 1 2 5 10
Favours bile acids Favours control
Analysis 12 Comparison 1 Bile acids for liver-transplanted patients Outcome 2 All-cause mortality worst-
best case and best-worst case scenarios
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 2 All-cause mortality worst-best case and best-worst case scenarios
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 Worst-best case scenario
Angelico 1999 516 217 65 266 [ 060 1180 ]
Barnes 1997 828 724 253 098 [ 042 230 ]
Fleckenstein 1998 314 416 125 086 [ 023 319 ]
Keiding 1997 1954 1048 355 169 [ 087 327 ]
Sama 1991 520 620 201 083 [ 030 229 ]
Subtotal (95 CI) 132 125 1000 130 [ 086 196 ]
Total events 40 (Bile acids) 29 (Control)
Heterogeneity Chi2 = 303 df = 4 (P = 055) I2 =00
Test for overall effect Z = 123 (P = 022)
2 Best-worst case scenario
005 02 1 5 20
Favours bile acids Favours control
(Continued )
34Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Angelico 1999 316 417 90 080 [ 021 302 ]
Barnes 1997 228 1124 274 016 [ 004 063 ]
Fleckenstein 1998 214 616 130 038 [ 009 159 ]
Keiding 1997 1454 1548 368 083 [ 045 154 ]
Sama 1991 520 620 139 083 [ 030 229 ]
Subtotal (95 CI) 132 125 1000 058 [ 038 090 ]
Total events 26 (Bile acids) 42 (Control)
Heterogeneity Chi2 = 567 df = 4 (P = 023) I2 =29
Test for overall effect Z = 247 (P = 0014)
005 02 1 5 20
Favours bile acids Favours control
Analysis 13 Comparison 1 Bile acids for liver-transplanted patients Outcome 3 Subgroup analyses all-
cause mortality at maximum follow-up according to time of start of bile acids
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 3 Subgroup analyses all-cause mortality at maximum follow-up according to time of start of bile acids
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 Less than three days after transplantation
Keiding 1997 1454 1048 355 124 [ 061 254 ]
Subtotal (95 CI) 54 48 355 124 [ 061 254 ]
Total events 14 (Bile acids) 10 (Control)
Heterogeneity not applicable
Test for overall effect Z = 060 (P = 055)
2 Three days or more after transplantation
Angelico 1999 316 217 65 159 [ 030 833 ]
Barnes 1997 228 724 253 024 [ 006 107 ]
Fleckenstein 1998 214 416 125 057 [ 012 266 ]
Sama 1991 520 620 201 083 [ 030 229 ]
005 02 1 5 20
Favours bile acids Favours control
(Continued )
35Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Subtotal (95 CI) 78 77 645 063 [ 033 120 ]
Total events 12 (Bile acids) 19 (Control)
Heterogeneity Chi2 = 310 df = 3 (P = 038) I2 =3
Test for overall effect Z = 141 (P = 016)
Total (95 CI) 132 125 1000 085 [ 053 136 ]
Total events 26 (Bile acids) 29 (Control)
Heterogeneity Chi2 = 466 df = 4 (P = 032) I2 =14
Test for overall effect Z = 069 (P = 049)
005 02 1 5 20
Favours bile acids Favours control
Analysis 14 Comparison 1 Bile acids for liver-transplanted patients Outcome 4 Subgroup analyses all
cause mortality at maximum follow-up according to treatment duration
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 4 Subgroup analyses all cause mortality at maximum follow-up according to treatment duration
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 Less than six months
Barnes 1997 228 724 253 024 [ 006 107 ]
Fleckenstein 1998 214 416 125 057 [ 012 266 ]
Keiding 1997 1454 1048 355 124 [ 061 254 ]
Subtotal (95 CI) 96 88 734 078 [ 045 138 ]
Total events 18 (Bile acids) 21 (Control)
Heterogeneity Chi2 = 417 df = 2 (P = 012) I2 =52
Test for overall effect Z = 084 (P = 040)
2 Six months or more
Angelico 1999 316 217 65 159 [ 030 833 ]
Sama 1991 520 620 201 083 [ 030 229 ]
Subtotal (95 CI) 36 37 266 102 [ 043 240 ]
Total events 8 (Bile acids) 8 (Control)
Heterogeneity Chi2 = 043 df = 1 (P = 051) I2 =00
005 02 1 5 20
Favours bile acids Favours control
(Continued )
36Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Test for overall effect Z = 004 (P = 097)
Total (95 CI) 132 125 1000 085 [ 053 136 ]
Total events 26 (Bile acids) 29 (Control)
Heterogeneity Chi2 = 466 df = 4 (P = 032) I2 =14
Test for overall effect Z = 069 (P = 049)
005 02 1 5 20
Favours bile acids Favours control
Analysis 15 Comparison 1 Bile acids for liver-transplanted patients Outcome 5 Number of deaths related
to rejection at maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 5 Number of deaths related to rejection at maximum follow-up
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 UDCA versus placebo
Keiding 1997 054 148 1000 030 [ 001 712 ]
Total (95 CI) 54 48 1000 030 [ 001 712 ]
Total events 0 (Bile acids) 1 (Control)
Heterogeneity not applicable
Test for overall effect Z = 075 (P = 045)
0001 001 01 1 10 100 1000
Favours bile acids Favours control
37Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 16 Comparison 1 Bile acids for liver-transplanted patients Outcome 6 Number of
retransplantations at maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 6 Number of retransplantations at maximum follow-up
Study or subgroup Bile acids Placebo Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Fleckenstein 1998 214 016 100 567 [ 029 10891 ]
Keiding 1997 154 448 900 022 [ 003 192 ]
Total (95 CI) 68 64 1000 076 [ 020 286 ]
Total events 3 (Bile acids) 4 (Placebo)
Heterogeneity Chi2 = 303 df = 1 (P = 008) I2 =67
Test for overall effect Z = 040 (P = 069)
0001 001 01 1 10 100 1000
Favours bile acids Favours placebo
Analysis 17 Comparison 1 Bile acids for liver-transplanted patients Outcome 7 Number of patients with
acute cellular rejection at maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 7 Number of patients with acute cellular rejection at maximum follow-up
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 UDCA versus placebo or no treatment
Barnes 1997 1728 1724 180 086 [ 058 127 ]
Fleckenstein 1998 814 916 83 102 [ 054 190 ]
Keiding 1997 3554 3248 333 097 [ 073 129 ]
Koneru 1993 316 916 89 033 [ 011 101 ]
Pageaux 1995 926 924 92 092 [ 044 193 ]
Sama 1991 1320 1320 128 100 [ 063 158 ]
Subtotal (95 CI) 158 148 905 089 [ 074 108 ]
01 02 05 1 2 5 10
Favours bile acids Favours control
(Continued )
38Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Total events 85 (Bile acids) 89 (Control)
Heterogeneity Chi2 = 387 df = 5 (P = 057) I2 =00
Test for overall effect Z = 120 (P = 023)
2 TUDCA versus no treatment
Angelico 1999 816 1017 95 085 [ 045 160 ]
Subtotal (95 CI) 16 17 95 085 [ 045 160 ]
Total events 8 (Bile acids) 10 (Control)
Heterogeneity not applicable
Test for overall effect Z = 050 (P = 061)
Total (95 CI) 174 165 1000 089 [ 074 106 ]
Total events 93 (Bile acids) 99 (Control)
Heterogeneity Chi2 = 392 df = 6 (P = 069) I2 =00
Test for overall effect Z = 130 (P = 019)
01 02 05 1 2 5 10
Favours bile acids Favours control
Analysis 18 Comparison 1 Bile acids for liver-transplanted patients Outcome 8 Subgroup analysis
number of patients with acute cellular rejection according to time of start of bile acid
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 8 Subgroup analysis number of patients with acute cellular rejection according to time of start of bile acid
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 Less than three days after transplantation
Keiding 1997 3554 3248 333 097 [ 073 129 ]
Koneru 1993 316 916 89 033 [ 011 101 ]
Subtotal (95 CI) 70 64 422 084 [ 063 111 ]
Total events 38 (Bile acids) 41 (Control)
Heterogeneity Chi2 = 374 df = 1 (P = 005) I2 =73
Test for overall effect Z = 124 (P = 022)
2 Three days or more after liver transplantation
Angelico 1999 816 1017 95 085 [ 045 160 ]
01 02 05 1 2 5 10
Favours bile acids Favours control
(Continued )
39Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Barnes 1997 1728 1724 180 086 [ 058 127 ]
Fleckenstein 1998 814 916 83 102 [ 054 190 ]
Pageaux 1995 926 924 92 092 [ 044 193 ]
Sama 1991 1320 1320 128 100 [ 063 158 ]
Subtotal (95 CI) 104 101 578 092 [ 072 117 ]
Total events 55 (Bile acids) 58 (Control)
Heterogeneity Chi2 = 041 df = 4 (P = 098) I2 =00
Test for overall effect Z = 067 (P = 050)
Total (95 CI) 174 165 1000 089 [ 074 106 ]
Total events 93 (Bile acids) 99 (Control)
Heterogeneity Chi2 = 392 df = 6 (P = 069) I2 =00
Test for overall effect Z = 130 (P = 019)
01 02 05 1 2 5 10
Favours bile acids Favours control
40Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 19 Comparison 1 Bile acids for liver-transplanted patients Outcome 9 Subgroup analysis
number of patients with acute cellular rejection according to treatment duration
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 9 Subgroup analysis number of patients with acute cellular rejection according to treatment duration
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 Less than six months
Barnes 1997 1728 1724 180 086 [ 058 127 ]
Fleckenstein 1998 814 916 83 102 [ 054 190 ]
Keiding 1997 3554 3248 333 097 [ 073 129 ]
Koneru 1993 316 916 89 033 [ 011 101 ]
Pageaux 1995 926 924 92 092 [ 044 193 ]
Subtotal (95 CI) 138 128 777 087 [ 071 107 ]
Total events 72 (Bile acids) 76 (Control)
Heterogeneity Chi2 = 374 df = 4 (P = 044) I2 =00
Test for overall effect Z = 129 (P = 020)
2 Six months or more
Angelico 1999 816 1017 95 085 [ 045 160 ]
Sama 1991 1320 1320 128 100 [ 063 158 ]
Subtotal (95 CI) 36 37 223 094 [ 065 136 ]
Total events 21 (Bile acids) 23 (Control)
Heterogeneity Chi2 = 017 df = 1 (P = 068) I2 =00
Test for overall effect Z = 035 (P = 073)
Total (95 CI) 174 165 1000 089 [ 074 106 ]
Total events 93 (Bile acids) 99 (Control)
Heterogeneity Chi2 = 392 df = 6 (P = 069) I2 =00
Test for overall effect Z = 130 (P = 019)
01 02 05 1 2 5 10
Favours bile acids Favours control
41Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 110 Comparison 1 Bile acids for liver-transplanted patients Outcome 10 Number of patients
with chronic rejection at maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 10 Number of patients with chronic rejection at maximum follow-up
Study or subgroup Bile acids Placebo Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Barnes 1997 128 624 611 014 [ 002 110 ]
Fleckenstein 1998 114 116 88 114 [ 008 1663 ]
Keiding 1997 154 348 300 030 [ 003 275 ]
Total (95 CI) 96 88 1000 028 [ 008 095 ]
Total events 3 (Bile acids) 10 (Placebo)
Heterogeneity Chi2 = 148 df = 2 (P = 048) I2 =00
Test for overall effect Z = 204 (P = 0041)
0001 001 01 1 10 100 1000
Favours bile acids Favours placebo
Analysis 111 Comparison 1 Bile acids for liver-transplanted patients Outcome 11 Number of patients
with steroid-resistant rejection at maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 11 Number of patients with steroid-resistant rejection at maximum follow-up
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Barnes 1997 328 724 277 037 [ 011 127 ]
Fleckenstein 1998 314 316 103 114 [ 027 478 ]
Keiding 1997 1454 1548 583 083 [ 045 154 ]
Pageaux 1995 226 124 38 185 [ 018 1908 ]
Total (95 CI) 122 112 1000 077 [ 047 127 ]
Total events 22 (Bile acids) 26 (Control)
Heterogeneity Chi2 = 226 df = 3 (P = 052) I2 =00
Test for overall effect Z = 102 (P = 031)
001 01 1 10 100
Favours bile acids Favours placebo
42Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 112 Comparison 1 Bile acids for liver-transplanted patients Outcome 12 Serum bilirubin (mgdl)
at the end of treatment
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 12 Serum bilirubin (mgdl) at the end of treatment
Study or subgroup Bile acids Placebo Mean Difference Weight Mean Difference
N Mean(SD) N Mean(SD) IVFixed95 CI IVFixed95 CI
Fleckenstein 1998 14 319 (68) 16 059 (022) 1000 260 [ -096 616 ]
Total (95 CI) 14 16 1000 260 [ -096 616 ]
Heterogeneity not applicable
Test for overall effect Z = 143 (P = 015)
-10 -5 0 5 10
Favours bile acids Favours placebo
Analysis 113 Comparison 1 Bile acids for liver-transplanted patients Outcome 13 Number of days of
hospitalisation after liver transplantation
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 13 Number of days of hospitalisation after liver transplantation
Study or subgroup Bile acids Placebo Mean Difference Weight Mean Difference
N Mean(SD) N Mean(SD) IVFixed95 CI IVFixed95 CI
Barnes 1997 28 25 (17) 24 335 (13) 1000 -850 [ -1667 -033 ]
Total (95 CI) 28 24 1000 -850 [ -1667 -033 ]
Heterogeneity not applicable
Test for overall effect Z = 204 (P = 0041)
-100 -50 0 50 100
Favours bile acids Favours placebo
43Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 114 Comparison 1 Bile acids for liver-transplanted patients Outcome 14 Adverse events
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 14 Adverse events
Study or subgroup Bile acids Placebo Risk Ratio Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Angelico 1999 016 017 00 [ 00 00 ]
Barnes 1997 128 124 086 [ 006 1298 ]
Keiding 1997 554 548 089 [ 027 288 ]
Total (95 CI) 98 89 088 [ 030 260 ]
Total events 6 (Bile acids) 6 (Placebo)
Heterogeneity Chi2 = 000 df = 1 (P = 098) I2 =00
Test for overall effect Z = 022 (P = 082)
001 01 1 10 100
Favours bile acids Favours placebo
A P P E N D I C E S
Appendix 1 Search strategies
Data Base Date of Search Search Strategy
The Cochrane Hepato-Biliary Group Con-
trolled Trials Register
September 2009 1 rsquoliver transplantationrsquo and rsquochenodeoxy-
cholicrsquo
2 rsquoliver transplantationrsquo and rsquocholicrsquo
3 rsquoliver transplantationrsquo and rsquodeoxycholicrsquo
4 rsquoliver transplantationrsquo and rsquoglycochen-
odeoxycholicrsquo
5 rsquoliver transplantationrsquo and rsquoglycocholicrsquo
6 rsquoliver transplantationrsquo and rsquoglycodeoxy-
cholicrsquo
7 rsquoliver transplantationrsquo and rsquoglycolitho-
cholicrsquo
8 rsquoliver transplantationrsquo and rsquohyodeoxy-
cholicrsquo
9 rsquoliver transplantationrsquo and rsquolithocholicrsquo
10 rsquoliver transplantationrsquo and rsquotaurochen-
odeoxycholicrsquo
44Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
11 rsquoliver transplantationrsquo and rsquotauro-
cholicrsquo
12 rsquoliver transplantationrsquo and rsquotaurodehy-
drocholicrsquo
13 rsquoliver transplantationrsquo and rsquotau-
rodeoxycholicrsquo
14 rsquoliver transplantationrsquo and rsquotauroglyco-
cholicrsquo
15 rsquoliver transplantationrsquo and rsquotaurolitho-
cholicrsquo
16 rsquoliver transplantationrsquo and rsquotaurosel-
cholicrsquo
17 rsquoliver transplantationrsquo and rsquotaurourso-
cholicrsquo
18 rsquoliver transplantationrsquo and rsquotaurour-
sodeoxycholicrsquo
19 rsquoliver transplantationrsquo and rsquoursocholicrsquo
20 rsquoliver transplantationrsquo and rsquoursodeoxy-
cholicrsquo
The Cochrane Central Register of Con-
trolled Trials in The Cochrane Library
Issue 3 2009 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
6 3 or 4
7 5 and 6
MEDLINE September 2009 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
45Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
6 3 or 4
7 5 and 6
8 RANDOMIZED-CONTROLLED-
TRIAL ME
9 RANDOM
10 8 or 9
11 7 and 10
EMBASE September 2009 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
6 3 or 4
7 5 and 6
8 RANDOMIZED-CONTROLLED-
TRIAL ME
9 RANDOM
10 8 or 9
11 7 and 10
46Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
Science Citation Index Expanded September 2009 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
6 3 or 4
7 5 and 6
8 RANDOMIZED-CONTROLLED-
TRIAL ME
9 RANDOM
10 8 or 9
11 7 and 10
The Chinese Biomedical Database Searched from January 1980 to April 2002 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
47Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
6 3 or 4
7 5 and 6
8 RANDOMIZED-CONTROLLED-
TRIAL ME
9 RANDOM
10 8 or 9
11 7 and 10
W H A T rsquo S N E W
Last assessed as up-to-date 8 February 2010
18 September 2009 New citation required but conclusions have not
changed
This review is an updated version of a review that was
published for the first time in Issue 3 2005 of TheCochrane Library by Chen 2003b
18 September 2009 New search has been performed No new studies fulfilled the inclusion criteria
H I S T O R Y
Protocol first published Issue 3 2003
Review first published Issue 3 2005
C O N T R I B U T I O N S O F A U T H O R S
GP and VG independently performed searches of relevant databases GP validated the search selected trials for inclusion contacted
the authors of the trials performed data extraction and data analysis and drafted the systematic review VG revised the review update
CG and DS revised the review update solved discrepancies of data extraction validated data analyses and provided consultation
D E C L A R A T I O N S O F I N T E R E S T
None known
48Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
S O U R C E S O F S U P P O R T
Internal sources
bull Copenhagen Trial Unit Denmark
External sources
bull Danish Medical Research Councilrsquos Grant on Getting Research into Practice (GRIP) Denmark
D I F F E R E N C E S B E T W E E N P R O T O C O L A N D R E V I E W
We assessed the risk of bias in the included studies for another four domains that were added to the review protocol (incomplete
outcome data selective outcome reporting baseline imbalance and early stopping of trial) In general the text of the risk of bias
domains were updated following Higgins 2008 Trials were considered at low risk of bias when judged as adequate in all domains
Quasi-randomised studies observational and case-control studies were included for the report of adverse events
We performed trial sequential analysis for outcomes demonstrating a statistically significant result
I N D E X T E R M S
Medical Subject Headings (MeSH)
lowastLiver Transplantation Cholagogues and Choleretics [lowasttherapeutic use] Graft Rejection [lowastprevention amp control] Randomized Con-
trolled Trials as Topic Taurochenodeoxycholic Acid [lowasttherapeutic use] Ursodeoxycholic Acid [lowasttherapeutic use]
MeSH check words
Humans
49Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Neuberger 1999
Neuberger J Incidence timing and risk factors for acute and
chronic rejection Liver Transplantation and Surgery 19995(4 Suppl
1)S30ndashS36 [MEDLINE 10431015]
Okolicsanyi 1986
Okolicsanyi L Lirussi F Strazzabosco M Jemmolo RM Orlando R
Nassuato G et alThe effect of drugs on bile flow and composition
An overview Drugs 198631(5)430ndash48 [MEDLINE 2872047]
Palmer 1972
Palmer RH Bile acids liver injury and liver disease Archives of
Internal Medicine 1972130(4)606ndash17 [MEDLINE 4627840]
Perez 2009
Perez MJ Briz O Bile-acid-induced cell injury and protection
World Journal of Gastroenterology 200915(14)1677ndash89
[MEDLINE 19360911]
Pogue 1997
Pogue JM Yusuf S Cumulating evidence from randomized trials
Utilizing sequential monitoring boundaries for cumulative meta-
analysis Controlled Clinical Trials 199718(6)580ndash93
[MEDLINE 9408720]
Pogue 1998
Pogue J Yusuf S Overcoming the limitations of current meta-
analysis of randomised controlled trials Lancet 1998351(9095)
45ndash52 [MEDLINE 9433436]
RevMan 2008
The Nordic Cochrane Centre The Cochrane Collaboration
Review Manager (RevMan) 50 Copenhagen The Nordic
Cochrane Centre The Cochrane Collaboration 2008
Royle 2003
Royle P Milne R Literature searching for randomized controlled
trials used in Cochrane reviews rapid versus exhaustive searches
International Journal of Technology Assessment in Health Care 2003
19(4)591ndash603
Schulz 1995
Schulz KF Chalmers I Hayer R Altman D Empirical evidence of
bias JAMA 1995273(5)408ndash12 [MEDLINE 7823387]
Sharara 1995
Sharara AI Camargo CA Clavien PA Ursodeoxycholic acid
prevents steroid resistant rejection in liver transplant recipients
Gastroenterology 1995108A1168
Sholmerich 1984
Sholmerich J Becher MS Schmidt KH Schubert R Kremer B
Felhaus S et alInfluence of hydroxylation and conjugation of bile
salts on their membrane damaging properties Hepatology 19844
(4)661ndash7 [MEDLINE 6745854]
Soderdahl 1998
Soderdahl G Nowak G Duraj F Wang FH Einarsson C Ericzon
BG Ursodeoxycholic acid increased bile flow and affects bile
composition in the early postoperative phase following liver
transplantation Transplantation International 199811(Suppl 1)
S231ndashS238 [MEDLINE 9664985]
Terasaki 1991
Terasaki S Nakanuma Y Ogino H Unoura M Kobayashi K
Hepatocellular and biliary expression of HLA antigens in primary
biliary cirrhosis before and after ursodeoxycholic acid therapy
American Journal of Gastroenterology 199186(9)1194ndash9
[MEDLINE 1882800]
Thalheimer 2002
Thalheimer U Capra F Liver transplantation making the best out
of what we have Digestive Diseases and Sciences 200247(5)
945ndash53 [MEDLINE 12018919]
Thorlund 2009
Thorlund K Devereaux PJ Wetterslev J Guyatt G Ioannidis JP
Thabane L et alCan trial sequential monitoring boundaries reduce
spurious inferences from meta-analyses International Journal of
Epidemiology 200938(1)276ndash86 [MEDLINE 18824467]
Thuluvath 2003
Thuluvath PJ Yoo HY Thompson RE A model to predict survival
at one month one year and five years after liver transplantation
based on pretransplant clinical characteristics Liver Transplantation
20039(5)527ndash32 [MEDLINE 12740799]
van den Berg 1998
van den Berg AP Twilhaar WN Mesander G van Son WJ van der
Bij W Klompmaker IJ et alQuantitation of immunosuppression
by flow cytometric measurement of the capacity of T cells for
interleukin-2 production Transplantation 199865(8)1066ndash71
[MEDLINE 9583867]
Vierling 1992
Vierling J Immunologic mechanisms of hepatic allograft rejection
Seminars in Liver Disease 199212(1)16ndash27 [MEDLINE
1570548]
Wetterslev 2008
Wetterslev J Thorlund K Brok J Gluud C Trial sequential
analysis may establish when firm evidence is reached in cumulative
meta-analysis Journal of Clinical Epidemiology 200861(1)64ndash75
[MEDLINE 18083463]
Wiesner 1992
Wiesner RH Acute cellular rejection following liver
transplantation incidence risk factors and outcome in the
NIDDK Liver Transplant Database (LTD) study Gastroenterology
1992102A910
Wood 2008
Wood L Egger M Gluud LL Schulz KF Juni P Altman DG et
alEmpirical evidence of bias in treatment effect estimates in
controlled trials with different interventions and outcomes meta-
epidemiological study BMJ (Clinical Research Ed) 2008336
(7644)601ndash5 [MEDLINE 18316340]
Yoshikawa 1998
Yoshikawa M Matsui Y Kawamoto H Toyohara M Matsumura
K Yamao J et alIntragastric administration of ursodeoxycholic
acid suppresses immunoglobulin secretion by lymphocytes from
liver but not from peripheral blood spleen or Peyerrsquos patches in
mice International Journal of Immunopharmacology 199820(1-3)
29ndash38 [MEDLINE 9717080]
References to other published versions of this review
17Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Chen 2003b
Chen W Gluud C Bile acids for liver transplanted patients
Cochrane Database of Systematic Reviews 2005 Issue 3 [DOI
10100214651858CD005442]lowast Indicates the major publication for the study
18Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
C H A R A C T E R I S T I C S O F S T U D I E S
Characteristics of included studies [ordered by study ID]
Angelico 1999
Methods Study design open-label randomised one-year pilot study
Participants Country Italy
Publication language English
Inclusion criteria
- patients who underwent liver transplantation from April 1994 to December 1994
Exclusion criteria
- not mentioned
Participants
Two patients in TUDCA group and two patients in control group were excluded from
the basic information of participants by the study due to withdrawal
- TUDCA group (n = 14)
Mean age (years +- SD)
467 +- 84
Ratio of sex (malefemale) 122
Origins of liver diseases
hepatitis C cirrhosis (9) hepatitis B cirrhosis (2) hepatitis B and C cirrhosis (1) cryp-
togenic cirrhosis (2) alcoholic cirrhosis (0) Wilson cirrhosis (0)
- Control group (n = 15)
Mean age (years +- SD)
474 +- 74
Ratio of sex (malefemale) 123
Origins of liver diseases
hepatitis C cirrhosis (7) hepatitis B cirrhosis (2) hepatitis B and C cirrhosis (2) cryp-
togenic cirrhosis (2) alcoholic cirrhosis (1) Wilson cirrhosis (1)
Interventions TUDCA group
- Dose 500 mgday in two divided doses
- Route orally
- Duration the treatment was started on day 5 after transplantation and continued for
one year
Control group
- no treatment
Co-interventions all patients received standard triple-drug regimens (steroids azathio-
prine and cyclosporine or tacrolimus)
Outcomes All cause mortality
Number of patients with rejection after liver transplantation
Notes Letter was sent to the authors in September 2009 A reply with additional information
was received shortly after
Risk of bias
19Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Angelico 1999 (Continued)
Item Authorsrsquo judgement Description
Adequate sequence generation Yes Computer generated table
Allocation concealment Unclear No information provided
Blinding No Not performed
Incomplete outcome data addressed
All outcomes
Yes Withdrawal two patients from the
TUDCA group and two patients from the
placebo group Three of them died due to
transplant non-function in the first postop-
erative week and one patient was regrafted
due to thrombosis of hepatic artery
Free of selective reporting Unclear Post-transplant cholestasis and liver bio-
chemistry specified as outcomes Differ-
ence reported as not significant but no ac-
tual data given
Sample size calculation No Not reported
Intention-to-treat analysis No Not stated and not used
Baseline imbalance Unclear Not enough information provided
Early stopping of trial Unclear Not enough information provided
Barnes 1997
Methods Study design randomised placebo-controlled double-blind trial
Participants Country United States
Publication language English
Inclusion criteria
- patients aged 18 years or older who underwent liver transplantation at the Cleveland
Clinic Foundation from April 1992 through June of 1994
Exclusion criteria
- patients who were found to have cancer at surgically resected margins of the biliary
tree
- patents who underwent retransplantation
Participants
- UDCA group (n = 28)
Mean age (years +- SD)
505 +- 116
Ratio of sex (malefemale) 1810
Child class A 7
20Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Barnes 1997 (Continued)
B 13
and C 8
Origins of liver diseases Laennecrsquos cirrhosis 4
PBC 3
cryptogenic cirrhosis 6
hepatitis Ccirrhosis 4
hepatitis Bcirrhosis 3
autoimmune hepatitis with cirrhosis 3
PSC 2
other 3
- Placebo group (n = 24)
Mean age (years +- SD)
507 +- 93
Ratio of sex (malefemale) 159
Child class A 6
B 14
and C 4
Origins of liver diseases Laennecrsquos cirrhosis 9
PBC 5
cryptogenic cirrhosis 1
hepatitis Ccirrhosis 1
hepatitis Bcirrhosis 1
autoimmune hepatitis with cirrhosis 1
PSC 2
other 4
Interventions UDCA group
- Dose 10-15 mgkg body weightday in divided doses
- Route orally
- Duration immediately after intestinal transit recovery usually between postoperative
days three and five and continue for three months
Placebo group
- identical-appearing capsules administered in the same quantity and manner
Co-interventions all patients received standard triple-drug regimens (steroids azathio-
prine and cyclosporine or tacrolimus)
Outcomes All cause mortality
Number of patients with acute cellular rejection
Number of patients with chronic rejection
Number of patients with steroid-resistant rejection
Number of days of hospitalisation
Adverse events
Notes Letter was sent to the authors in September 2009 A reply with additional information
was received shortly after
Risk of bias
Item Authorsrsquo judgement Description
21Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Barnes 1997 (Continued)
Adequate sequence generation Yes Computer generated table
Allocation concealment Unclear No information provided
Blinding Yes Quote ldquorandomised to receive either
UDCA or an identical placebo capsulerdquo
Incomplete outcome data addressed
All outcomes
Yes Mean follow-up time 18 months Ten pa-
tients withdrawn from study 6 in UDCA
group and 4 in placebo group Reasons
for withdrawal were reported Four patients
died in the placebo group
Free of selective reporting Yes All expected outcomes reported
Sample size calculation Unclear The trial reported the method of sample
size calculation but the actual number of
patients needed was not reported
Intention-to-treat analysis Yes Stated and used
Baseline imbalance Unclear Not enough information provided
Early stopping of trial Unclear The number of patients needed to gain the
actual power was not reported Whether
the trial was terminated early is not clear
Fleckenstein 1998
Methods Study design prospective randomised double-blind trial
Participants Country United States
Publication language English
Inclusion criteria
- patients who underwent liver transplantation at the Johns Hopkins Hospital
Exclusion criteria
- patients who were under 18 years old undergoing repeat transplantation had primary
graft nonfunction or refused consent
Participants
- UDCA group (n = 14)
Mean age (years +- SD)
443 +- 127
Ratio of sex (malefemale) 68
Origins of liver diseases hepatitis C 6
alcohol 2
autoimmune 1
PBC 2
22Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Fleckenstein 1998 (Continued)
PSC 1
autoimmune cholangiopathy 1
hepatitis B 1
- Placebo group (n = 16)
Mean age (years +- SD)
496 +- 109
Ratio of sex (malefemale) 124
Origins of liver diseases hepatitis C 3
alcohol 3
autoimmune 3
PBC 1
PSC 2
cryptogenic 2
hepatitis B 1
alpha1-antitrypsin deficiency 1
Interventions UDCA group
- Dose 15 mgkg body weightday in divided doses
- Route orally
- Duration immediately after intestinal transit recovery usually between postoperative
days three and five and continue for three months
Placebo group
- Identical-appearing capsules administered in the same quantity and manner
Co-interventions all patients received standard triple-drug regimens (steroids azathio-
prine and cyclosporine or tacrolimus)
Outcomes All cause mortality
Number with retransplantation
Number of patients with acute cellular rejection
Number of patients with chronic rejection
Serum bilirubin levels at the end of treatment
Notes Follow-up time nine months
Letter was sent to the authors in September 2009 No reply was received
Risk of bias
Item Authorsrsquo judgement Description
Adequate sequence generation Unclear No information provided
Allocation concealment Unclear No information provided
Blinding Yes Method of blinding not described but
probably adequate
Incomplete outcome data addressed
All outcomes
Yes Withdrawal one patient from the UDCA
group and two patients from the placebo
group because of capsule size
23Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Fleckenstein 1998 (Continued)
Free of selective reporting Unclear Outcomes were not completely described
Sample size calculation No Not reported
Intention-to-treat analysis Yes Quote ldquoThree patients withdrew after in-
clusionThey were included in the statis-
tical analysisrdquo
Baseline imbalance Unclear Not enough information provided
Early stopping of trial Unclear Not enough information provided
Keiding 1997
Methods Study design prospective randomised placebo-controlled multicenter study
Participants Country Denmark Finland Norway and Sweden
Publication language English
Inclusion criteria
- patients who underwent liver transplantation in Denmark Finland Norway and Swe-
den from September 1 1992 to May 31 1994
Exclusion criteria
- patients with malignant diseases
Participants
The age of the children ranged from 0 to 13 years (median 15) and the age of adults
ranged from 14 to 59 years old (median 44) MaleFemale ratio was 96 for children and
4344 for adults
- UDCA group (n = 54)
Origins of liver diseases
paracetamol intoxication 1 hepatitis B 1 autoimmune hepatitis 0 biliary atresia 2
metabolic diseases 7 neonatal hepatitis 2 PBC 13 post hepatitis cirrhosis 8 PSC 3
cryptogenic cirrhosis 7 alcoholic cirrhosis 2 other reasons 8
- Placebo group (n = 48)
Origins of liver diseases paracetamol intoxication 1 hepatitis B 0 autoimmune hepatitis
1 biliary atresia 3 metabolic diseases 11 neonatal hepatitis 0 PBC 7 post hepatitis
cirrhosis 5 PSC 7 cryptogenic cirrhosis 2 alcoholic cirrhosis 6 other reasons 5
Interventions UDCA group
- Dose 15 mgkg body weightday in two or three divided doses
- Route orally
- Duration immediately after intestinal transit recovery usually between postoperative
days three and five and continue for three months
Placebo group
- Identical-appearing capsules administered in the same quantity and manner
Co-interventions all patients received standard triple-drug regimens (steroids azathio-
prine and cyclosporine or tacrolimus)
24Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Keiding 1997 (Continued)
Outcomes All cause mortality
Number of deaths related to rejection
Number of patients with acute cellular rejection
Number of patients with chronic rejection
Number of patients with steroid-resistant rejection
Adverse events
Notes Letter was sent to the authors in September 2009 No reply was received
Risk of bias
Item Authorsrsquo judgement Description
Adequate sequence generation Unclear Patients were randomised at a ratio of 11
Allocation concealment Yes Quote ldquo The allocation was performed in
blocks of 10 patients using the sealed serial
envelope methodrdquo
Blinding Yes Quote ldquoThe UDCA and the placebo cap-
sules had identical appearance and tasterdquo
Incomplete outcome data addressed
All outcomes
Yes Follow-up time 12 months Five UDCA
patients and five placebo patients withdrew
from study Reasons were reported
Free of selective reporting Unclear Insufficient information
Sample size calculation Yes Performed and allowed for a difference in
the incidence of at least one episode of
acute rejection of 50 between the treat-
ment and placebo groups with 90 statisti-
cal power and a significance level of P value
less than 005 The calculated sample size
was 80 patients
Intention-to-treat analysis Yes Stated and used
Baseline imbalance Yes The study seems to be free of baseline im-
balance
Early stopping of trial Yes Study attained the pre-specified sample
size
25Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Koneru 1993
Methods Study design randomised controlled trial
Participants Country United States
Publication language English
Inclusion criteria
- patients who underwent liver transplantation
Exclusion criteria
- not mentioned
Participants
- UDCA group (n = 16)
Mean age (years +- SD)
no information
Ratio of sex (malefemale) no information
Origins of liver diseases
no information
- Control group (n = 16)
Mean age (years +- SD)
no information
Ratio of sex (malefemale) no information
Origins of liver diseases
no information
Interventions UDCA group
- Dose 900 mgday
- Route orally
- Duration immediately after intestinal transit recovery usually between postoperative
days three and five and continue for three months
Control group
- no treatment
Co-interventions all patients received standard triple-drug regimens (steroids azathio-
prine and cyclosporine)
Outcomes Number of patients with retransplantation due to rejection
Number of patients with rejection episodes
Notes Abstract
Letter was sent to the authors in September 2009 No reply was received
Risk of bias
Item Authorsrsquo judgement Description
Adequate sequence generation Unclear No information provided
Allocation concealment Unclear No information provided
Blinding No Not performed
26Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Koneru 1993 (Continued)
Incomplete outcome data addressed
All outcomes
Unclear The study gives the impression that there
were no withdrawals but this was not ex-
plicitly stated
Free of selective reporting Unclear Insufficient information provided
Sample size calculation No Not performed
Intention-to-treat analysis Unclear No information provided
Baseline imbalance Unclear Not enough information provided
Early stopping of trial Unclear Not enough information provided
Pageaux 1995
Methods Study design double-blind randomised study
Participants Country France
Publication language English
Inclusion criteria
- patients who underwent liver transplantation
Exclusion criteria
- not mentioned
Participants
- UDCA group (n=26)
Mean age (years +- SD)
47 +- 10
Ratio of sex (malefemale) 179
Origins of liver diseases alcoholic cirrhosis 14
post-hepatic B cirrhosis 2
post-hepatitis C cirrhosis 4
PBC 2
liver cancer 2
fulminant hepatitis 1
miscellaneous 1
- Placebo group (n = 24)
Mean age (years +- SD)
51+- 9
Ratio of sex (malefemale) 159
Origins of liver diseases alcoholic cirrhosis 10
post-hepatic B cirrhosis 0
post-hepatic C cirrhosis 6
PBC 3
liver cancer 4
fulminant hepatitis 0
miscellaneous 1
27Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Pageaux 1995 (Continued)
Interventions UDCA group
- Dose 600 mgday in three divided doses
- Route orally
- Duration immediately after intestinal transit recovery usually between postoperative
days three and five and continue for two months
Placebo group
- identical-appearing capsules administered in the same quantity and manner
Co-interventions all patients received standard triple-drug regimens (steroids azathio-
prine and cyclosporine or tacrolimus)
Outcomes Number of patients with acute cellular rejection
Number of patients with steroid-resistant rejection
Notes Letter was sent to the authors in September 2009 No reply was received
Risk of bias
Item Authorsrsquo judgement Description
Adequate sequence generation Unclear No information provided
Allocation concealment Unclear No information provided
Blinding Unclear Method of blinding not described
Incomplete outcome data addressed
All outcomes
Yes Five patients died from non-immunologi-
cal causes before the end of the first month
and were excluded from the study Reasons
were reported
Free of selective reporting Unclear Not enough information provided
Sample size calculation No Not performed
Intention-to-treat analysis No Not stated and not used
Baseline imbalance Unclear Not enough information provided
Early stopping of trial Unclear Not enough information provided
Sama 1991
Methods Study design randomised controlled trial
Participants Country Italy
Publication language English
Inclusion criteria
28Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Sama 1991 (Continued)
- patients who underwent liver transplantation
Exclusion criteria
- not mentioned
Participants
- UDCA group (n = 20)
Mean age (years +- SD)
no information
Ratio of sex (malefemale) no information
Origins of liver diseases
no information
- Control group (n = 20)
Mean age (years +- SD)
no information
Ratio of sex (malefemale) no information
Origins of liver diseases
no information
Interventions UDCA group
- Dose 600 mgday in two divided doses
- Route orally
- Duration immediately after intestinal transit recovery usually between postoperative
day five and day seven and continue for six months
Control group
- no treatment
Co-interventions all patients received standard immunosuppressive treatment (steroids
and cyclosporine)
Outcomes All cause mortality
Number of patients with acute cellular rejection
Notes Abstract
Letter was sent to the authors in September 2009 No reply was received
Risk of bias
Item Authorsrsquo judgement Description
Adequate sequence generation Unclear A randomisation list was performed before
patients were admitted to the trial (infor-
mation from principal author)
Allocation concealment Unclear No information provided
Blinding Unclear The principle author provided information
that the study was made according to a
single-blind randomised protocol The pri-
mary outcome was the occurrence of biopsy
proven rejection episodes The pathologists
were blind but the patients were not
29Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Sama 1991 (Continued)
Incomplete outcome data addressed
All outcomes
Unclear Five patients from the UDCA group and
six patients from the placebo group were
excluded Reasons for exclusion were not
fully stated
Free of selective reporting No Data about survival of patients were not
adequately reported
Sample size calculation No Not performed
Intention-to-treat analysis No Not stated and not used
Baseline imbalance Unclear Basic characteristics of patients not re-
ported
Early stopping of trial Unclear Not enough information provided
UDCA = ursodeoxycholic acid
TUDCA = tauroursodeoxycholic acid
PBC = primary biliary cirrhosis
PSC = primary sclerosing cholangitis
OKT3 = anti-CD3 monoclonal antibody
Characteristics of excluded studies [ordered by study ID]
Assy 2007 A randomised controlled trial that included only recipients of liver transplantation with stable graft function and
no episodes of rejection for at least 2 years that were then offered total immunosuppression withdrawal Fourteen
patients received UDCA (15 mgkg body weightday) and 12 received placebo Rejection occurred in 43 and
75 of patients respectively (no significant difference) None developed chronic rejection After follow-up two
patients were free of immunosuppression 80 were steroid free and 50 were able to reduce their dose of
cyclosporine
Clavien 1996 Case series Fifty consecutive liver-transplanted patients were treated with a standard cyclosporine immunosup-
pressive regimen Twenty three of the 43 survivors developed an episode of rejection and UDCA (10 mgkg
weightday) was initiated Only one patient had a second episode of rejection
Friman 1992 Observational study Thirty-three liver-transplanted patients received 10 mg UDCAkg body weightday for
median of 10 months (range four to 21 months) Eight historical liver-transplanted patients served as control
group The rejection incidence was significantly lower in the patients who received the treatment with UDCA
Biochemistry one month after transplantation demonstrated significantly lower average values of aminotrans-
ferases and alkaline phosphatases in patients treated with UDCA than in the control group
30Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
Heathcote 1999 Observational study From 1987 to 1996 37 UDCA treated and 53 placebo treated patients with primary biliary
cirrhosis were referred for transplantation Posttransplantation survival rates at one month were 939 in the
UDCA group and 884 in the placebo group and one year survival rates were 903 and 784 respectively
(no significant differences) However rejection (type not defined - a secondary outcome measure) occurred
significantly less often in the UDCA group (429) than in placebo group (688)
Henriksson 1991 Observational study All patients in this study were given sequential quadruple immunosuppression with anti-
lymphocyte globulin azathioprine steroids and cyclosporine All patients with primary graft function (n = 11)
were treated with 10 mg UDCAkg body weightday starting during the first postoperative week Patients who
received liver transplantation in the first 6 months of 1989 (n = 8) served as controls In the control group one
patient died after 9 months with chronic graft dysfunction and six patients had rejection episodes during the
first postoperative month All patients in the UDCA group were alive without rejection episodes
Persson 1990 Observational study All 11 adult patients transplanted between August 1989 and January 1990 with primary
graft function were treated with 10 mg UDCA kg body weightday Eight patients transplanted during the first
half of 1989 served as control UDCA was started during the first postoperative week and the treatment was
continued for six months All patients in the UDCA treated group survived with satisfactory graft function In
the control group six patients had at least one rejection episode needing treatment during the first postoperative
month
Rafael 1995 Observational study Seventeen patients who underwent liver transplantation between February 1990 and April
1993 and developed biliary complications after transplantation were retrospectively analysed regarding treatment
with UDCA UDCA was given in a dose of 500 to 1000 mgday Ten patients were treated for at least one year while
seven patients were treated for 14 to 250 days UDCA significantly improved gammaglutamyl transpeptidase in
liver graft recipients with biliary complications There was also a trend towards improvement in serum bilirubin
and alanine transaminase values
Sama 1998 Observational study Thirty-four patients who underwent liver transplantation between January 1995 and June
1996 were included in the study Seventeen were treated with UDCA 10 mgkg body weightday during 6
months while 17 served as controls on the basis of having undergone liver transplantation closest to UDCA
patients A significant decrease in serum bilirubin levels was observed in UDCA patients There was a significantly
higher incidence of recurrent hepatitis in the control group
UDCA ursodeoxycholic acid
31Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
D A T A A N D A N A L Y S E S
Comparison 1 Bile acids for liver-transplanted patients
Outcome or subgroup titleNo of
studies
No of
participants Statistical method Effect size
1 All-cause mortality at maximum
follow-up
5 257 Risk Ratio (M-H Fixed 95 CI) 085 [053 136]
11 UDCA versus placebo or
no treatment
4 224 Risk Ratio (M-H Fixed 95 CI) 080 [049 130]
12 TUDCA versus no
treatment
1 33 Risk Ratio (M-H Fixed 95 CI) 159 [030 833]
2 All-cause mortality worst-best
case and best-worst case
scenarios
5 Risk Ratio (M-H Fixed 95 CI) Subtotals only
21 Worst-best case scenario 5 257 Risk Ratio (M-H Fixed 95 CI) 130 [086 196]
22 Best-worst case scenario 5 257 Risk Ratio (M-H Fixed 95 CI) 058 [038 090]
3 Subgroup analyses all-cause
mortality at maximum
follow-up according to time of
start of bile acids
5 257 Risk Ratio (M-H Fixed 95 CI) 085 [053 136]
31 Less than three days after
transplantation
1 102 Risk Ratio (M-H Fixed 95 CI) 124 [061 254]
32 Three days or more after
transplantation
4 155 Risk Ratio (M-H Fixed 95 CI) 063 [033 120]
4 Subgroup analyses all cause
mortality at maximum
follow-up according to
treatment duration
5 257 Risk Ratio (M-H Fixed 95 CI) 085 [053 136]
41 Less than six months 3 184 Risk Ratio (M-H Fixed 95 CI) 078 [045 138]
42 Six months or more 2 73 Risk Ratio (M-H Fixed 95 CI) 102 [043 240]
5 Number of deaths related
to rejection at maximum
follow-up
1 102 Risk Ratio (M-H Fixed 95 CI) 030 [001 712]
51 UDCA versus placebo 1 102 Risk Ratio (M-H Fixed 95 CI) 030 [001 712]
6 Number of retransplantations at
maximum follow-up
2 132 Risk Ratio (M-H Fixed 95 CI) 076 [020 286]
7 Number of patients with acute
cellular rejection at maximum
follow-up
7 339 Risk Ratio (M-H Fixed 95 CI) 089 [074 106]
71 UDCA versus placebo or
no treatment
6 306 Risk Ratio (M-H Fixed 95 CI) 089 [074 108]
72 TUDCA versus no
treatment
1 33 Risk Ratio (M-H Fixed 95 CI) 085 [045 160]
8 Subgroup analysis number of
patients with acute cellular
rejection according to time of
start of bile acid
7 339 Risk Ratio (M-H Fixed 95 CI) 089 [074 106]
32Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
81 Less than three days after
transplantation
2 134 Risk Ratio (M-H Fixed 95 CI) 084 [063 111]
82 Three days or more after
liver transplantation
5 205 Risk Ratio (M-H Fixed 95 CI) 092 [072 117]
9 Subgroup analysis number
of patients with acute
cellular rejection according to
treatment duration
7 339 Risk Ratio (M-H Fixed 95 CI) 089 [074 106]
91 Less than six months 5 266 Risk Ratio (M-H Fixed 95 CI) 087 [071 107]
92 Six months or more 2 73 Risk Ratio (M-H Fixed 95 CI) 094 [065 136]
10 Number of patients with
chronic rejection at maximum
follow-up
3 184 Risk Ratio (M-H Fixed 95 CI) 028 [008 095]
11 Number of patients with
steroid-resistant rejection at
maximum follow-up
4 234 Risk Ratio (M-H Fixed 95 CI) 077 [047 127]
12 Serum bilirubin (mgdl) at the
end of treatment
1 30 Mean Difference (IV Fixed 95 CI) 26 [-096 616]
13 Number of days of
hospitalisation after liver
transplantation
1 52 Mean Difference (IV Fixed 95 CI) -85 [-1667 -033]
14 Adverse events 3 187 Risk Ratio (M-H Fixed 95 CI) 088 [030 260]
Analysis 11 Comparison 1 Bile acids for liver-transplanted patients Outcome 1 All-cause mortality at
maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 1 All-cause mortality at maximum follow-up
Study or subgroup Favours bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 UDCA versus placebo or no treatment
Barnes 1997 228 724 253 024 [ 006 107 ]
Fleckenstein 1998 214 416 125 057 [ 012 266 ]
Keiding 1997 1454 1048 355 124 [ 061 254 ]
Sama 1991 520 620 201 083 [ 030 229 ]
Subtotal (95 CI) 116 108 935 080 [ 049 130 ]
Total events 23 (Favours bile acids) 27 (Control)
Heterogeneity Chi2 = 416 df = 3 (P = 025) I2 =28
Test for overall effect Z = 091 (P = 036)
01 02 05 1 2 5 10
Favours bile acids Favours control
(Continued )
33Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Favours bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
2 TUDCA versus no treatment
Angelico 1999 316 217 65 159 [ 030 833 ]
Subtotal (95 CI) 16 17 65 159 [ 030 833 ]
Total events 3 (Favours bile acids) 2 (Control)
Heterogeneity not applicable
Test for overall effect Z = 055 (P = 058)
Total (95 CI) 132 125 1000 085 [ 053 136 ]
Total events 26 (Favours bile acids) 29 (Control)
Heterogeneity Chi2 = 466 df = 4 (P = 032) I2 =14
Test for overall effect Z = 069 (P = 049)
01 02 05 1 2 5 10
Favours bile acids Favours control
Analysis 12 Comparison 1 Bile acids for liver-transplanted patients Outcome 2 All-cause mortality worst-
best case and best-worst case scenarios
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 2 All-cause mortality worst-best case and best-worst case scenarios
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 Worst-best case scenario
Angelico 1999 516 217 65 266 [ 060 1180 ]
Barnes 1997 828 724 253 098 [ 042 230 ]
Fleckenstein 1998 314 416 125 086 [ 023 319 ]
Keiding 1997 1954 1048 355 169 [ 087 327 ]
Sama 1991 520 620 201 083 [ 030 229 ]
Subtotal (95 CI) 132 125 1000 130 [ 086 196 ]
Total events 40 (Bile acids) 29 (Control)
Heterogeneity Chi2 = 303 df = 4 (P = 055) I2 =00
Test for overall effect Z = 123 (P = 022)
2 Best-worst case scenario
005 02 1 5 20
Favours bile acids Favours control
(Continued )
34Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Angelico 1999 316 417 90 080 [ 021 302 ]
Barnes 1997 228 1124 274 016 [ 004 063 ]
Fleckenstein 1998 214 616 130 038 [ 009 159 ]
Keiding 1997 1454 1548 368 083 [ 045 154 ]
Sama 1991 520 620 139 083 [ 030 229 ]
Subtotal (95 CI) 132 125 1000 058 [ 038 090 ]
Total events 26 (Bile acids) 42 (Control)
Heterogeneity Chi2 = 567 df = 4 (P = 023) I2 =29
Test for overall effect Z = 247 (P = 0014)
005 02 1 5 20
Favours bile acids Favours control
Analysis 13 Comparison 1 Bile acids for liver-transplanted patients Outcome 3 Subgroup analyses all-
cause mortality at maximum follow-up according to time of start of bile acids
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 3 Subgroup analyses all-cause mortality at maximum follow-up according to time of start of bile acids
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 Less than three days after transplantation
Keiding 1997 1454 1048 355 124 [ 061 254 ]
Subtotal (95 CI) 54 48 355 124 [ 061 254 ]
Total events 14 (Bile acids) 10 (Control)
Heterogeneity not applicable
Test for overall effect Z = 060 (P = 055)
2 Three days or more after transplantation
Angelico 1999 316 217 65 159 [ 030 833 ]
Barnes 1997 228 724 253 024 [ 006 107 ]
Fleckenstein 1998 214 416 125 057 [ 012 266 ]
Sama 1991 520 620 201 083 [ 030 229 ]
005 02 1 5 20
Favours bile acids Favours control
(Continued )
35Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Subtotal (95 CI) 78 77 645 063 [ 033 120 ]
Total events 12 (Bile acids) 19 (Control)
Heterogeneity Chi2 = 310 df = 3 (P = 038) I2 =3
Test for overall effect Z = 141 (P = 016)
Total (95 CI) 132 125 1000 085 [ 053 136 ]
Total events 26 (Bile acids) 29 (Control)
Heterogeneity Chi2 = 466 df = 4 (P = 032) I2 =14
Test for overall effect Z = 069 (P = 049)
005 02 1 5 20
Favours bile acids Favours control
Analysis 14 Comparison 1 Bile acids for liver-transplanted patients Outcome 4 Subgroup analyses all
cause mortality at maximum follow-up according to treatment duration
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 4 Subgroup analyses all cause mortality at maximum follow-up according to treatment duration
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 Less than six months
Barnes 1997 228 724 253 024 [ 006 107 ]
Fleckenstein 1998 214 416 125 057 [ 012 266 ]
Keiding 1997 1454 1048 355 124 [ 061 254 ]
Subtotal (95 CI) 96 88 734 078 [ 045 138 ]
Total events 18 (Bile acids) 21 (Control)
Heterogeneity Chi2 = 417 df = 2 (P = 012) I2 =52
Test for overall effect Z = 084 (P = 040)
2 Six months or more
Angelico 1999 316 217 65 159 [ 030 833 ]
Sama 1991 520 620 201 083 [ 030 229 ]
Subtotal (95 CI) 36 37 266 102 [ 043 240 ]
Total events 8 (Bile acids) 8 (Control)
Heterogeneity Chi2 = 043 df = 1 (P = 051) I2 =00
005 02 1 5 20
Favours bile acids Favours control
(Continued )
36Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Test for overall effect Z = 004 (P = 097)
Total (95 CI) 132 125 1000 085 [ 053 136 ]
Total events 26 (Bile acids) 29 (Control)
Heterogeneity Chi2 = 466 df = 4 (P = 032) I2 =14
Test for overall effect Z = 069 (P = 049)
005 02 1 5 20
Favours bile acids Favours control
Analysis 15 Comparison 1 Bile acids for liver-transplanted patients Outcome 5 Number of deaths related
to rejection at maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 5 Number of deaths related to rejection at maximum follow-up
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 UDCA versus placebo
Keiding 1997 054 148 1000 030 [ 001 712 ]
Total (95 CI) 54 48 1000 030 [ 001 712 ]
Total events 0 (Bile acids) 1 (Control)
Heterogeneity not applicable
Test for overall effect Z = 075 (P = 045)
0001 001 01 1 10 100 1000
Favours bile acids Favours control
37Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 16 Comparison 1 Bile acids for liver-transplanted patients Outcome 6 Number of
retransplantations at maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 6 Number of retransplantations at maximum follow-up
Study or subgroup Bile acids Placebo Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Fleckenstein 1998 214 016 100 567 [ 029 10891 ]
Keiding 1997 154 448 900 022 [ 003 192 ]
Total (95 CI) 68 64 1000 076 [ 020 286 ]
Total events 3 (Bile acids) 4 (Placebo)
Heterogeneity Chi2 = 303 df = 1 (P = 008) I2 =67
Test for overall effect Z = 040 (P = 069)
0001 001 01 1 10 100 1000
Favours bile acids Favours placebo
Analysis 17 Comparison 1 Bile acids for liver-transplanted patients Outcome 7 Number of patients with
acute cellular rejection at maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 7 Number of patients with acute cellular rejection at maximum follow-up
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 UDCA versus placebo or no treatment
Barnes 1997 1728 1724 180 086 [ 058 127 ]
Fleckenstein 1998 814 916 83 102 [ 054 190 ]
Keiding 1997 3554 3248 333 097 [ 073 129 ]
Koneru 1993 316 916 89 033 [ 011 101 ]
Pageaux 1995 926 924 92 092 [ 044 193 ]
Sama 1991 1320 1320 128 100 [ 063 158 ]
Subtotal (95 CI) 158 148 905 089 [ 074 108 ]
01 02 05 1 2 5 10
Favours bile acids Favours control
(Continued )
38Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Total events 85 (Bile acids) 89 (Control)
Heterogeneity Chi2 = 387 df = 5 (P = 057) I2 =00
Test for overall effect Z = 120 (P = 023)
2 TUDCA versus no treatment
Angelico 1999 816 1017 95 085 [ 045 160 ]
Subtotal (95 CI) 16 17 95 085 [ 045 160 ]
Total events 8 (Bile acids) 10 (Control)
Heterogeneity not applicable
Test for overall effect Z = 050 (P = 061)
Total (95 CI) 174 165 1000 089 [ 074 106 ]
Total events 93 (Bile acids) 99 (Control)
Heterogeneity Chi2 = 392 df = 6 (P = 069) I2 =00
Test for overall effect Z = 130 (P = 019)
01 02 05 1 2 5 10
Favours bile acids Favours control
Analysis 18 Comparison 1 Bile acids for liver-transplanted patients Outcome 8 Subgroup analysis
number of patients with acute cellular rejection according to time of start of bile acid
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 8 Subgroup analysis number of patients with acute cellular rejection according to time of start of bile acid
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 Less than three days after transplantation
Keiding 1997 3554 3248 333 097 [ 073 129 ]
Koneru 1993 316 916 89 033 [ 011 101 ]
Subtotal (95 CI) 70 64 422 084 [ 063 111 ]
Total events 38 (Bile acids) 41 (Control)
Heterogeneity Chi2 = 374 df = 1 (P = 005) I2 =73
Test for overall effect Z = 124 (P = 022)
2 Three days or more after liver transplantation
Angelico 1999 816 1017 95 085 [ 045 160 ]
01 02 05 1 2 5 10
Favours bile acids Favours control
(Continued )
39Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Barnes 1997 1728 1724 180 086 [ 058 127 ]
Fleckenstein 1998 814 916 83 102 [ 054 190 ]
Pageaux 1995 926 924 92 092 [ 044 193 ]
Sama 1991 1320 1320 128 100 [ 063 158 ]
Subtotal (95 CI) 104 101 578 092 [ 072 117 ]
Total events 55 (Bile acids) 58 (Control)
Heterogeneity Chi2 = 041 df = 4 (P = 098) I2 =00
Test for overall effect Z = 067 (P = 050)
Total (95 CI) 174 165 1000 089 [ 074 106 ]
Total events 93 (Bile acids) 99 (Control)
Heterogeneity Chi2 = 392 df = 6 (P = 069) I2 =00
Test for overall effect Z = 130 (P = 019)
01 02 05 1 2 5 10
Favours bile acids Favours control
40Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 19 Comparison 1 Bile acids for liver-transplanted patients Outcome 9 Subgroup analysis
number of patients with acute cellular rejection according to treatment duration
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 9 Subgroup analysis number of patients with acute cellular rejection according to treatment duration
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 Less than six months
Barnes 1997 1728 1724 180 086 [ 058 127 ]
Fleckenstein 1998 814 916 83 102 [ 054 190 ]
Keiding 1997 3554 3248 333 097 [ 073 129 ]
Koneru 1993 316 916 89 033 [ 011 101 ]
Pageaux 1995 926 924 92 092 [ 044 193 ]
Subtotal (95 CI) 138 128 777 087 [ 071 107 ]
Total events 72 (Bile acids) 76 (Control)
Heterogeneity Chi2 = 374 df = 4 (P = 044) I2 =00
Test for overall effect Z = 129 (P = 020)
2 Six months or more
Angelico 1999 816 1017 95 085 [ 045 160 ]
Sama 1991 1320 1320 128 100 [ 063 158 ]
Subtotal (95 CI) 36 37 223 094 [ 065 136 ]
Total events 21 (Bile acids) 23 (Control)
Heterogeneity Chi2 = 017 df = 1 (P = 068) I2 =00
Test for overall effect Z = 035 (P = 073)
Total (95 CI) 174 165 1000 089 [ 074 106 ]
Total events 93 (Bile acids) 99 (Control)
Heterogeneity Chi2 = 392 df = 6 (P = 069) I2 =00
Test for overall effect Z = 130 (P = 019)
01 02 05 1 2 5 10
Favours bile acids Favours control
41Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 110 Comparison 1 Bile acids for liver-transplanted patients Outcome 10 Number of patients
with chronic rejection at maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 10 Number of patients with chronic rejection at maximum follow-up
Study or subgroup Bile acids Placebo Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Barnes 1997 128 624 611 014 [ 002 110 ]
Fleckenstein 1998 114 116 88 114 [ 008 1663 ]
Keiding 1997 154 348 300 030 [ 003 275 ]
Total (95 CI) 96 88 1000 028 [ 008 095 ]
Total events 3 (Bile acids) 10 (Placebo)
Heterogeneity Chi2 = 148 df = 2 (P = 048) I2 =00
Test for overall effect Z = 204 (P = 0041)
0001 001 01 1 10 100 1000
Favours bile acids Favours placebo
Analysis 111 Comparison 1 Bile acids for liver-transplanted patients Outcome 11 Number of patients
with steroid-resistant rejection at maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 11 Number of patients with steroid-resistant rejection at maximum follow-up
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Barnes 1997 328 724 277 037 [ 011 127 ]
Fleckenstein 1998 314 316 103 114 [ 027 478 ]
Keiding 1997 1454 1548 583 083 [ 045 154 ]
Pageaux 1995 226 124 38 185 [ 018 1908 ]
Total (95 CI) 122 112 1000 077 [ 047 127 ]
Total events 22 (Bile acids) 26 (Control)
Heterogeneity Chi2 = 226 df = 3 (P = 052) I2 =00
Test for overall effect Z = 102 (P = 031)
001 01 1 10 100
Favours bile acids Favours placebo
42Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 112 Comparison 1 Bile acids for liver-transplanted patients Outcome 12 Serum bilirubin (mgdl)
at the end of treatment
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 12 Serum bilirubin (mgdl) at the end of treatment
Study or subgroup Bile acids Placebo Mean Difference Weight Mean Difference
N Mean(SD) N Mean(SD) IVFixed95 CI IVFixed95 CI
Fleckenstein 1998 14 319 (68) 16 059 (022) 1000 260 [ -096 616 ]
Total (95 CI) 14 16 1000 260 [ -096 616 ]
Heterogeneity not applicable
Test for overall effect Z = 143 (P = 015)
-10 -5 0 5 10
Favours bile acids Favours placebo
Analysis 113 Comparison 1 Bile acids for liver-transplanted patients Outcome 13 Number of days of
hospitalisation after liver transplantation
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 13 Number of days of hospitalisation after liver transplantation
Study or subgroup Bile acids Placebo Mean Difference Weight Mean Difference
N Mean(SD) N Mean(SD) IVFixed95 CI IVFixed95 CI
Barnes 1997 28 25 (17) 24 335 (13) 1000 -850 [ -1667 -033 ]
Total (95 CI) 28 24 1000 -850 [ -1667 -033 ]
Heterogeneity not applicable
Test for overall effect Z = 204 (P = 0041)
-100 -50 0 50 100
Favours bile acids Favours placebo
43Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 114 Comparison 1 Bile acids for liver-transplanted patients Outcome 14 Adverse events
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 14 Adverse events
Study or subgroup Bile acids Placebo Risk Ratio Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Angelico 1999 016 017 00 [ 00 00 ]
Barnes 1997 128 124 086 [ 006 1298 ]
Keiding 1997 554 548 089 [ 027 288 ]
Total (95 CI) 98 89 088 [ 030 260 ]
Total events 6 (Bile acids) 6 (Placebo)
Heterogeneity Chi2 = 000 df = 1 (P = 098) I2 =00
Test for overall effect Z = 022 (P = 082)
001 01 1 10 100
Favours bile acids Favours placebo
A P P E N D I C E S
Appendix 1 Search strategies
Data Base Date of Search Search Strategy
The Cochrane Hepato-Biliary Group Con-
trolled Trials Register
September 2009 1 rsquoliver transplantationrsquo and rsquochenodeoxy-
cholicrsquo
2 rsquoliver transplantationrsquo and rsquocholicrsquo
3 rsquoliver transplantationrsquo and rsquodeoxycholicrsquo
4 rsquoliver transplantationrsquo and rsquoglycochen-
odeoxycholicrsquo
5 rsquoliver transplantationrsquo and rsquoglycocholicrsquo
6 rsquoliver transplantationrsquo and rsquoglycodeoxy-
cholicrsquo
7 rsquoliver transplantationrsquo and rsquoglycolitho-
cholicrsquo
8 rsquoliver transplantationrsquo and rsquohyodeoxy-
cholicrsquo
9 rsquoliver transplantationrsquo and rsquolithocholicrsquo
10 rsquoliver transplantationrsquo and rsquotaurochen-
odeoxycholicrsquo
44Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
11 rsquoliver transplantationrsquo and rsquotauro-
cholicrsquo
12 rsquoliver transplantationrsquo and rsquotaurodehy-
drocholicrsquo
13 rsquoliver transplantationrsquo and rsquotau-
rodeoxycholicrsquo
14 rsquoliver transplantationrsquo and rsquotauroglyco-
cholicrsquo
15 rsquoliver transplantationrsquo and rsquotaurolitho-
cholicrsquo
16 rsquoliver transplantationrsquo and rsquotaurosel-
cholicrsquo
17 rsquoliver transplantationrsquo and rsquotaurourso-
cholicrsquo
18 rsquoliver transplantationrsquo and rsquotaurour-
sodeoxycholicrsquo
19 rsquoliver transplantationrsquo and rsquoursocholicrsquo
20 rsquoliver transplantationrsquo and rsquoursodeoxy-
cholicrsquo
The Cochrane Central Register of Con-
trolled Trials in The Cochrane Library
Issue 3 2009 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
6 3 or 4
7 5 and 6
MEDLINE September 2009 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
45Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
6 3 or 4
7 5 and 6
8 RANDOMIZED-CONTROLLED-
TRIAL ME
9 RANDOM
10 8 or 9
11 7 and 10
EMBASE September 2009 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
6 3 or 4
7 5 and 6
8 RANDOMIZED-CONTROLLED-
TRIAL ME
9 RANDOM
10 8 or 9
11 7 and 10
46Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
Science Citation Index Expanded September 2009 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
6 3 or 4
7 5 and 6
8 RANDOMIZED-CONTROLLED-
TRIAL ME
9 RANDOM
10 8 or 9
11 7 and 10
The Chinese Biomedical Database Searched from January 1980 to April 2002 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
47Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
6 3 or 4
7 5 and 6
8 RANDOMIZED-CONTROLLED-
TRIAL ME
9 RANDOM
10 8 or 9
11 7 and 10
W H A T rsquo S N E W
Last assessed as up-to-date 8 February 2010
18 September 2009 New citation required but conclusions have not
changed
This review is an updated version of a review that was
published for the first time in Issue 3 2005 of TheCochrane Library by Chen 2003b
18 September 2009 New search has been performed No new studies fulfilled the inclusion criteria
H I S T O R Y
Protocol first published Issue 3 2003
Review first published Issue 3 2005
C O N T R I B U T I O N S O F A U T H O R S
GP and VG independently performed searches of relevant databases GP validated the search selected trials for inclusion contacted
the authors of the trials performed data extraction and data analysis and drafted the systematic review VG revised the review update
CG and DS revised the review update solved discrepancies of data extraction validated data analyses and provided consultation
D E C L A R A T I O N S O F I N T E R E S T
None known
48Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
S O U R C E S O F S U P P O R T
Internal sources
bull Copenhagen Trial Unit Denmark
External sources
bull Danish Medical Research Councilrsquos Grant on Getting Research into Practice (GRIP) Denmark
D I F F E R E N C E S B E T W E E N P R O T O C O L A N D R E V I E W
We assessed the risk of bias in the included studies for another four domains that were added to the review protocol (incomplete
outcome data selective outcome reporting baseline imbalance and early stopping of trial) In general the text of the risk of bias
domains were updated following Higgins 2008 Trials were considered at low risk of bias when judged as adequate in all domains
Quasi-randomised studies observational and case-control studies were included for the report of adverse events
We performed trial sequential analysis for outcomes demonstrating a statistically significant result
I N D E X T E R M S
Medical Subject Headings (MeSH)
lowastLiver Transplantation Cholagogues and Choleretics [lowasttherapeutic use] Graft Rejection [lowastprevention amp control] Randomized Con-
trolled Trials as Topic Taurochenodeoxycholic Acid [lowasttherapeutic use] Ursodeoxycholic Acid [lowasttherapeutic use]
MeSH check words
Humans
49Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Chen 2003b
Chen W Gluud C Bile acids for liver transplanted patients
Cochrane Database of Systematic Reviews 2005 Issue 3 [DOI
10100214651858CD005442]lowast Indicates the major publication for the study
18Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
C H A R A C T E R I S T I C S O F S T U D I E S
Characteristics of included studies [ordered by study ID]
Angelico 1999
Methods Study design open-label randomised one-year pilot study
Participants Country Italy
Publication language English
Inclusion criteria
- patients who underwent liver transplantation from April 1994 to December 1994
Exclusion criteria
- not mentioned
Participants
Two patients in TUDCA group and two patients in control group were excluded from
the basic information of participants by the study due to withdrawal
- TUDCA group (n = 14)
Mean age (years +- SD)
467 +- 84
Ratio of sex (malefemale) 122
Origins of liver diseases
hepatitis C cirrhosis (9) hepatitis B cirrhosis (2) hepatitis B and C cirrhosis (1) cryp-
togenic cirrhosis (2) alcoholic cirrhosis (0) Wilson cirrhosis (0)
- Control group (n = 15)
Mean age (years +- SD)
474 +- 74
Ratio of sex (malefemale) 123
Origins of liver diseases
hepatitis C cirrhosis (7) hepatitis B cirrhosis (2) hepatitis B and C cirrhosis (2) cryp-
togenic cirrhosis (2) alcoholic cirrhosis (1) Wilson cirrhosis (1)
Interventions TUDCA group
- Dose 500 mgday in two divided doses
- Route orally
- Duration the treatment was started on day 5 after transplantation and continued for
one year
Control group
- no treatment
Co-interventions all patients received standard triple-drug regimens (steroids azathio-
prine and cyclosporine or tacrolimus)
Outcomes All cause mortality
Number of patients with rejection after liver transplantation
Notes Letter was sent to the authors in September 2009 A reply with additional information
was received shortly after
Risk of bias
19Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Angelico 1999 (Continued)
Item Authorsrsquo judgement Description
Adequate sequence generation Yes Computer generated table
Allocation concealment Unclear No information provided
Blinding No Not performed
Incomplete outcome data addressed
All outcomes
Yes Withdrawal two patients from the
TUDCA group and two patients from the
placebo group Three of them died due to
transplant non-function in the first postop-
erative week and one patient was regrafted
due to thrombosis of hepatic artery
Free of selective reporting Unclear Post-transplant cholestasis and liver bio-
chemistry specified as outcomes Differ-
ence reported as not significant but no ac-
tual data given
Sample size calculation No Not reported
Intention-to-treat analysis No Not stated and not used
Baseline imbalance Unclear Not enough information provided
Early stopping of trial Unclear Not enough information provided
Barnes 1997
Methods Study design randomised placebo-controlled double-blind trial
Participants Country United States
Publication language English
Inclusion criteria
- patients aged 18 years or older who underwent liver transplantation at the Cleveland
Clinic Foundation from April 1992 through June of 1994
Exclusion criteria
- patients who were found to have cancer at surgically resected margins of the biliary
tree
- patents who underwent retransplantation
Participants
- UDCA group (n = 28)
Mean age (years +- SD)
505 +- 116
Ratio of sex (malefemale) 1810
Child class A 7
20Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Barnes 1997 (Continued)
B 13
and C 8
Origins of liver diseases Laennecrsquos cirrhosis 4
PBC 3
cryptogenic cirrhosis 6
hepatitis Ccirrhosis 4
hepatitis Bcirrhosis 3
autoimmune hepatitis with cirrhosis 3
PSC 2
other 3
- Placebo group (n = 24)
Mean age (years +- SD)
507 +- 93
Ratio of sex (malefemale) 159
Child class A 6
B 14
and C 4
Origins of liver diseases Laennecrsquos cirrhosis 9
PBC 5
cryptogenic cirrhosis 1
hepatitis Ccirrhosis 1
hepatitis Bcirrhosis 1
autoimmune hepatitis with cirrhosis 1
PSC 2
other 4
Interventions UDCA group
- Dose 10-15 mgkg body weightday in divided doses
- Route orally
- Duration immediately after intestinal transit recovery usually between postoperative
days three and five and continue for three months
Placebo group
- identical-appearing capsules administered in the same quantity and manner
Co-interventions all patients received standard triple-drug regimens (steroids azathio-
prine and cyclosporine or tacrolimus)
Outcomes All cause mortality
Number of patients with acute cellular rejection
Number of patients with chronic rejection
Number of patients with steroid-resistant rejection
Number of days of hospitalisation
Adverse events
Notes Letter was sent to the authors in September 2009 A reply with additional information
was received shortly after
Risk of bias
Item Authorsrsquo judgement Description
21Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Barnes 1997 (Continued)
Adequate sequence generation Yes Computer generated table
Allocation concealment Unclear No information provided
Blinding Yes Quote ldquorandomised to receive either
UDCA or an identical placebo capsulerdquo
Incomplete outcome data addressed
All outcomes
Yes Mean follow-up time 18 months Ten pa-
tients withdrawn from study 6 in UDCA
group and 4 in placebo group Reasons
for withdrawal were reported Four patients
died in the placebo group
Free of selective reporting Yes All expected outcomes reported
Sample size calculation Unclear The trial reported the method of sample
size calculation but the actual number of
patients needed was not reported
Intention-to-treat analysis Yes Stated and used
Baseline imbalance Unclear Not enough information provided
Early stopping of trial Unclear The number of patients needed to gain the
actual power was not reported Whether
the trial was terminated early is not clear
Fleckenstein 1998
Methods Study design prospective randomised double-blind trial
Participants Country United States
Publication language English
Inclusion criteria
- patients who underwent liver transplantation at the Johns Hopkins Hospital
Exclusion criteria
- patients who were under 18 years old undergoing repeat transplantation had primary
graft nonfunction or refused consent
Participants
- UDCA group (n = 14)
Mean age (years +- SD)
443 +- 127
Ratio of sex (malefemale) 68
Origins of liver diseases hepatitis C 6
alcohol 2
autoimmune 1
PBC 2
22Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Fleckenstein 1998 (Continued)
PSC 1
autoimmune cholangiopathy 1
hepatitis B 1
- Placebo group (n = 16)
Mean age (years +- SD)
496 +- 109
Ratio of sex (malefemale) 124
Origins of liver diseases hepatitis C 3
alcohol 3
autoimmune 3
PBC 1
PSC 2
cryptogenic 2
hepatitis B 1
alpha1-antitrypsin deficiency 1
Interventions UDCA group
- Dose 15 mgkg body weightday in divided doses
- Route orally
- Duration immediately after intestinal transit recovery usually between postoperative
days three and five and continue for three months
Placebo group
- Identical-appearing capsules administered in the same quantity and manner
Co-interventions all patients received standard triple-drug regimens (steroids azathio-
prine and cyclosporine or tacrolimus)
Outcomes All cause mortality
Number with retransplantation
Number of patients with acute cellular rejection
Number of patients with chronic rejection
Serum bilirubin levels at the end of treatment
Notes Follow-up time nine months
Letter was sent to the authors in September 2009 No reply was received
Risk of bias
Item Authorsrsquo judgement Description
Adequate sequence generation Unclear No information provided
Allocation concealment Unclear No information provided
Blinding Yes Method of blinding not described but
probably adequate
Incomplete outcome data addressed
All outcomes
Yes Withdrawal one patient from the UDCA
group and two patients from the placebo
group because of capsule size
23Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Fleckenstein 1998 (Continued)
Free of selective reporting Unclear Outcomes were not completely described
Sample size calculation No Not reported
Intention-to-treat analysis Yes Quote ldquoThree patients withdrew after in-
clusionThey were included in the statis-
tical analysisrdquo
Baseline imbalance Unclear Not enough information provided
Early stopping of trial Unclear Not enough information provided
Keiding 1997
Methods Study design prospective randomised placebo-controlled multicenter study
Participants Country Denmark Finland Norway and Sweden
Publication language English
Inclusion criteria
- patients who underwent liver transplantation in Denmark Finland Norway and Swe-
den from September 1 1992 to May 31 1994
Exclusion criteria
- patients with malignant diseases
Participants
The age of the children ranged from 0 to 13 years (median 15) and the age of adults
ranged from 14 to 59 years old (median 44) MaleFemale ratio was 96 for children and
4344 for adults
- UDCA group (n = 54)
Origins of liver diseases
paracetamol intoxication 1 hepatitis B 1 autoimmune hepatitis 0 biliary atresia 2
metabolic diseases 7 neonatal hepatitis 2 PBC 13 post hepatitis cirrhosis 8 PSC 3
cryptogenic cirrhosis 7 alcoholic cirrhosis 2 other reasons 8
- Placebo group (n = 48)
Origins of liver diseases paracetamol intoxication 1 hepatitis B 0 autoimmune hepatitis
1 biliary atresia 3 metabolic diseases 11 neonatal hepatitis 0 PBC 7 post hepatitis
cirrhosis 5 PSC 7 cryptogenic cirrhosis 2 alcoholic cirrhosis 6 other reasons 5
Interventions UDCA group
- Dose 15 mgkg body weightday in two or three divided doses
- Route orally
- Duration immediately after intestinal transit recovery usually between postoperative
days three and five and continue for three months
Placebo group
- Identical-appearing capsules administered in the same quantity and manner
Co-interventions all patients received standard triple-drug regimens (steroids azathio-
prine and cyclosporine or tacrolimus)
24Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Keiding 1997 (Continued)
Outcomes All cause mortality
Number of deaths related to rejection
Number of patients with acute cellular rejection
Number of patients with chronic rejection
Number of patients with steroid-resistant rejection
Adverse events
Notes Letter was sent to the authors in September 2009 No reply was received
Risk of bias
Item Authorsrsquo judgement Description
Adequate sequence generation Unclear Patients were randomised at a ratio of 11
Allocation concealment Yes Quote ldquo The allocation was performed in
blocks of 10 patients using the sealed serial
envelope methodrdquo
Blinding Yes Quote ldquoThe UDCA and the placebo cap-
sules had identical appearance and tasterdquo
Incomplete outcome data addressed
All outcomes
Yes Follow-up time 12 months Five UDCA
patients and five placebo patients withdrew
from study Reasons were reported
Free of selective reporting Unclear Insufficient information
Sample size calculation Yes Performed and allowed for a difference in
the incidence of at least one episode of
acute rejection of 50 between the treat-
ment and placebo groups with 90 statisti-
cal power and a significance level of P value
less than 005 The calculated sample size
was 80 patients
Intention-to-treat analysis Yes Stated and used
Baseline imbalance Yes The study seems to be free of baseline im-
balance
Early stopping of trial Yes Study attained the pre-specified sample
size
25Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Koneru 1993
Methods Study design randomised controlled trial
Participants Country United States
Publication language English
Inclusion criteria
- patients who underwent liver transplantation
Exclusion criteria
- not mentioned
Participants
- UDCA group (n = 16)
Mean age (years +- SD)
no information
Ratio of sex (malefemale) no information
Origins of liver diseases
no information
- Control group (n = 16)
Mean age (years +- SD)
no information
Ratio of sex (malefemale) no information
Origins of liver diseases
no information
Interventions UDCA group
- Dose 900 mgday
- Route orally
- Duration immediately after intestinal transit recovery usually between postoperative
days three and five and continue for three months
Control group
- no treatment
Co-interventions all patients received standard triple-drug regimens (steroids azathio-
prine and cyclosporine)
Outcomes Number of patients with retransplantation due to rejection
Number of patients with rejection episodes
Notes Abstract
Letter was sent to the authors in September 2009 No reply was received
Risk of bias
Item Authorsrsquo judgement Description
Adequate sequence generation Unclear No information provided
Allocation concealment Unclear No information provided
Blinding No Not performed
26Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Koneru 1993 (Continued)
Incomplete outcome data addressed
All outcomes
Unclear The study gives the impression that there
were no withdrawals but this was not ex-
plicitly stated
Free of selective reporting Unclear Insufficient information provided
Sample size calculation No Not performed
Intention-to-treat analysis Unclear No information provided
Baseline imbalance Unclear Not enough information provided
Early stopping of trial Unclear Not enough information provided
Pageaux 1995
Methods Study design double-blind randomised study
Participants Country France
Publication language English
Inclusion criteria
- patients who underwent liver transplantation
Exclusion criteria
- not mentioned
Participants
- UDCA group (n=26)
Mean age (years +- SD)
47 +- 10
Ratio of sex (malefemale) 179
Origins of liver diseases alcoholic cirrhosis 14
post-hepatic B cirrhosis 2
post-hepatitis C cirrhosis 4
PBC 2
liver cancer 2
fulminant hepatitis 1
miscellaneous 1
- Placebo group (n = 24)
Mean age (years +- SD)
51+- 9
Ratio of sex (malefemale) 159
Origins of liver diseases alcoholic cirrhosis 10
post-hepatic B cirrhosis 0
post-hepatic C cirrhosis 6
PBC 3
liver cancer 4
fulminant hepatitis 0
miscellaneous 1
27Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Pageaux 1995 (Continued)
Interventions UDCA group
- Dose 600 mgday in three divided doses
- Route orally
- Duration immediately after intestinal transit recovery usually between postoperative
days three and five and continue for two months
Placebo group
- identical-appearing capsules administered in the same quantity and manner
Co-interventions all patients received standard triple-drug regimens (steroids azathio-
prine and cyclosporine or tacrolimus)
Outcomes Number of patients with acute cellular rejection
Number of patients with steroid-resistant rejection
Notes Letter was sent to the authors in September 2009 No reply was received
Risk of bias
Item Authorsrsquo judgement Description
Adequate sequence generation Unclear No information provided
Allocation concealment Unclear No information provided
Blinding Unclear Method of blinding not described
Incomplete outcome data addressed
All outcomes
Yes Five patients died from non-immunologi-
cal causes before the end of the first month
and were excluded from the study Reasons
were reported
Free of selective reporting Unclear Not enough information provided
Sample size calculation No Not performed
Intention-to-treat analysis No Not stated and not used
Baseline imbalance Unclear Not enough information provided
Early stopping of trial Unclear Not enough information provided
Sama 1991
Methods Study design randomised controlled trial
Participants Country Italy
Publication language English
Inclusion criteria
28Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Sama 1991 (Continued)
- patients who underwent liver transplantation
Exclusion criteria
- not mentioned
Participants
- UDCA group (n = 20)
Mean age (years +- SD)
no information
Ratio of sex (malefemale) no information
Origins of liver diseases
no information
- Control group (n = 20)
Mean age (years +- SD)
no information
Ratio of sex (malefemale) no information
Origins of liver diseases
no information
Interventions UDCA group
- Dose 600 mgday in two divided doses
- Route orally
- Duration immediately after intestinal transit recovery usually between postoperative
day five and day seven and continue for six months
Control group
- no treatment
Co-interventions all patients received standard immunosuppressive treatment (steroids
and cyclosporine)
Outcomes All cause mortality
Number of patients with acute cellular rejection
Notes Abstract
Letter was sent to the authors in September 2009 No reply was received
Risk of bias
Item Authorsrsquo judgement Description
Adequate sequence generation Unclear A randomisation list was performed before
patients were admitted to the trial (infor-
mation from principal author)
Allocation concealment Unclear No information provided
Blinding Unclear The principle author provided information
that the study was made according to a
single-blind randomised protocol The pri-
mary outcome was the occurrence of biopsy
proven rejection episodes The pathologists
were blind but the patients were not
29Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Sama 1991 (Continued)
Incomplete outcome data addressed
All outcomes
Unclear Five patients from the UDCA group and
six patients from the placebo group were
excluded Reasons for exclusion were not
fully stated
Free of selective reporting No Data about survival of patients were not
adequately reported
Sample size calculation No Not performed
Intention-to-treat analysis No Not stated and not used
Baseline imbalance Unclear Basic characteristics of patients not re-
ported
Early stopping of trial Unclear Not enough information provided
UDCA = ursodeoxycholic acid
TUDCA = tauroursodeoxycholic acid
PBC = primary biliary cirrhosis
PSC = primary sclerosing cholangitis
OKT3 = anti-CD3 monoclonal antibody
Characteristics of excluded studies [ordered by study ID]
Assy 2007 A randomised controlled trial that included only recipients of liver transplantation with stable graft function and
no episodes of rejection for at least 2 years that were then offered total immunosuppression withdrawal Fourteen
patients received UDCA (15 mgkg body weightday) and 12 received placebo Rejection occurred in 43 and
75 of patients respectively (no significant difference) None developed chronic rejection After follow-up two
patients were free of immunosuppression 80 were steroid free and 50 were able to reduce their dose of
cyclosporine
Clavien 1996 Case series Fifty consecutive liver-transplanted patients were treated with a standard cyclosporine immunosup-
pressive regimen Twenty three of the 43 survivors developed an episode of rejection and UDCA (10 mgkg
weightday) was initiated Only one patient had a second episode of rejection
Friman 1992 Observational study Thirty-three liver-transplanted patients received 10 mg UDCAkg body weightday for
median of 10 months (range four to 21 months) Eight historical liver-transplanted patients served as control
group The rejection incidence was significantly lower in the patients who received the treatment with UDCA
Biochemistry one month after transplantation demonstrated significantly lower average values of aminotrans-
ferases and alkaline phosphatases in patients treated with UDCA than in the control group
30Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
Heathcote 1999 Observational study From 1987 to 1996 37 UDCA treated and 53 placebo treated patients with primary biliary
cirrhosis were referred for transplantation Posttransplantation survival rates at one month were 939 in the
UDCA group and 884 in the placebo group and one year survival rates were 903 and 784 respectively
(no significant differences) However rejection (type not defined - a secondary outcome measure) occurred
significantly less often in the UDCA group (429) than in placebo group (688)
Henriksson 1991 Observational study All patients in this study were given sequential quadruple immunosuppression with anti-
lymphocyte globulin azathioprine steroids and cyclosporine All patients with primary graft function (n = 11)
were treated with 10 mg UDCAkg body weightday starting during the first postoperative week Patients who
received liver transplantation in the first 6 months of 1989 (n = 8) served as controls In the control group one
patient died after 9 months with chronic graft dysfunction and six patients had rejection episodes during the
first postoperative month All patients in the UDCA group were alive without rejection episodes
Persson 1990 Observational study All 11 adult patients transplanted between August 1989 and January 1990 with primary
graft function were treated with 10 mg UDCA kg body weightday Eight patients transplanted during the first
half of 1989 served as control UDCA was started during the first postoperative week and the treatment was
continued for six months All patients in the UDCA treated group survived with satisfactory graft function In
the control group six patients had at least one rejection episode needing treatment during the first postoperative
month
Rafael 1995 Observational study Seventeen patients who underwent liver transplantation between February 1990 and April
1993 and developed biliary complications after transplantation were retrospectively analysed regarding treatment
with UDCA UDCA was given in a dose of 500 to 1000 mgday Ten patients were treated for at least one year while
seven patients were treated for 14 to 250 days UDCA significantly improved gammaglutamyl transpeptidase in
liver graft recipients with biliary complications There was also a trend towards improvement in serum bilirubin
and alanine transaminase values
Sama 1998 Observational study Thirty-four patients who underwent liver transplantation between January 1995 and June
1996 were included in the study Seventeen were treated with UDCA 10 mgkg body weightday during 6
months while 17 served as controls on the basis of having undergone liver transplantation closest to UDCA
patients A significant decrease in serum bilirubin levels was observed in UDCA patients There was a significantly
higher incidence of recurrent hepatitis in the control group
UDCA ursodeoxycholic acid
31Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
D A T A A N D A N A L Y S E S
Comparison 1 Bile acids for liver-transplanted patients
Outcome or subgroup titleNo of
studies
No of
participants Statistical method Effect size
1 All-cause mortality at maximum
follow-up
5 257 Risk Ratio (M-H Fixed 95 CI) 085 [053 136]
11 UDCA versus placebo or
no treatment
4 224 Risk Ratio (M-H Fixed 95 CI) 080 [049 130]
12 TUDCA versus no
treatment
1 33 Risk Ratio (M-H Fixed 95 CI) 159 [030 833]
2 All-cause mortality worst-best
case and best-worst case
scenarios
5 Risk Ratio (M-H Fixed 95 CI) Subtotals only
21 Worst-best case scenario 5 257 Risk Ratio (M-H Fixed 95 CI) 130 [086 196]
22 Best-worst case scenario 5 257 Risk Ratio (M-H Fixed 95 CI) 058 [038 090]
3 Subgroup analyses all-cause
mortality at maximum
follow-up according to time of
start of bile acids
5 257 Risk Ratio (M-H Fixed 95 CI) 085 [053 136]
31 Less than three days after
transplantation
1 102 Risk Ratio (M-H Fixed 95 CI) 124 [061 254]
32 Three days or more after
transplantation
4 155 Risk Ratio (M-H Fixed 95 CI) 063 [033 120]
4 Subgroup analyses all cause
mortality at maximum
follow-up according to
treatment duration
5 257 Risk Ratio (M-H Fixed 95 CI) 085 [053 136]
41 Less than six months 3 184 Risk Ratio (M-H Fixed 95 CI) 078 [045 138]
42 Six months or more 2 73 Risk Ratio (M-H Fixed 95 CI) 102 [043 240]
5 Number of deaths related
to rejection at maximum
follow-up
1 102 Risk Ratio (M-H Fixed 95 CI) 030 [001 712]
51 UDCA versus placebo 1 102 Risk Ratio (M-H Fixed 95 CI) 030 [001 712]
6 Number of retransplantations at
maximum follow-up
2 132 Risk Ratio (M-H Fixed 95 CI) 076 [020 286]
7 Number of patients with acute
cellular rejection at maximum
follow-up
7 339 Risk Ratio (M-H Fixed 95 CI) 089 [074 106]
71 UDCA versus placebo or
no treatment
6 306 Risk Ratio (M-H Fixed 95 CI) 089 [074 108]
72 TUDCA versus no
treatment
1 33 Risk Ratio (M-H Fixed 95 CI) 085 [045 160]
8 Subgroup analysis number of
patients with acute cellular
rejection according to time of
start of bile acid
7 339 Risk Ratio (M-H Fixed 95 CI) 089 [074 106]
32Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
81 Less than three days after
transplantation
2 134 Risk Ratio (M-H Fixed 95 CI) 084 [063 111]
82 Three days or more after
liver transplantation
5 205 Risk Ratio (M-H Fixed 95 CI) 092 [072 117]
9 Subgroup analysis number
of patients with acute
cellular rejection according to
treatment duration
7 339 Risk Ratio (M-H Fixed 95 CI) 089 [074 106]
91 Less than six months 5 266 Risk Ratio (M-H Fixed 95 CI) 087 [071 107]
92 Six months or more 2 73 Risk Ratio (M-H Fixed 95 CI) 094 [065 136]
10 Number of patients with
chronic rejection at maximum
follow-up
3 184 Risk Ratio (M-H Fixed 95 CI) 028 [008 095]
11 Number of patients with
steroid-resistant rejection at
maximum follow-up
4 234 Risk Ratio (M-H Fixed 95 CI) 077 [047 127]
12 Serum bilirubin (mgdl) at the
end of treatment
1 30 Mean Difference (IV Fixed 95 CI) 26 [-096 616]
13 Number of days of
hospitalisation after liver
transplantation
1 52 Mean Difference (IV Fixed 95 CI) -85 [-1667 -033]
14 Adverse events 3 187 Risk Ratio (M-H Fixed 95 CI) 088 [030 260]
Analysis 11 Comparison 1 Bile acids for liver-transplanted patients Outcome 1 All-cause mortality at
maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 1 All-cause mortality at maximum follow-up
Study or subgroup Favours bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 UDCA versus placebo or no treatment
Barnes 1997 228 724 253 024 [ 006 107 ]
Fleckenstein 1998 214 416 125 057 [ 012 266 ]
Keiding 1997 1454 1048 355 124 [ 061 254 ]
Sama 1991 520 620 201 083 [ 030 229 ]
Subtotal (95 CI) 116 108 935 080 [ 049 130 ]
Total events 23 (Favours bile acids) 27 (Control)
Heterogeneity Chi2 = 416 df = 3 (P = 025) I2 =28
Test for overall effect Z = 091 (P = 036)
01 02 05 1 2 5 10
Favours bile acids Favours control
(Continued )
33Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Favours bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
2 TUDCA versus no treatment
Angelico 1999 316 217 65 159 [ 030 833 ]
Subtotal (95 CI) 16 17 65 159 [ 030 833 ]
Total events 3 (Favours bile acids) 2 (Control)
Heterogeneity not applicable
Test for overall effect Z = 055 (P = 058)
Total (95 CI) 132 125 1000 085 [ 053 136 ]
Total events 26 (Favours bile acids) 29 (Control)
Heterogeneity Chi2 = 466 df = 4 (P = 032) I2 =14
Test for overall effect Z = 069 (P = 049)
01 02 05 1 2 5 10
Favours bile acids Favours control
Analysis 12 Comparison 1 Bile acids for liver-transplanted patients Outcome 2 All-cause mortality worst-
best case and best-worst case scenarios
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 2 All-cause mortality worst-best case and best-worst case scenarios
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 Worst-best case scenario
Angelico 1999 516 217 65 266 [ 060 1180 ]
Barnes 1997 828 724 253 098 [ 042 230 ]
Fleckenstein 1998 314 416 125 086 [ 023 319 ]
Keiding 1997 1954 1048 355 169 [ 087 327 ]
Sama 1991 520 620 201 083 [ 030 229 ]
Subtotal (95 CI) 132 125 1000 130 [ 086 196 ]
Total events 40 (Bile acids) 29 (Control)
Heterogeneity Chi2 = 303 df = 4 (P = 055) I2 =00
Test for overall effect Z = 123 (P = 022)
2 Best-worst case scenario
005 02 1 5 20
Favours bile acids Favours control
(Continued )
34Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Angelico 1999 316 417 90 080 [ 021 302 ]
Barnes 1997 228 1124 274 016 [ 004 063 ]
Fleckenstein 1998 214 616 130 038 [ 009 159 ]
Keiding 1997 1454 1548 368 083 [ 045 154 ]
Sama 1991 520 620 139 083 [ 030 229 ]
Subtotal (95 CI) 132 125 1000 058 [ 038 090 ]
Total events 26 (Bile acids) 42 (Control)
Heterogeneity Chi2 = 567 df = 4 (P = 023) I2 =29
Test for overall effect Z = 247 (P = 0014)
005 02 1 5 20
Favours bile acids Favours control
Analysis 13 Comparison 1 Bile acids for liver-transplanted patients Outcome 3 Subgroup analyses all-
cause mortality at maximum follow-up according to time of start of bile acids
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 3 Subgroup analyses all-cause mortality at maximum follow-up according to time of start of bile acids
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 Less than three days after transplantation
Keiding 1997 1454 1048 355 124 [ 061 254 ]
Subtotal (95 CI) 54 48 355 124 [ 061 254 ]
Total events 14 (Bile acids) 10 (Control)
Heterogeneity not applicable
Test for overall effect Z = 060 (P = 055)
2 Three days or more after transplantation
Angelico 1999 316 217 65 159 [ 030 833 ]
Barnes 1997 228 724 253 024 [ 006 107 ]
Fleckenstein 1998 214 416 125 057 [ 012 266 ]
Sama 1991 520 620 201 083 [ 030 229 ]
005 02 1 5 20
Favours bile acids Favours control
(Continued )
35Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Subtotal (95 CI) 78 77 645 063 [ 033 120 ]
Total events 12 (Bile acids) 19 (Control)
Heterogeneity Chi2 = 310 df = 3 (P = 038) I2 =3
Test for overall effect Z = 141 (P = 016)
Total (95 CI) 132 125 1000 085 [ 053 136 ]
Total events 26 (Bile acids) 29 (Control)
Heterogeneity Chi2 = 466 df = 4 (P = 032) I2 =14
Test for overall effect Z = 069 (P = 049)
005 02 1 5 20
Favours bile acids Favours control
Analysis 14 Comparison 1 Bile acids for liver-transplanted patients Outcome 4 Subgroup analyses all
cause mortality at maximum follow-up according to treatment duration
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 4 Subgroup analyses all cause mortality at maximum follow-up according to treatment duration
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 Less than six months
Barnes 1997 228 724 253 024 [ 006 107 ]
Fleckenstein 1998 214 416 125 057 [ 012 266 ]
Keiding 1997 1454 1048 355 124 [ 061 254 ]
Subtotal (95 CI) 96 88 734 078 [ 045 138 ]
Total events 18 (Bile acids) 21 (Control)
Heterogeneity Chi2 = 417 df = 2 (P = 012) I2 =52
Test for overall effect Z = 084 (P = 040)
2 Six months or more
Angelico 1999 316 217 65 159 [ 030 833 ]
Sama 1991 520 620 201 083 [ 030 229 ]
Subtotal (95 CI) 36 37 266 102 [ 043 240 ]
Total events 8 (Bile acids) 8 (Control)
Heterogeneity Chi2 = 043 df = 1 (P = 051) I2 =00
005 02 1 5 20
Favours bile acids Favours control
(Continued )
36Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Test for overall effect Z = 004 (P = 097)
Total (95 CI) 132 125 1000 085 [ 053 136 ]
Total events 26 (Bile acids) 29 (Control)
Heterogeneity Chi2 = 466 df = 4 (P = 032) I2 =14
Test for overall effect Z = 069 (P = 049)
005 02 1 5 20
Favours bile acids Favours control
Analysis 15 Comparison 1 Bile acids for liver-transplanted patients Outcome 5 Number of deaths related
to rejection at maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 5 Number of deaths related to rejection at maximum follow-up
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 UDCA versus placebo
Keiding 1997 054 148 1000 030 [ 001 712 ]
Total (95 CI) 54 48 1000 030 [ 001 712 ]
Total events 0 (Bile acids) 1 (Control)
Heterogeneity not applicable
Test for overall effect Z = 075 (P = 045)
0001 001 01 1 10 100 1000
Favours bile acids Favours control
37Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 16 Comparison 1 Bile acids for liver-transplanted patients Outcome 6 Number of
retransplantations at maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 6 Number of retransplantations at maximum follow-up
Study or subgroup Bile acids Placebo Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Fleckenstein 1998 214 016 100 567 [ 029 10891 ]
Keiding 1997 154 448 900 022 [ 003 192 ]
Total (95 CI) 68 64 1000 076 [ 020 286 ]
Total events 3 (Bile acids) 4 (Placebo)
Heterogeneity Chi2 = 303 df = 1 (P = 008) I2 =67
Test for overall effect Z = 040 (P = 069)
0001 001 01 1 10 100 1000
Favours bile acids Favours placebo
Analysis 17 Comparison 1 Bile acids for liver-transplanted patients Outcome 7 Number of patients with
acute cellular rejection at maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 7 Number of patients with acute cellular rejection at maximum follow-up
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 UDCA versus placebo or no treatment
Barnes 1997 1728 1724 180 086 [ 058 127 ]
Fleckenstein 1998 814 916 83 102 [ 054 190 ]
Keiding 1997 3554 3248 333 097 [ 073 129 ]
Koneru 1993 316 916 89 033 [ 011 101 ]
Pageaux 1995 926 924 92 092 [ 044 193 ]
Sama 1991 1320 1320 128 100 [ 063 158 ]
Subtotal (95 CI) 158 148 905 089 [ 074 108 ]
01 02 05 1 2 5 10
Favours bile acids Favours control
(Continued )
38Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Total events 85 (Bile acids) 89 (Control)
Heterogeneity Chi2 = 387 df = 5 (P = 057) I2 =00
Test for overall effect Z = 120 (P = 023)
2 TUDCA versus no treatment
Angelico 1999 816 1017 95 085 [ 045 160 ]
Subtotal (95 CI) 16 17 95 085 [ 045 160 ]
Total events 8 (Bile acids) 10 (Control)
Heterogeneity not applicable
Test for overall effect Z = 050 (P = 061)
Total (95 CI) 174 165 1000 089 [ 074 106 ]
Total events 93 (Bile acids) 99 (Control)
Heterogeneity Chi2 = 392 df = 6 (P = 069) I2 =00
Test for overall effect Z = 130 (P = 019)
01 02 05 1 2 5 10
Favours bile acids Favours control
Analysis 18 Comparison 1 Bile acids for liver-transplanted patients Outcome 8 Subgroup analysis
number of patients with acute cellular rejection according to time of start of bile acid
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 8 Subgroup analysis number of patients with acute cellular rejection according to time of start of bile acid
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 Less than three days after transplantation
Keiding 1997 3554 3248 333 097 [ 073 129 ]
Koneru 1993 316 916 89 033 [ 011 101 ]
Subtotal (95 CI) 70 64 422 084 [ 063 111 ]
Total events 38 (Bile acids) 41 (Control)
Heterogeneity Chi2 = 374 df = 1 (P = 005) I2 =73
Test for overall effect Z = 124 (P = 022)
2 Three days or more after liver transplantation
Angelico 1999 816 1017 95 085 [ 045 160 ]
01 02 05 1 2 5 10
Favours bile acids Favours control
(Continued )
39Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Barnes 1997 1728 1724 180 086 [ 058 127 ]
Fleckenstein 1998 814 916 83 102 [ 054 190 ]
Pageaux 1995 926 924 92 092 [ 044 193 ]
Sama 1991 1320 1320 128 100 [ 063 158 ]
Subtotal (95 CI) 104 101 578 092 [ 072 117 ]
Total events 55 (Bile acids) 58 (Control)
Heterogeneity Chi2 = 041 df = 4 (P = 098) I2 =00
Test for overall effect Z = 067 (P = 050)
Total (95 CI) 174 165 1000 089 [ 074 106 ]
Total events 93 (Bile acids) 99 (Control)
Heterogeneity Chi2 = 392 df = 6 (P = 069) I2 =00
Test for overall effect Z = 130 (P = 019)
01 02 05 1 2 5 10
Favours bile acids Favours control
40Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 19 Comparison 1 Bile acids for liver-transplanted patients Outcome 9 Subgroup analysis
number of patients with acute cellular rejection according to treatment duration
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 9 Subgroup analysis number of patients with acute cellular rejection according to treatment duration
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 Less than six months
Barnes 1997 1728 1724 180 086 [ 058 127 ]
Fleckenstein 1998 814 916 83 102 [ 054 190 ]
Keiding 1997 3554 3248 333 097 [ 073 129 ]
Koneru 1993 316 916 89 033 [ 011 101 ]
Pageaux 1995 926 924 92 092 [ 044 193 ]
Subtotal (95 CI) 138 128 777 087 [ 071 107 ]
Total events 72 (Bile acids) 76 (Control)
Heterogeneity Chi2 = 374 df = 4 (P = 044) I2 =00
Test for overall effect Z = 129 (P = 020)
2 Six months or more
Angelico 1999 816 1017 95 085 [ 045 160 ]
Sama 1991 1320 1320 128 100 [ 063 158 ]
Subtotal (95 CI) 36 37 223 094 [ 065 136 ]
Total events 21 (Bile acids) 23 (Control)
Heterogeneity Chi2 = 017 df = 1 (P = 068) I2 =00
Test for overall effect Z = 035 (P = 073)
Total (95 CI) 174 165 1000 089 [ 074 106 ]
Total events 93 (Bile acids) 99 (Control)
Heterogeneity Chi2 = 392 df = 6 (P = 069) I2 =00
Test for overall effect Z = 130 (P = 019)
01 02 05 1 2 5 10
Favours bile acids Favours control
41Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 110 Comparison 1 Bile acids for liver-transplanted patients Outcome 10 Number of patients
with chronic rejection at maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 10 Number of patients with chronic rejection at maximum follow-up
Study or subgroup Bile acids Placebo Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Barnes 1997 128 624 611 014 [ 002 110 ]
Fleckenstein 1998 114 116 88 114 [ 008 1663 ]
Keiding 1997 154 348 300 030 [ 003 275 ]
Total (95 CI) 96 88 1000 028 [ 008 095 ]
Total events 3 (Bile acids) 10 (Placebo)
Heterogeneity Chi2 = 148 df = 2 (P = 048) I2 =00
Test for overall effect Z = 204 (P = 0041)
0001 001 01 1 10 100 1000
Favours bile acids Favours placebo
Analysis 111 Comparison 1 Bile acids for liver-transplanted patients Outcome 11 Number of patients
with steroid-resistant rejection at maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 11 Number of patients with steroid-resistant rejection at maximum follow-up
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Barnes 1997 328 724 277 037 [ 011 127 ]
Fleckenstein 1998 314 316 103 114 [ 027 478 ]
Keiding 1997 1454 1548 583 083 [ 045 154 ]
Pageaux 1995 226 124 38 185 [ 018 1908 ]
Total (95 CI) 122 112 1000 077 [ 047 127 ]
Total events 22 (Bile acids) 26 (Control)
Heterogeneity Chi2 = 226 df = 3 (P = 052) I2 =00
Test for overall effect Z = 102 (P = 031)
001 01 1 10 100
Favours bile acids Favours placebo
42Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 112 Comparison 1 Bile acids for liver-transplanted patients Outcome 12 Serum bilirubin (mgdl)
at the end of treatment
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 12 Serum bilirubin (mgdl) at the end of treatment
Study or subgroup Bile acids Placebo Mean Difference Weight Mean Difference
N Mean(SD) N Mean(SD) IVFixed95 CI IVFixed95 CI
Fleckenstein 1998 14 319 (68) 16 059 (022) 1000 260 [ -096 616 ]
Total (95 CI) 14 16 1000 260 [ -096 616 ]
Heterogeneity not applicable
Test for overall effect Z = 143 (P = 015)
-10 -5 0 5 10
Favours bile acids Favours placebo
Analysis 113 Comparison 1 Bile acids for liver-transplanted patients Outcome 13 Number of days of
hospitalisation after liver transplantation
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 13 Number of days of hospitalisation after liver transplantation
Study or subgroup Bile acids Placebo Mean Difference Weight Mean Difference
N Mean(SD) N Mean(SD) IVFixed95 CI IVFixed95 CI
Barnes 1997 28 25 (17) 24 335 (13) 1000 -850 [ -1667 -033 ]
Total (95 CI) 28 24 1000 -850 [ -1667 -033 ]
Heterogeneity not applicable
Test for overall effect Z = 204 (P = 0041)
-100 -50 0 50 100
Favours bile acids Favours placebo
43Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 114 Comparison 1 Bile acids for liver-transplanted patients Outcome 14 Adverse events
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 14 Adverse events
Study or subgroup Bile acids Placebo Risk Ratio Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Angelico 1999 016 017 00 [ 00 00 ]
Barnes 1997 128 124 086 [ 006 1298 ]
Keiding 1997 554 548 089 [ 027 288 ]
Total (95 CI) 98 89 088 [ 030 260 ]
Total events 6 (Bile acids) 6 (Placebo)
Heterogeneity Chi2 = 000 df = 1 (P = 098) I2 =00
Test for overall effect Z = 022 (P = 082)
001 01 1 10 100
Favours bile acids Favours placebo
A P P E N D I C E S
Appendix 1 Search strategies
Data Base Date of Search Search Strategy
The Cochrane Hepato-Biliary Group Con-
trolled Trials Register
September 2009 1 rsquoliver transplantationrsquo and rsquochenodeoxy-
cholicrsquo
2 rsquoliver transplantationrsquo and rsquocholicrsquo
3 rsquoliver transplantationrsquo and rsquodeoxycholicrsquo
4 rsquoliver transplantationrsquo and rsquoglycochen-
odeoxycholicrsquo
5 rsquoliver transplantationrsquo and rsquoglycocholicrsquo
6 rsquoliver transplantationrsquo and rsquoglycodeoxy-
cholicrsquo
7 rsquoliver transplantationrsquo and rsquoglycolitho-
cholicrsquo
8 rsquoliver transplantationrsquo and rsquohyodeoxy-
cholicrsquo
9 rsquoliver transplantationrsquo and rsquolithocholicrsquo
10 rsquoliver transplantationrsquo and rsquotaurochen-
odeoxycholicrsquo
44Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
11 rsquoliver transplantationrsquo and rsquotauro-
cholicrsquo
12 rsquoliver transplantationrsquo and rsquotaurodehy-
drocholicrsquo
13 rsquoliver transplantationrsquo and rsquotau-
rodeoxycholicrsquo
14 rsquoliver transplantationrsquo and rsquotauroglyco-
cholicrsquo
15 rsquoliver transplantationrsquo and rsquotaurolitho-
cholicrsquo
16 rsquoliver transplantationrsquo and rsquotaurosel-
cholicrsquo
17 rsquoliver transplantationrsquo and rsquotaurourso-
cholicrsquo
18 rsquoliver transplantationrsquo and rsquotaurour-
sodeoxycholicrsquo
19 rsquoliver transplantationrsquo and rsquoursocholicrsquo
20 rsquoliver transplantationrsquo and rsquoursodeoxy-
cholicrsquo
The Cochrane Central Register of Con-
trolled Trials in The Cochrane Library
Issue 3 2009 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
6 3 or 4
7 5 and 6
MEDLINE September 2009 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
45Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
6 3 or 4
7 5 and 6
8 RANDOMIZED-CONTROLLED-
TRIAL ME
9 RANDOM
10 8 or 9
11 7 and 10
EMBASE September 2009 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
6 3 or 4
7 5 and 6
8 RANDOMIZED-CONTROLLED-
TRIAL ME
9 RANDOM
10 8 or 9
11 7 and 10
46Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
Science Citation Index Expanded September 2009 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
6 3 or 4
7 5 and 6
8 RANDOMIZED-CONTROLLED-
TRIAL ME
9 RANDOM
10 8 or 9
11 7 and 10
The Chinese Biomedical Database Searched from January 1980 to April 2002 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
47Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
6 3 or 4
7 5 and 6
8 RANDOMIZED-CONTROLLED-
TRIAL ME
9 RANDOM
10 8 or 9
11 7 and 10
W H A T rsquo S N E W
Last assessed as up-to-date 8 February 2010
18 September 2009 New citation required but conclusions have not
changed
This review is an updated version of a review that was
published for the first time in Issue 3 2005 of TheCochrane Library by Chen 2003b
18 September 2009 New search has been performed No new studies fulfilled the inclusion criteria
H I S T O R Y
Protocol first published Issue 3 2003
Review first published Issue 3 2005
C O N T R I B U T I O N S O F A U T H O R S
GP and VG independently performed searches of relevant databases GP validated the search selected trials for inclusion contacted
the authors of the trials performed data extraction and data analysis and drafted the systematic review VG revised the review update
CG and DS revised the review update solved discrepancies of data extraction validated data analyses and provided consultation
D E C L A R A T I O N S O F I N T E R E S T
None known
48Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
S O U R C E S O F S U P P O R T
Internal sources
bull Copenhagen Trial Unit Denmark
External sources
bull Danish Medical Research Councilrsquos Grant on Getting Research into Practice (GRIP) Denmark
D I F F E R E N C E S B E T W E E N P R O T O C O L A N D R E V I E W
We assessed the risk of bias in the included studies for another four domains that were added to the review protocol (incomplete
outcome data selective outcome reporting baseline imbalance and early stopping of trial) In general the text of the risk of bias
domains were updated following Higgins 2008 Trials were considered at low risk of bias when judged as adequate in all domains
Quasi-randomised studies observational and case-control studies were included for the report of adverse events
We performed trial sequential analysis for outcomes demonstrating a statistically significant result
I N D E X T E R M S
Medical Subject Headings (MeSH)
lowastLiver Transplantation Cholagogues and Choleretics [lowasttherapeutic use] Graft Rejection [lowastprevention amp control] Randomized Con-
trolled Trials as Topic Taurochenodeoxycholic Acid [lowasttherapeutic use] Ursodeoxycholic Acid [lowasttherapeutic use]
MeSH check words
Humans
49Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
C H A R A C T E R I S T I C S O F S T U D I E S
Characteristics of included studies [ordered by study ID]
Angelico 1999
Methods Study design open-label randomised one-year pilot study
Participants Country Italy
Publication language English
Inclusion criteria
- patients who underwent liver transplantation from April 1994 to December 1994
Exclusion criteria
- not mentioned
Participants
Two patients in TUDCA group and two patients in control group were excluded from
the basic information of participants by the study due to withdrawal
- TUDCA group (n = 14)
Mean age (years +- SD)
467 +- 84
Ratio of sex (malefemale) 122
Origins of liver diseases
hepatitis C cirrhosis (9) hepatitis B cirrhosis (2) hepatitis B and C cirrhosis (1) cryp-
togenic cirrhosis (2) alcoholic cirrhosis (0) Wilson cirrhosis (0)
- Control group (n = 15)
Mean age (years +- SD)
474 +- 74
Ratio of sex (malefemale) 123
Origins of liver diseases
hepatitis C cirrhosis (7) hepatitis B cirrhosis (2) hepatitis B and C cirrhosis (2) cryp-
togenic cirrhosis (2) alcoholic cirrhosis (1) Wilson cirrhosis (1)
Interventions TUDCA group
- Dose 500 mgday in two divided doses
- Route orally
- Duration the treatment was started on day 5 after transplantation and continued for
one year
Control group
- no treatment
Co-interventions all patients received standard triple-drug regimens (steroids azathio-
prine and cyclosporine or tacrolimus)
Outcomes All cause mortality
Number of patients with rejection after liver transplantation
Notes Letter was sent to the authors in September 2009 A reply with additional information
was received shortly after
Risk of bias
19Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Angelico 1999 (Continued)
Item Authorsrsquo judgement Description
Adequate sequence generation Yes Computer generated table
Allocation concealment Unclear No information provided
Blinding No Not performed
Incomplete outcome data addressed
All outcomes
Yes Withdrawal two patients from the
TUDCA group and two patients from the
placebo group Three of them died due to
transplant non-function in the first postop-
erative week and one patient was regrafted
due to thrombosis of hepatic artery
Free of selective reporting Unclear Post-transplant cholestasis and liver bio-
chemistry specified as outcomes Differ-
ence reported as not significant but no ac-
tual data given
Sample size calculation No Not reported
Intention-to-treat analysis No Not stated and not used
Baseline imbalance Unclear Not enough information provided
Early stopping of trial Unclear Not enough information provided
Barnes 1997
Methods Study design randomised placebo-controlled double-blind trial
Participants Country United States
Publication language English
Inclusion criteria
- patients aged 18 years or older who underwent liver transplantation at the Cleveland
Clinic Foundation from April 1992 through June of 1994
Exclusion criteria
- patients who were found to have cancer at surgically resected margins of the biliary
tree
- patents who underwent retransplantation
Participants
- UDCA group (n = 28)
Mean age (years +- SD)
505 +- 116
Ratio of sex (malefemale) 1810
Child class A 7
20Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Barnes 1997 (Continued)
B 13
and C 8
Origins of liver diseases Laennecrsquos cirrhosis 4
PBC 3
cryptogenic cirrhosis 6
hepatitis Ccirrhosis 4
hepatitis Bcirrhosis 3
autoimmune hepatitis with cirrhosis 3
PSC 2
other 3
- Placebo group (n = 24)
Mean age (years +- SD)
507 +- 93
Ratio of sex (malefemale) 159
Child class A 6
B 14
and C 4
Origins of liver diseases Laennecrsquos cirrhosis 9
PBC 5
cryptogenic cirrhosis 1
hepatitis Ccirrhosis 1
hepatitis Bcirrhosis 1
autoimmune hepatitis with cirrhosis 1
PSC 2
other 4
Interventions UDCA group
- Dose 10-15 mgkg body weightday in divided doses
- Route orally
- Duration immediately after intestinal transit recovery usually between postoperative
days three and five and continue for three months
Placebo group
- identical-appearing capsules administered in the same quantity and manner
Co-interventions all patients received standard triple-drug regimens (steroids azathio-
prine and cyclosporine or tacrolimus)
Outcomes All cause mortality
Number of patients with acute cellular rejection
Number of patients with chronic rejection
Number of patients with steroid-resistant rejection
Number of days of hospitalisation
Adverse events
Notes Letter was sent to the authors in September 2009 A reply with additional information
was received shortly after
Risk of bias
Item Authorsrsquo judgement Description
21Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Barnes 1997 (Continued)
Adequate sequence generation Yes Computer generated table
Allocation concealment Unclear No information provided
Blinding Yes Quote ldquorandomised to receive either
UDCA or an identical placebo capsulerdquo
Incomplete outcome data addressed
All outcomes
Yes Mean follow-up time 18 months Ten pa-
tients withdrawn from study 6 in UDCA
group and 4 in placebo group Reasons
for withdrawal were reported Four patients
died in the placebo group
Free of selective reporting Yes All expected outcomes reported
Sample size calculation Unclear The trial reported the method of sample
size calculation but the actual number of
patients needed was not reported
Intention-to-treat analysis Yes Stated and used
Baseline imbalance Unclear Not enough information provided
Early stopping of trial Unclear The number of patients needed to gain the
actual power was not reported Whether
the trial was terminated early is not clear
Fleckenstein 1998
Methods Study design prospective randomised double-blind trial
Participants Country United States
Publication language English
Inclusion criteria
- patients who underwent liver transplantation at the Johns Hopkins Hospital
Exclusion criteria
- patients who were under 18 years old undergoing repeat transplantation had primary
graft nonfunction or refused consent
Participants
- UDCA group (n = 14)
Mean age (years +- SD)
443 +- 127
Ratio of sex (malefemale) 68
Origins of liver diseases hepatitis C 6
alcohol 2
autoimmune 1
PBC 2
22Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Fleckenstein 1998 (Continued)
PSC 1
autoimmune cholangiopathy 1
hepatitis B 1
- Placebo group (n = 16)
Mean age (years +- SD)
496 +- 109
Ratio of sex (malefemale) 124
Origins of liver diseases hepatitis C 3
alcohol 3
autoimmune 3
PBC 1
PSC 2
cryptogenic 2
hepatitis B 1
alpha1-antitrypsin deficiency 1
Interventions UDCA group
- Dose 15 mgkg body weightday in divided doses
- Route orally
- Duration immediately after intestinal transit recovery usually between postoperative
days three and five and continue for three months
Placebo group
- Identical-appearing capsules administered in the same quantity and manner
Co-interventions all patients received standard triple-drug regimens (steroids azathio-
prine and cyclosporine or tacrolimus)
Outcomes All cause mortality
Number with retransplantation
Number of patients with acute cellular rejection
Number of patients with chronic rejection
Serum bilirubin levels at the end of treatment
Notes Follow-up time nine months
Letter was sent to the authors in September 2009 No reply was received
Risk of bias
Item Authorsrsquo judgement Description
Adequate sequence generation Unclear No information provided
Allocation concealment Unclear No information provided
Blinding Yes Method of blinding not described but
probably adequate
Incomplete outcome data addressed
All outcomes
Yes Withdrawal one patient from the UDCA
group and two patients from the placebo
group because of capsule size
23Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Fleckenstein 1998 (Continued)
Free of selective reporting Unclear Outcomes were not completely described
Sample size calculation No Not reported
Intention-to-treat analysis Yes Quote ldquoThree patients withdrew after in-
clusionThey were included in the statis-
tical analysisrdquo
Baseline imbalance Unclear Not enough information provided
Early stopping of trial Unclear Not enough information provided
Keiding 1997
Methods Study design prospective randomised placebo-controlled multicenter study
Participants Country Denmark Finland Norway and Sweden
Publication language English
Inclusion criteria
- patients who underwent liver transplantation in Denmark Finland Norway and Swe-
den from September 1 1992 to May 31 1994
Exclusion criteria
- patients with malignant diseases
Participants
The age of the children ranged from 0 to 13 years (median 15) and the age of adults
ranged from 14 to 59 years old (median 44) MaleFemale ratio was 96 for children and
4344 for adults
- UDCA group (n = 54)
Origins of liver diseases
paracetamol intoxication 1 hepatitis B 1 autoimmune hepatitis 0 biliary atresia 2
metabolic diseases 7 neonatal hepatitis 2 PBC 13 post hepatitis cirrhosis 8 PSC 3
cryptogenic cirrhosis 7 alcoholic cirrhosis 2 other reasons 8
- Placebo group (n = 48)
Origins of liver diseases paracetamol intoxication 1 hepatitis B 0 autoimmune hepatitis
1 biliary atresia 3 metabolic diseases 11 neonatal hepatitis 0 PBC 7 post hepatitis
cirrhosis 5 PSC 7 cryptogenic cirrhosis 2 alcoholic cirrhosis 6 other reasons 5
Interventions UDCA group
- Dose 15 mgkg body weightday in two or three divided doses
- Route orally
- Duration immediately after intestinal transit recovery usually between postoperative
days three and five and continue for three months
Placebo group
- Identical-appearing capsules administered in the same quantity and manner
Co-interventions all patients received standard triple-drug regimens (steroids azathio-
prine and cyclosporine or tacrolimus)
24Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Keiding 1997 (Continued)
Outcomes All cause mortality
Number of deaths related to rejection
Number of patients with acute cellular rejection
Number of patients with chronic rejection
Number of patients with steroid-resistant rejection
Adverse events
Notes Letter was sent to the authors in September 2009 No reply was received
Risk of bias
Item Authorsrsquo judgement Description
Adequate sequence generation Unclear Patients were randomised at a ratio of 11
Allocation concealment Yes Quote ldquo The allocation was performed in
blocks of 10 patients using the sealed serial
envelope methodrdquo
Blinding Yes Quote ldquoThe UDCA and the placebo cap-
sules had identical appearance and tasterdquo
Incomplete outcome data addressed
All outcomes
Yes Follow-up time 12 months Five UDCA
patients and five placebo patients withdrew
from study Reasons were reported
Free of selective reporting Unclear Insufficient information
Sample size calculation Yes Performed and allowed for a difference in
the incidence of at least one episode of
acute rejection of 50 between the treat-
ment and placebo groups with 90 statisti-
cal power and a significance level of P value
less than 005 The calculated sample size
was 80 patients
Intention-to-treat analysis Yes Stated and used
Baseline imbalance Yes The study seems to be free of baseline im-
balance
Early stopping of trial Yes Study attained the pre-specified sample
size
25Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Koneru 1993
Methods Study design randomised controlled trial
Participants Country United States
Publication language English
Inclusion criteria
- patients who underwent liver transplantation
Exclusion criteria
- not mentioned
Participants
- UDCA group (n = 16)
Mean age (years +- SD)
no information
Ratio of sex (malefemale) no information
Origins of liver diseases
no information
- Control group (n = 16)
Mean age (years +- SD)
no information
Ratio of sex (malefemale) no information
Origins of liver diseases
no information
Interventions UDCA group
- Dose 900 mgday
- Route orally
- Duration immediately after intestinal transit recovery usually between postoperative
days three and five and continue for three months
Control group
- no treatment
Co-interventions all patients received standard triple-drug regimens (steroids azathio-
prine and cyclosporine)
Outcomes Number of patients with retransplantation due to rejection
Number of patients with rejection episodes
Notes Abstract
Letter was sent to the authors in September 2009 No reply was received
Risk of bias
Item Authorsrsquo judgement Description
Adequate sequence generation Unclear No information provided
Allocation concealment Unclear No information provided
Blinding No Not performed
26Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Koneru 1993 (Continued)
Incomplete outcome data addressed
All outcomes
Unclear The study gives the impression that there
were no withdrawals but this was not ex-
plicitly stated
Free of selective reporting Unclear Insufficient information provided
Sample size calculation No Not performed
Intention-to-treat analysis Unclear No information provided
Baseline imbalance Unclear Not enough information provided
Early stopping of trial Unclear Not enough information provided
Pageaux 1995
Methods Study design double-blind randomised study
Participants Country France
Publication language English
Inclusion criteria
- patients who underwent liver transplantation
Exclusion criteria
- not mentioned
Participants
- UDCA group (n=26)
Mean age (years +- SD)
47 +- 10
Ratio of sex (malefemale) 179
Origins of liver diseases alcoholic cirrhosis 14
post-hepatic B cirrhosis 2
post-hepatitis C cirrhosis 4
PBC 2
liver cancer 2
fulminant hepatitis 1
miscellaneous 1
- Placebo group (n = 24)
Mean age (years +- SD)
51+- 9
Ratio of sex (malefemale) 159
Origins of liver diseases alcoholic cirrhosis 10
post-hepatic B cirrhosis 0
post-hepatic C cirrhosis 6
PBC 3
liver cancer 4
fulminant hepatitis 0
miscellaneous 1
27Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Pageaux 1995 (Continued)
Interventions UDCA group
- Dose 600 mgday in three divided doses
- Route orally
- Duration immediately after intestinal transit recovery usually between postoperative
days three and five and continue for two months
Placebo group
- identical-appearing capsules administered in the same quantity and manner
Co-interventions all patients received standard triple-drug regimens (steroids azathio-
prine and cyclosporine or tacrolimus)
Outcomes Number of patients with acute cellular rejection
Number of patients with steroid-resistant rejection
Notes Letter was sent to the authors in September 2009 No reply was received
Risk of bias
Item Authorsrsquo judgement Description
Adequate sequence generation Unclear No information provided
Allocation concealment Unclear No information provided
Blinding Unclear Method of blinding not described
Incomplete outcome data addressed
All outcomes
Yes Five patients died from non-immunologi-
cal causes before the end of the first month
and were excluded from the study Reasons
were reported
Free of selective reporting Unclear Not enough information provided
Sample size calculation No Not performed
Intention-to-treat analysis No Not stated and not used
Baseline imbalance Unclear Not enough information provided
Early stopping of trial Unclear Not enough information provided
Sama 1991
Methods Study design randomised controlled trial
Participants Country Italy
Publication language English
Inclusion criteria
28Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Sama 1991 (Continued)
- patients who underwent liver transplantation
Exclusion criteria
- not mentioned
Participants
- UDCA group (n = 20)
Mean age (years +- SD)
no information
Ratio of sex (malefemale) no information
Origins of liver diseases
no information
- Control group (n = 20)
Mean age (years +- SD)
no information
Ratio of sex (malefemale) no information
Origins of liver diseases
no information
Interventions UDCA group
- Dose 600 mgday in two divided doses
- Route orally
- Duration immediately after intestinal transit recovery usually between postoperative
day five and day seven and continue for six months
Control group
- no treatment
Co-interventions all patients received standard immunosuppressive treatment (steroids
and cyclosporine)
Outcomes All cause mortality
Number of patients with acute cellular rejection
Notes Abstract
Letter was sent to the authors in September 2009 No reply was received
Risk of bias
Item Authorsrsquo judgement Description
Adequate sequence generation Unclear A randomisation list was performed before
patients were admitted to the trial (infor-
mation from principal author)
Allocation concealment Unclear No information provided
Blinding Unclear The principle author provided information
that the study was made according to a
single-blind randomised protocol The pri-
mary outcome was the occurrence of biopsy
proven rejection episodes The pathologists
were blind but the patients were not
29Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Sama 1991 (Continued)
Incomplete outcome data addressed
All outcomes
Unclear Five patients from the UDCA group and
six patients from the placebo group were
excluded Reasons for exclusion were not
fully stated
Free of selective reporting No Data about survival of patients were not
adequately reported
Sample size calculation No Not performed
Intention-to-treat analysis No Not stated and not used
Baseline imbalance Unclear Basic characteristics of patients not re-
ported
Early stopping of trial Unclear Not enough information provided
UDCA = ursodeoxycholic acid
TUDCA = tauroursodeoxycholic acid
PBC = primary biliary cirrhosis
PSC = primary sclerosing cholangitis
OKT3 = anti-CD3 monoclonal antibody
Characteristics of excluded studies [ordered by study ID]
Assy 2007 A randomised controlled trial that included only recipients of liver transplantation with stable graft function and
no episodes of rejection for at least 2 years that were then offered total immunosuppression withdrawal Fourteen
patients received UDCA (15 mgkg body weightday) and 12 received placebo Rejection occurred in 43 and
75 of patients respectively (no significant difference) None developed chronic rejection After follow-up two
patients were free of immunosuppression 80 were steroid free and 50 were able to reduce their dose of
cyclosporine
Clavien 1996 Case series Fifty consecutive liver-transplanted patients were treated with a standard cyclosporine immunosup-
pressive regimen Twenty three of the 43 survivors developed an episode of rejection and UDCA (10 mgkg
weightday) was initiated Only one patient had a second episode of rejection
Friman 1992 Observational study Thirty-three liver-transplanted patients received 10 mg UDCAkg body weightday for
median of 10 months (range four to 21 months) Eight historical liver-transplanted patients served as control
group The rejection incidence was significantly lower in the patients who received the treatment with UDCA
Biochemistry one month after transplantation demonstrated significantly lower average values of aminotrans-
ferases and alkaline phosphatases in patients treated with UDCA than in the control group
30Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
Heathcote 1999 Observational study From 1987 to 1996 37 UDCA treated and 53 placebo treated patients with primary biliary
cirrhosis were referred for transplantation Posttransplantation survival rates at one month were 939 in the
UDCA group and 884 in the placebo group and one year survival rates were 903 and 784 respectively
(no significant differences) However rejection (type not defined - a secondary outcome measure) occurred
significantly less often in the UDCA group (429) than in placebo group (688)
Henriksson 1991 Observational study All patients in this study were given sequential quadruple immunosuppression with anti-
lymphocyte globulin azathioprine steroids and cyclosporine All patients with primary graft function (n = 11)
were treated with 10 mg UDCAkg body weightday starting during the first postoperative week Patients who
received liver transplantation in the first 6 months of 1989 (n = 8) served as controls In the control group one
patient died after 9 months with chronic graft dysfunction and six patients had rejection episodes during the
first postoperative month All patients in the UDCA group were alive without rejection episodes
Persson 1990 Observational study All 11 adult patients transplanted between August 1989 and January 1990 with primary
graft function were treated with 10 mg UDCA kg body weightday Eight patients transplanted during the first
half of 1989 served as control UDCA was started during the first postoperative week and the treatment was
continued for six months All patients in the UDCA treated group survived with satisfactory graft function In
the control group six patients had at least one rejection episode needing treatment during the first postoperative
month
Rafael 1995 Observational study Seventeen patients who underwent liver transplantation between February 1990 and April
1993 and developed biliary complications after transplantation were retrospectively analysed regarding treatment
with UDCA UDCA was given in a dose of 500 to 1000 mgday Ten patients were treated for at least one year while
seven patients were treated for 14 to 250 days UDCA significantly improved gammaglutamyl transpeptidase in
liver graft recipients with biliary complications There was also a trend towards improvement in serum bilirubin
and alanine transaminase values
Sama 1998 Observational study Thirty-four patients who underwent liver transplantation between January 1995 and June
1996 were included in the study Seventeen were treated with UDCA 10 mgkg body weightday during 6
months while 17 served as controls on the basis of having undergone liver transplantation closest to UDCA
patients A significant decrease in serum bilirubin levels was observed in UDCA patients There was a significantly
higher incidence of recurrent hepatitis in the control group
UDCA ursodeoxycholic acid
31Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
D A T A A N D A N A L Y S E S
Comparison 1 Bile acids for liver-transplanted patients
Outcome or subgroup titleNo of
studies
No of
participants Statistical method Effect size
1 All-cause mortality at maximum
follow-up
5 257 Risk Ratio (M-H Fixed 95 CI) 085 [053 136]
11 UDCA versus placebo or
no treatment
4 224 Risk Ratio (M-H Fixed 95 CI) 080 [049 130]
12 TUDCA versus no
treatment
1 33 Risk Ratio (M-H Fixed 95 CI) 159 [030 833]
2 All-cause mortality worst-best
case and best-worst case
scenarios
5 Risk Ratio (M-H Fixed 95 CI) Subtotals only
21 Worst-best case scenario 5 257 Risk Ratio (M-H Fixed 95 CI) 130 [086 196]
22 Best-worst case scenario 5 257 Risk Ratio (M-H Fixed 95 CI) 058 [038 090]
3 Subgroup analyses all-cause
mortality at maximum
follow-up according to time of
start of bile acids
5 257 Risk Ratio (M-H Fixed 95 CI) 085 [053 136]
31 Less than three days after
transplantation
1 102 Risk Ratio (M-H Fixed 95 CI) 124 [061 254]
32 Three days or more after
transplantation
4 155 Risk Ratio (M-H Fixed 95 CI) 063 [033 120]
4 Subgroup analyses all cause
mortality at maximum
follow-up according to
treatment duration
5 257 Risk Ratio (M-H Fixed 95 CI) 085 [053 136]
41 Less than six months 3 184 Risk Ratio (M-H Fixed 95 CI) 078 [045 138]
42 Six months or more 2 73 Risk Ratio (M-H Fixed 95 CI) 102 [043 240]
5 Number of deaths related
to rejection at maximum
follow-up
1 102 Risk Ratio (M-H Fixed 95 CI) 030 [001 712]
51 UDCA versus placebo 1 102 Risk Ratio (M-H Fixed 95 CI) 030 [001 712]
6 Number of retransplantations at
maximum follow-up
2 132 Risk Ratio (M-H Fixed 95 CI) 076 [020 286]
7 Number of patients with acute
cellular rejection at maximum
follow-up
7 339 Risk Ratio (M-H Fixed 95 CI) 089 [074 106]
71 UDCA versus placebo or
no treatment
6 306 Risk Ratio (M-H Fixed 95 CI) 089 [074 108]
72 TUDCA versus no
treatment
1 33 Risk Ratio (M-H Fixed 95 CI) 085 [045 160]
8 Subgroup analysis number of
patients with acute cellular
rejection according to time of
start of bile acid
7 339 Risk Ratio (M-H Fixed 95 CI) 089 [074 106]
32Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
81 Less than three days after
transplantation
2 134 Risk Ratio (M-H Fixed 95 CI) 084 [063 111]
82 Three days or more after
liver transplantation
5 205 Risk Ratio (M-H Fixed 95 CI) 092 [072 117]
9 Subgroup analysis number
of patients with acute
cellular rejection according to
treatment duration
7 339 Risk Ratio (M-H Fixed 95 CI) 089 [074 106]
91 Less than six months 5 266 Risk Ratio (M-H Fixed 95 CI) 087 [071 107]
92 Six months or more 2 73 Risk Ratio (M-H Fixed 95 CI) 094 [065 136]
10 Number of patients with
chronic rejection at maximum
follow-up
3 184 Risk Ratio (M-H Fixed 95 CI) 028 [008 095]
11 Number of patients with
steroid-resistant rejection at
maximum follow-up
4 234 Risk Ratio (M-H Fixed 95 CI) 077 [047 127]
12 Serum bilirubin (mgdl) at the
end of treatment
1 30 Mean Difference (IV Fixed 95 CI) 26 [-096 616]
13 Number of days of
hospitalisation after liver
transplantation
1 52 Mean Difference (IV Fixed 95 CI) -85 [-1667 -033]
14 Adverse events 3 187 Risk Ratio (M-H Fixed 95 CI) 088 [030 260]
Analysis 11 Comparison 1 Bile acids for liver-transplanted patients Outcome 1 All-cause mortality at
maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 1 All-cause mortality at maximum follow-up
Study or subgroup Favours bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 UDCA versus placebo or no treatment
Barnes 1997 228 724 253 024 [ 006 107 ]
Fleckenstein 1998 214 416 125 057 [ 012 266 ]
Keiding 1997 1454 1048 355 124 [ 061 254 ]
Sama 1991 520 620 201 083 [ 030 229 ]
Subtotal (95 CI) 116 108 935 080 [ 049 130 ]
Total events 23 (Favours bile acids) 27 (Control)
Heterogeneity Chi2 = 416 df = 3 (P = 025) I2 =28
Test for overall effect Z = 091 (P = 036)
01 02 05 1 2 5 10
Favours bile acids Favours control
(Continued )
33Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Favours bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
2 TUDCA versus no treatment
Angelico 1999 316 217 65 159 [ 030 833 ]
Subtotal (95 CI) 16 17 65 159 [ 030 833 ]
Total events 3 (Favours bile acids) 2 (Control)
Heterogeneity not applicable
Test for overall effect Z = 055 (P = 058)
Total (95 CI) 132 125 1000 085 [ 053 136 ]
Total events 26 (Favours bile acids) 29 (Control)
Heterogeneity Chi2 = 466 df = 4 (P = 032) I2 =14
Test for overall effect Z = 069 (P = 049)
01 02 05 1 2 5 10
Favours bile acids Favours control
Analysis 12 Comparison 1 Bile acids for liver-transplanted patients Outcome 2 All-cause mortality worst-
best case and best-worst case scenarios
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 2 All-cause mortality worst-best case and best-worst case scenarios
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 Worst-best case scenario
Angelico 1999 516 217 65 266 [ 060 1180 ]
Barnes 1997 828 724 253 098 [ 042 230 ]
Fleckenstein 1998 314 416 125 086 [ 023 319 ]
Keiding 1997 1954 1048 355 169 [ 087 327 ]
Sama 1991 520 620 201 083 [ 030 229 ]
Subtotal (95 CI) 132 125 1000 130 [ 086 196 ]
Total events 40 (Bile acids) 29 (Control)
Heterogeneity Chi2 = 303 df = 4 (P = 055) I2 =00
Test for overall effect Z = 123 (P = 022)
2 Best-worst case scenario
005 02 1 5 20
Favours bile acids Favours control
(Continued )
34Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Angelico 1999 316 417 90 080 [ 021 302 ]
Barnes 1997 228 1124 274 016 [ 004 063 ]
Fleckenstein 1998 214 616 130 038 [ 009 159 ]
Keiding 1997 1454 1548 368 083 [ 045 154 ]
Sama 1991 520 620 139 083 [ 030 229 ]
Subtotal (95 CI) 132 125 1000 058 [ 038 090 ]
Total events 26 (Bile acids) 42 (Control)
Heterogeneity Chi2 = 567 df = 4 (P = 023) I2 =29
Test for overall effect Z = 247 (P = 0014)
005 02 1 5 20
Favours bile acids Favours control
Analysis 13 Comparison 1 Bile acids for liver-transplanted patients Outcome 3 Subgroup analyses all-
cause mortality at maximum follow-up according to time of start of bile acids
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 3 Subgroup analyses all-cause mortality at maximum follow-up according to time of start of bile acids
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 Less than three days after transplantation
Keiding 1997 1454 1048 355 124 [ 061 254 ]
Subtotal (95 CI) 54 48 355 124 [ 061 254 ]
Total events 14 (Bile acids) 10 (Control)
Heterogeneity not applicable
Test for overall effect Z = 060 (P = 055)
2 Three days or more after transplantation
Angelico 1999 316 217 65 159 [ 030 833 ]
Barnes 1997 228 724 253 024 [ 006 107 ]
Fleckenstein 1998 214 416 125 057 [ 012 266 ]
Sama 1991 520 620 201 083 [ 030 229 ]
005 02 1 5 20
Favours bile acids Favours control
(Continued )
35Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Subtotal (95 CI) 78 77 645 063 [ 033 120 ]
Total events 12 (Bile acids) 19 (Control)
Heterogeneity Chi2 = 310 df = 3 (P = 038) I2 =3
Test for overall effect Z = 141 (P = 016)
Total (95 CI) 132 125 1000 085 [ 053 136 ]
Total events 26 (Bile acids) 29 (Control)
Heterogeneity Chi2 = 466 df = 4 (P = 032) I2 =14
Test for overall effect Z = 069 (P = 049)
005 02 1 5 20
Favours bile acids Favours control
Analysis 14 Comparison 1 Bile acids for liver-transplanted patients Outcome 4 Subgroup analyses all
cause mortality at maximum follow-up according to treatment duration
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 4 Subgroup analyses all cause mortality at maximum follow-up according to treatment duration
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 Less than six months
Barnes 1997 228 724 253 024 [ 006 107 ]
Fleckenstein 1998 214 416 125 057 [ 012 266 ]
Keiding 1997 1454 1048 355 124 [ 061 254 ]
Subtotal (95 CI) 96 88 734 078 [ 045 138 ]
Total events 18 (Bile acids) 21 (Control)
Heterogeneity Chi2 = 417 df = 2 (P = 012) I2 =52
Test for overall effect Z = 084 (P = 040)
2 Six months or more
Angelico 1999 316 217 65 159 [ 030 833 ]
Sama 1991 520 620 201 083 [ 030 229 ]
Subtotal (95 CI) 36 37 266 102 [ 043 240 ]
Total events 8 (Bile acids) 8 (Control)
Heterogeneity Chi2 = 043 df = 1 (P = 051) I2 =00
005 02 1 5 20
Favours bile acids Favours control
(Continued )
36Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Test for overall effect Z = 004 (P = 097)
Total (95 CI) 132 125 1000 085 [ 053 136 ]
Total events 26 (Bile acids) 29 (Control)
Heterogeneity Chi2 = 466 df = 4 (P = 032) I2 =14
Test for overall effect Z = 069 (P = 049)
005 02 1 5 20
Favours bile acids Favours control
Analysis 15 Comparison 1 Bile acids for liver-transplanted patients Outcome 5 Number of deaths related
to rejection at maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 5 Number of deaths related to rejection at maximum follow-up
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 UDCA versus placebo
Keiding 1997 054 148 1000 030 [ 001 712 ]
Total (95 CI) 54 48 1000 030 [ 001 712 ]
Total events 0 (Bile acids) 1 (Control)
Heterogeneity not applicable
Test for overall effect Z = 075 (P = 045)
0001 001 01 1 10 100 1000
Favours bile acids Favours control
37Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 16 Comparison 1 Bile acids for liver-transplanted patients Outcome 6 Number of
retransplantations at maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 6 Number of retransplantations at maximum follow-up
Study or subgroup Bile acids Placebo Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Fleckenstein 1998 214 016 100 567 [ 029 10891 ]
Keiding 1997 154 448 900 022 [ 003 192 ]
Total (95 CI) 68 64 1000 076 [ 020 286 ]
Total events 3 (Bile acids) 4 (Placebo)
Heterogeneity Chi2 = 303 df = 1 (P = 008) I2 =67
Test for overall effect Z = 040 (P = 069)
0001 001 01 1 10 100 1000
Favours bile acids Favours placebo
Analysis 17 Comparison 1 Bile acids for liver-transplanted patients Outcome 7 Number of patients with
acute cellular rejection at maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 7 Number of patients with acute cellular rejection at maximum follow-up
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 UDCA versus placebo or no treatment
Barnes 1997 1728 1724 180 086 [ 058 127 ]
Fleckenstein 1998 814 916 83 102 [ 054 190 ]
Keiding 1997 3554 3248 333 097 [ 073 129 ]
Koneru 1993 316 916 89 033 [ 011 101 ]
Pageaux 1995 926 924 92 092 [ 044 193 ]
Sama 1991 1320 1320 128 100 [ 063 158 ]
Subtotal (95 CI) 158 148 905 089 [ 074 108 ]
01 02 05 1 2 5 10
Favours bile acids Favours control
(Continued )
38Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Total events 85 (Bile acids) 89 (Control)
Heterogeneity Chi2 = 387 df = 5 (P = 057) I2 =00
Test for overall effect Z = 120 (P = 023)
2 TUDCA versus no treatment
Angelico 1999 816 1017 95 085 [ 045 160 ]
Subtotal (95 CI) 16 17 95 085 [ 045 160 ]
Total events 8 (Bile acids) 10 (Control)
Heterogeneity not applicable
Test for overall effect Z = 050 (P = 061)
Total (95 CI) 174 165 1000 089 [ 074 106 ]
Total events 93 (Bile acids) 99 (Control)
Heterogeneity Chi2 = 392 df = 6 (P = 069) I2 =00
Test for overall effect Z = 130 (P = 019)
01 02 05 1 2 5 10
Favours bile acids Favours control
Analysis 18 Comparison 1 Bile acids for liver-transplanted patients Outcome 8 Subgroup analysis
number of patients with acute cellular rejection according to time of start of bile acid
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 8 Subgroup analysis number of patients with acute cellular rejection according to time of start of bile acid
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 Less than three days after transplantation
Keiding 1997 3554 3248 333 097 [ 073 129 ]
Koneru 1993 316 916 89 033 [ 011 101 ]
Subtotal (95 CI) 70 64 422 084 [ 063 111 ]
Total events 38 (Bile acids) 41 (Control)
Heterogeneity Chi2 = 374 df = 1 (P = 005) I2 =73
Test for overall effect Z = 124 (P = 022)
2 Three days or more after liver transplantation
Angelico 1999 816 1017 95 085 [ 045 160 ]
01 02 05 1 2 5 10
Favours bile acids Favours control
(Continued )
39Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Barnes 1997 1728 1724 180 086 [ 058 127 ]
Fleckenstein 1998 814 916 83 102 [ 054 190 ]
Pageaux 1995 926 924 92 092 [ 044 193 ]
Sama 1991 1320 1320 128 100 [ 063 158 ]
Subtotal (95 CI) 104 101 578 092 [ 072 117 ]
Total events 55 (Bile acids) 58 (Control)
Heterogeneity Chi2 = 041 df = 4 (P = 098) I2 =00
Test for overall effect Z = 067 (P = 050)
Total (95 CI) 174 165 1000 089 [ 074 106 ]
Total events 93 (Bile acids) 99 (Control)
Heterogeneity Chi2 = 392 df = 6 (P = 069) I2 =00
Test for overall effect Z = 130 (P = 019)
01 02 05 1 2 5 10
Favours bile acids Favours control
40Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 19 Comparison 1 Bile acids for liver-transplanted patients Outcome 9 Subgroup analysis
number of patients with acute cellular rejection according to treatment duration
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 9 Subgroup analysis number of patients with acute cellular rejection according to treatment duration
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 Less than six months
Barnes 1997 1728 1724 180 086 [ 058 127 ]
Fleckenstein 1998 814 916 83 102 [ 054 190 ]
Keiding 1997 3554 3248 333 097 [ 073 129 ]
Koneru 1993 316 916 89 033 [ 011 101 ]
Pageaux 1995 926 924 92 092 [ 044 193 ]
Subtotal (95 CI) 138 128 777 087 [ 071 107 ]
Total events 72 (Bile acids) 76 (Control)
Heterogeneity Chi2 = 374 df = 4 (P = 044) I2 =00
Test for overall effect Z = 129 (P = 020)
2 Six months or more
Angelico 1999 816 1017 95 085 [ 045 160 ]
Sama 1991 1320 1320 128 100 [ 063 158 ]
Subtotal (95 CI) 36 37 223 094 [ 065 136 ]
Total events 21 (Bile acids) 23 (Control)
Heterogeneity Chi2 = 017 df = 1 (P = 068) I2 =00
Test for overall effect Z = 035 (P = 073)
Total (95 CI) 174 165 1000 089 [ 074 106 ]
Total events 93 (Bile acids) 99 (Control)
Heterogeneity Chi2 = 392 df = 6 (P = 069) I2 =00
Test for overall effect Z = 130 (P = 019)
01 02 05 1 2 5 10
Favours bile acids Favours control
41Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 110 Comparison 1 Bile acids for liver-transplanted patients Outcome 10 Number of patients
with chronic rejection at maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 10 Number of patients with chronic rejection at maximum follow-up
Study or subgroup Bile acids Placebo Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Barnes 1997 128 624 611 014 [ 002 110 ]
Fleckenstein 1998 114 116 88 114 [ 008 1663 ]
Keiding 1997 154 348 300 030 [ 003 275 ]
Total (95 CI) 96 88 1000 028 [ 008 095 ]
Total events 3 (Bile acids) 10 (Placebo)
Heterogeneity Chi2 = 148 df = 2 (P = 048) I2 =00
Test for overall effect Z = 204 (P = 0041)
0001 001 01 1 10 100 1000
Favours bile acids Favours placebo
Analysis 111 Comparison 1 Bile acids for liver-transplanted patients Outcome 11 Number of patients
with steroid-resistant rejection at maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 11 Number of patients with steroid-resistant rejection at maximum follow-up
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Barnes 1997 328 724 277 037 [ 011 127 ]
Fleckenstein 1998 314 316 103 114 [ 027 478 ]
Keiding 1997 1454 1548 583 083 [ 045 154 ]
Pageaux 1995 226 124 38 185 [ 018 1908 ]
Total (95 CI) 122 112 1000 077 [ 047 127 ]
Total events 22 (Bile acids) 26 (Control)
Heterogeneity Chi2 = 226 df = 3 (P = 052) I2 =00
Test for overall effect Z = 102 (P = 031)
001 01 1 10 100
Favours bile acids Favours placebo
42Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 112 Comparison 1 Bile acids for liver-transplanted patients Outcome 12 Serum bilirubin (mgdl)
at the end of treatment
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 12 Serum bilirubin (mgdl) at the end of treatment
Study or subgroup Bile acids Placebo Mean Difference Weight Mean Difference
N Mean(SD) N Mean(SD) IVFixed95 CI IVFixed95 CI
Fleckenstein 1998 14 319 (68) 16 059 (022) 1000 260 [ -096 616 ]
Total (95 CI) 14 16 1000 260 [ -096 616 ]
Heterogeneity not applicable
Test for overall effect Z = 143 (P = 015)
-10 -5 0 5 10
Favours bile acids Favours placebo
Analysis 113 Comparison 1 Bile acids for liver-transplanted patients Outcome 13 Number of days of
hospitalisation after liver transplantation
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 13 Number of days of hospitalisation after liver transplantation
Study or subgroup Bile acids Placebo Mean Difference Weight Mean Difference
N Mean(SD) N Mean(SD) IVFixed95 CI IVFixed95 CI
Barnes 1997 28 25 (17) 24 335 (13) 1000 -850 [ -1667 -033 ]
Total (95 CI) 28 24 1000 -850 [ -1667 -033 ]
Heterogeneity not applicable
Test for overall effect Z = 204 (P = 0041)
-100 -50 0 50 100
Favours bile acids Favours placebo
43Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 114 Comparison 1 Bile acids for liver-transplanted patients Outcome 14 Adverse events
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 14 Adverse events
Study or subgroup Bile acids Placebo Risk Ratio Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Angelico 1999 016 017 00 [ 00 00 ]
Barnes 1997 128 124 086 [ 006 1298 ]
Keiding 1997 554 548 089 [ 027 288 ]
Total (95 CI) 98 89 088 [ 030 260 ]
Total events 6 (Bile acids) 6 (Placebo)
Heterogeneity Chi2 = 000 df = 1 (P = 098) I2 =00
Test for overall effect Z = 022 (P = 082)
001 01 1 10 100
Favours bile acids Favours placebo
A P P E N D I C E S
Appendix 1 Search strategies
Data Base Date of Search Search Strategy
The Cochrane Hepato-Biliary Group Con-
trolled Trials Register
September 2009 1 rsquoliver transplantationrsquo and rsquochenodeoxy-
cholicrsquo
2 rsquoliver transplantationrsquo and rsquocholicrsquo
3 rsquoliver transplantationrsquo and rsquodeoxycholicrsquo
4 rsquoliver transplantationrsquo and rsquoglycochen-
odeoxycholicrsquo
5 rsquoliver transplantationrsquo and rsquoglycocholicrsquo
6 rsquoliver transplantationrsquo and rsquoglycodeoxy-
cholicrsquo
7 rsquoliver transplantationrsquo and rsquoglycolitho-
cholicrsquo
8 rsquoliver transplantationrsquo and rsquohyodeoxy-
cholicrsquo
9 rsquoliver transplantationrsquo and rsquolithocholicrsquo
10 rsquoliver transplantationrsquo and rsquotaurochen-
odeoxycholicrsquo
44Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
11 rsquoliver transplantationrsquo and rsquotauro-
cholicrsquo
12 rsquoliver transplantationrsquo and rsquotaurodehy-
drocholicrsquo
13 rsquoliver transplantationrsquo and rsquotau-
rodeoxycholicrsquo
14 rsquoliver transplantationrsquo and rsquotauroglyco-
cholicrsquo
15 rsquoliver transplantationrsquo and rsquotaurolitho-
cholicrsquo
16 rsquoliver transplantationrsquo and rsquotaurosel-
cholicrsquo
17 rsquoliver transplantationrsquo and rsquotaurourso-
cholicrsquo
18 rsquoliver transplantationrsquo and rsquotaurour-
sodeoxycholicrsquo
19 rsquoliver transplantationrsquo and rsquoursocholicrsquo
20 rsquoliver transplantationrsquo and rsquoursodeoxy-
cholicrsquo
The Cochrane Central Register of Con-
trolled Trials in The Cochrane Library
Issue 3 2009 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
6 3 or 4
7 5 and 6
MEDLINE September 2009 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
45Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
6 3 or 4
7 5 and 6
8 RANDOMIZED-CONTROLLED-
TRIAL ME
9 RANDOM
10 8 or 9
11 7 and 10
EMBASE September 2009 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
6 3 or 4
7 5 and 6
8 RANDOMIZED-CONTROLLED-
TRIAL ME
9 RANDOM
10 8 or 9
11 7 and 10
46Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
Science Citation Index Expanded September 2009 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
6 3 or 4
7 5 and 6
8 RANDOMIZED-CONTROLLED-
TRIAL ME
9 RANDOM
10 8 or 9
11 7 and 10
The Chinese Biomedical Database Searched from January 1980 to April 2002 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
47Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
6 3 or 4
7 5 and 6
8 RANDOMIZED-CONTROLLED-
TRIAL ME
9 RANDOM
10 8 or 9
11 7 and 10
W H A T rsquo S N E W
Last assessed as up-to-date 8 February 2010
18 September 2009 New citation required but conclusions have not
changed
This review is an updated version of a review that was
published for the first time in Issue 3 2005 of TheCochrane Library by Chen 2003b
18 September 2009 New search has been performed No new studies fulfilled the inclusion criteria
H I S T O R Y
Protocol first published Issue 3 2003
Review first published Issue 3 2005
C O N T R I B U T I O N S O F A U T H O R S
GP and VG independently performed searches of relevant databases GP validated the search selected trials for inclusion contacted
the authors of the trials performed data extraction and data analysis and drafted the systematic review VG revised the review update
CG and DS revised the review update solved discrepancies of data extraction validated data analyses and provided consultation
D E C L A R A T I O N S O F I N T E R E S T
None known
48Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
S O U R C E S O F S U P P O R T
Internal sources
bull Copenhagen Trial Unit Denmark
External sources
bull Danish Medical Research Councilrsquos Grant on Getting Research into Practice (GRIP) Denmark
D I F F E R E N C E S B E T W E E N P R O T O C O L A N D R E V I E W
We assessed the risk of bias in the included studies for another four domains that were added to the review protocol (incomplete
outcome data selective outcome reporting baseline imbalance and early stopping of trial) In general the text of the risk of bias
domains were updated following Higgins 2008 Trials were considered at low risk of bias when judged as adequate in all domains
Quasi-randomised studies observational and case-control studies were included for the report of adverse events
We performed trial sequential analysis for outcomes demonstrating a statistically significant result
I N D E X T E R M S
Medical Subject Headings (MeSH)
lowastLiver Transplantation Cholagogues and Choleretics [lowasttherapeutic use] Graft Rejection [lowastprevention amp control] Randomized Con-
trolled Trials as Topic Taurochenodeoxycholic Acid [lowasttherapeutic use] Ursodeoxycholic Acid [lowasttherapeutic use]
MeSH check words
Humans
49Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Angelico 1999 (Continued)
Item Authorsrsquo judgement Description
Adequate sequence generation Yes Computer generated table
Allocation concealment Unclear No information provided
Blinding No Not performed
Incomplete outcome data addressed
All outcomes
Yes Withdrawal two patients from the
TUDCA group and two patients from the
placebo group Three of them died due to
transplant non-function in the first postop-
erative week and one patient was regrafted
due to thrombosis of hepatic artery
Free of selective reporting Unclear Post-transplant cholestasis and liver bio-
chemistry specified as outcomes Differ-
ence reported as not significant but no ac-
tual data given
Sample size calculation No Not reported
Intention-to-treat analysis No Not stated and not used
Baseline imbalance Unclear Not enough information provided
Early stopping of trial Unclear Not enough information provided
Barnes 1997
Methods Study design randomised placebo-controlled double-blind trial
Participants Country United States
Publication language English
Inclusion criteria
- patients aged 18 years or older who underwent liver transplantation at the Cleveland
Clinic Foundation from April 1992 through June of 1994
Exclusion criteria
- patients who were found to have cancer at surgically resected margins of the biliary
tree
- patents who underwent retransplantation
Participants
- UDCA group (n = 28)
Mean age (years +- SD)
505 +- 116
Ratio of sex (malefemale) 1810
Child class A 7
20Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Barnes 1997 (Continued)
B 13
and C 8
Origins of liver diseases Laennecrsquos cirrhosis 4
PBC 3
cryptogenic cirrhosis 6
hepatitis Ccirrhosis 4
hepatitis Bcirrhosis 3
autoimmune hepatitis with cirrhosis 3
PSC 2
other 3
- Placebo group (n = 24)
Mean age (years +- SD)
507 +- 93
Ratio of sex (malefemale) 159
Child class A 6
B 14
and C 4
Origins of liver diseases Laennecrsquos cirrhosis 9
PBC 5
cryptogenic cirrhosis 1
hepatitis Ccirrhosis 1
hepatitis Bcirrhosis 1
autoimmune hepatitis with cirrhosis 1
PSC 2
other 4
Interventions UDCA group
- Dose 10-15 mgkg body weightday in divided doses
- Route orally
- Duration immediately after intestinal transit recovery usually between postoperative
days three and five and continue for three months
Placebo group
- identical-appearing capsules administered in the same quantity and manner
Co-interventions all patients received standard triple-drug regimens (steroids azathio-
prine and cyclosporine or tacrolimus)
Outcomes All cause mortality
Number of patients with acute cellular rejection
Number of patients with chronic rejection
Number of patients with steroid-resistant rejection
Number of days of hospitalisation
Adverse events
Notes Letter was sent to the authors in September 2009 A reply with additional information
was received shortly after
Risk of bias
Item Authorsrsquo judgement Description
21Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Barnes 1997 (Continued)
Adequate sequence generation Yes Computer generated table
Allocation concealment Unclear No information provided
Blinding Yes Quote ldquorandomised to receive either
UDCA or an identical placebo capsulerdquo
Incomplete outcome data addressed
All outcomes
Yes Mean follow-up time 18 months Ten pa-
tients withdrawn from study 6 in UDCA
group and 4 in placebo group Reasons
for withdrawal were reported Four patients
died in the placebo group
Free of selective reporting Yes All expected outcomes reported
Sample size calculation Unclear The trial reported the method of sample
size calculation but the actual number of
patients needed was not reported
Intention-to-treat analysis Yes Stated and used
Baseline imbalance Unclear Not enough information provided
Early stopping of trial Unclear The number of patients needed to gain the
actual power was not reported Whether
the trial was terminated early is not clear
Fleckenstein 1998
Methods Study design prospective randomised double-blind trial
Participants Country United States
Publication language English
Inclusion criteria
- patients who underwent liver transplantation at the Johns Hopkins Hospital
Exclusion criteria
- patients who were under 18 years old undergoing repeat transplantation had primary
graft nonfunction or refused consent
Participants
- UDCA group (n = 14)
Mean age (years +- SD)
443 +- 127
Ratio of sex (malefemale) 68
Origins of liver diseases hepatitis C 6
alcohol 2
autoimmune 1
PBC 2
22Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Fleckenstein 1998 (Continued)
PSC 1
autoimmune cholangiopathy 1
hepatitis B 1
- Placebo group (n = 16)
Mean age (years +- SD)
496 +- 109
Ratio of sex (malefemale) 124
Origins of liver diseases hepatitis C 3
alcohol 3
autoimmune 3
PBC 1
PSC 2
cryptogenic 2
hepatitis B 1
alpha1-antitrypsin deficiency 1
Interventions UDCA group
- Dose 15 mgkg body weightday in divided doses
- Route orally
- Duration immediately after intestinal transit recovery usually between postoperative
days three and five and continue for three months
Placebo group
- Identical-appearing capsules administered in the same quantity and manner
Co-interventions all patients received standard triple-drug regimens (steroids azathio-
prine and cyclosporine or tacrolimus)
Outcomes All cause mortality
Number with retransplantation
Number of patients with acute cellular rejection
Number of patients with chronic rejection
Serum bilirubin levels at the end of treatment
Notes Follow-up time nine months
Letter was sent to the authors in September 2009 No reply was received
Risk of bias
Item Authorsrsquo judgement Description
Adequate sequence generation Unclear No information provided
Allocation concealment Unclear No information provided
Blinding Yes Method of blinding not described but
probably adequate
Incomplete outcome data addressed
All outcomes
Yes Withdrawal one patient from the UDCA
group and two patients from the placebo
group because of capsule size
23Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Fleckenstein 1998 (Continued)
Free of selective reporting Unclear Outcomes were not completely described
Sample size calculation No Not reported
Intention-to-treat analysis Yes Quote ldquoThree patients withdrew after in-
clusionThey were included in the statis-
tical analysisrdquo
Baseline imbalance Unclear Not enough information provided
Early stopping of trial Unclear Not enough information provided
Keiding 1997
Methods Study design prospective randomised placebo-controlled multicenter study
Participants Country Denmark Finland Norway and Sweden
Publication language English
Inclusion criteria
- patients who underwent liver transplantation in Denmark Finland Norway and Swe-
den from September 1 1992 to May 31 1994
Exclusion criteria
- patients with malignant diseases
Participants
The age of the children ranged from 0 to 13 years (median 15) and the age of adults
ranged from 14 to 59 years old (median 44) MaleFemale ratio was 96 for children and
4344 for adults
- UDCA group (n = 54)
Origins of liver diseases
paracetamol intoxication 1 hepatitis B 1 autoimmune hepatitis 0 biliary atresia 2
metabolic diseases 7 neonatal hepatitis 2 PBC 13 post hepatitis cirrhosis 8 PSC 3
cryptogenic cirrhosis 7 alcoholic cirrhosis 2 other reasons 8
- Placebo group (n = 48)
Origins of liver diseases paracetamol intoxication 1 hepatitis B 0 autoimmune hepatitis
1 biliary atresia 3 metabolic diseases 11 neonatal hepatitis 0 PBC 7 post hepatitis
cirrhosis 5 PSC 7 cryptogenic cirrhosis 2 alcoholic cirrhosis 6 other reasons 5
Interventions UDCA group
- Dose 15 mgkg body weightday in two or three divided doses
- Route orally
- Duration immediately after intestinal transit recovery usually between postoperative
days three and five and continue for three months
Placebo group
- Identical-appearing capsules administered in the same quantity and manner
Co-interventions all patients received standard triple-drug regimens (steroids azathio-
prine and cyclosporine or tacrolimus)
24Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Keiding 1997 (Continued)
Outcomes All cause mortality
Number of deaths related to rejection
Number of patients with acute cellular rejection
Number of patients with chronic rejection
Number of patients with steroid-resistant rejection
Adverse events
Notes Letter was sent to the authors in September 2009 No reply was received
Risk of bias
Item Authorsrsquo judgement Description
Adequate sequence generation Unclear Patients were randomised at a ratio of 11
Allocation concealment Yes Quote ldquo The allocation was performed in
blocks of 10 patients using the sealed serial
envelope methodrdquo
Blinding Yes Quote ldquoThe UDCA and the placebo cap-
sules had identical appearance and tasterdquo
Incomplete outcome data addressed
All outcomes
Yes Follow-up time 12 months Five UDCA
patients and five placebo patients withdrew
from study Reasons were reported
Free of selective reporting Unclear Insufficient information
Sample size calculation Yes Performed and allowed for a difference in
the incidence of at least one episode of
acute rejection of 50 between the treat-
ment and placebo groups with 90 statisti-
cal power and a significance level of P value
less than 005 The calculated sample size
was 80 patients
Intention-to-treat analysis Yes Stated and used
Baseline imbalance Yes The study seems to be free of baseline im-
balance
Early stopping of trial Yes Study attained the pre-specified sample
size
25Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Koneru 1993
Methods Study design randomised controlled trial
Participants Country United States
Publication language English
Inclusion criteria
- patients who underwent liver transplantation
Exclusion criteria
- not mentioned
Participants
- UDCA group (n = 16)
Mean age (years +- SD)
no information
Ratio of sex (malefemale) no information
Origins of liver diseases
no information
- Control group (n = 16)
Mean age (years +- SD)
no information
Ratio of sex (malefemale) no information
Origins of liver diseases
no information
Interventions UDCA group
- Dose 900 mgday
- Route orally
- Duration immediately after intestinal transit recovery usually between postoperative
days three and five and continue for three months
Control group
- no treatment
Co-interventions all patients received standard triple-drug regimens (steroids azathio-
prine and cyclosporine)
Outcomes Number of patients with retransplantation due to rejection
Number of patients with rejection episodes
Notes Abstract
Letter was sent to the authors in September 2009 No reply was received
Risk of bias
Item Authorsrsquo judgement Description
Adequate sequence generation Unclear No information provided
Allocation concealment Unclear No information provided
Blinding No Not performed
26Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Koneru 1993 (Continued)
Incomplete outcome data addressed
All outcomes
Unclear The study gives the impression that there
were no withdrawals but this was not ex-
plicitly stated
Free of selective reporting Unclear Insufficient information provided
Sample size calculation No Not performed
Intention-to-treat analysis Unclear No information provided
Baseline imbalance Unclear Not enough information provided
Early stopping of trial Unclear Not enough information provided
Pageaux 1995
Methods Study design double-blind randomised study
Participants Country France
Publication language English
Inclusion criteria
- patients who underwent liver transplantation
Exclusion criteria
- not mentioned
Participants
- UDCA group (n=26)
Mean age (years +- SD)
47 +- 10
Ratio of sex (malefemale) 179
Origins of liver diseases alcoholic cirrhosis 14
post-hepatic B cirrhosis 2
post-hepatitis C cirrhosis 4
PBC 2
liver cancer 2
fulminant hepatitis 1
miscellaneous 1
- Placebo group (n = 24)
Mean age (years +- SD)
51+- 9
Ratio of sex (malefemale) 159
Origins of liver diseases alcoholic cirrhosis 10
post-hepatic B cirrhosis 0
post-hepatic C cirrhosis 6
PBC 3
liver cancer 4
fulminant hepatitis 0
miscellaneous 1
27Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Pageaux 1995 (Continued)
Interventions UDCA group
- Dose 600 mgday in three divided doses
- Route orally
- Duration immediately after intestinal transit recovery usually between postoperative
days three and five and continue for two months
Placebo group
- identical-appearing capsules administered in the same quantity and manner
Co-interventions all patients received standard triple-drug regimens (steroids azathio-
prine and cyclosporine or tacrolimus)
Outcomes Number of patients with acute cellular rejection
Number of patients with steroid-resistant rejection
Notes Letter was sent to the authors in September 2009 No reply was received
Risk of bias
Item Authorsrsquo judgement Description
Adequate sequence generation Unclear No information provided
Allocation concealment Unclear No information provided
Blinding Unclear Method of blinding not described
Incomplete outcome data addressed
All outcomes
Yes Five patients died from non-immunologi-
cal causes before the end of the first month
and were excluded from the study Reasons
were reported
Free of selective reporting Unclear Not enough information provided
Sample size calculation No Not performed
Intention-to-treat analysis No Not stated and not used
Baseline imbalance Unclear Not enough information provided
Early stopping of trial Unclear Not enough information provided
Sama 1991
Methods Study design randomised controlled trial
Participants Country Italy
Publication language English
Inclusion criteria
28Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Sama 1991 (Continued)
- patients who underwent liver transplantation
Exclusion criteria
- not mentioned
Participants
- UDCA group (n = 20)
Mean age (years +- SD)
no information
Ratio of sex (malefemale) no information
Origins of liver diseases
no information
- Control group (n = 20)
Mean age (years +- SD)
no information
Ratio of sex (malefemale) no information
Origins of liver diseases
no information
Interventions UDCA group
- Dose 600 mgday in two divided doses
- Route orally
- Duration immediately after intestinal transit recovery usually between postoperative
day five and day seven and continue for six months
Control group
- no treatment
Co-interventions all patients received standard immunosuppressive treatment (steroids
and cyclosporine)
Outcomes All cause mortality
Number of patients with acute cellular rejection
Notes Abstract
Letter was sent to the authors in September 2009 No reply was received
Risk of bias
Item Authorsrsquo judgement Description
Adequate sequence generation Unclear A randomisation list was performed before
patients were admitted to the trial (infor-
mation from principal author)
Allocation concealment Unclear No information provided
Blinding Unclear The principle author provided information
that the study was made according to a
single-blind randomised protocol The pri-
mary outcome was the occurrence of biopsy
proven rejection episodes The pathologists
were blind but the patients were not
29Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Sama 1991 (Continued)
Incomplete outcome data addressed
All outcomes
Unclear Five patients from the UDCA group and
six patients from the placebo group were
excluded Reasons for exclusion were not
fully stated
Free of selective reporting No Data about survival of patients were not
adequately reported
Sample size calculation No Not performed
Intention-to-treat analysis No Not stated and not used
Baseline imbalance Unclear Basic characteristics of patients not re-
ported
Early stopping of trial Unclear Not enough information provided
UDCA = ursodeoxycholic acid
TUDCA = tauroursodeoxycholic acid
PBC = primary biliary cirrhosis
PSC = primary sclerosing cholangitis
OKT3 = anti-CD3 monoclonal antibody
Characteristics of excluded studies [ordered by study ID]
Assy 2007 A randomised controlled trial that included only recipients of liver transplantation with stable graft function and
no episodes of rejection for at least 2 years that were then offered total immunosuppression withdrawal Fourteen
patients received UDCA (15 mgkg body weightday) and 12 received placebo Rejection occurred in 43 and
75 of patients respectively (no significant difference) None developed chronic rejection After follow-up two
patients were free of immunosuppression 80 were steroid free and 50 were able to reduce their dose of
cyclosporine
Clavien 1996 Case series Fifty consecutive liver-transplanted patients were treated with a standard cyclosporine immunosup-
pressive regimen Twenty three of the 43 survivors developed an episode of rejection and UDCA (10 mgkg
weightday) was initiated Only one patient had a second episode of rejection
Friman 1992 Observational study Thirty-three liver-transplanted patients received 10 mg UDCAkg body weightday for
median of 10 months (range four to 21 months) Eight historical liver-transplanted patients served as control
group The rejection incidence was significantly lower in the patients who received the treatment with UDCA
Biochemistry one month after transplantation demonstrated significantly lower average values of aminotrans-
ferases and alkaline phosphatases in patients treated with UDCA than in the control group
30Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
Heathcote 1999 Observational study From 1987 to 1996 37 UDCA treated and 53 placebo treated patients with primary biliary
cirrhosis were referred for transplantation Posttransplantation survival rates at one month were 939 in the
UDCA group and 884 in the placebo group and one year survival rates were 903 and 784 respectively
(no significant differences) However rejection (type not defined - a secondary outcome measure) occurred
significantly less often in the UDCA group (429) than in placebo group (688)
Henriksson 1991 Observational study All patients in this study were given sequential quadruple immunosuppression with anti-
lymphocyte globulin azathioprine steroids and cyclosporine All patients with primary graft function (n = 11)
were treated with 10 mg UDCAkg body weightday starting during the first postoperative week Patients who
received liver transplantation in the first 6 months of 1989 (n = 8) served as controls In the control group one
patient died after 9 months with chronic graft dysfunction and six patients had rejection episodes during the
first postoperative month All patients in the UDCA group were alive without rejection episodes
Persson 1990 Observational study All 11 adult patients transplanted between August 1989 and January 1990 with primary
graft function were treated with 10 mg UDCA kg body weightday Eight patients transplanted during the first
half of 1989 served as control UDCA was started during the first postoperative week and the treatment was
continued for six months All patients in the UDCA treated group survived with satisfactory graft function In
the control group six patients had at least one rejection episode needing treatment during the first postoperative
month
Rafael 1995 Observational study Seventeen patients who underwent liver transplantation between February 1990 and April
1993 and developed biliary complications after transplantation were retrospectively analysed regarding treatment
with UDCA UDCA was given in a dose of 500 to 1000 mgday Ten patients were treated for at least one year while
seven patients were treated for 14 to 250 days UDCA significantly improved gammaglutamyl transpeptidase in
liver graft recipients with biliary complications There was also a trend towards improvement in serum bilirubin
and alanine transaminase values
Sama 1998 Observational study Thirty-four patients who underwent liver transplantation between January 1995 and June
1996 were included in the study Seventeen were treated with UDCA 10 mgkg body weightday during 6
months while 17 served as controls on the basis of having undergone liver transplantation closest to UDCA
patients A significant decrease in serum bilirubin levels was observed in UDCA patients There was a significantly
higher incidence of recurrent hepatitis in the control group
UDCA ursodeoxycholic acid
31Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
D A T A A N D A N A L Y S E S
Comparison 1 Bile acids for liver-transplanted patients
Outcome or subgroup titleNo of
studies
No of
participants Statistical method Effect size
1 All-cause mortality at maximum
follow-up
5 257 Risk Ratio (M-H Fixed 95 CI) 085 [053 136]
11 UDCA versus placebo or
no treatment
4 224 Risk Ratio (M-H Fixed 95 CI) 080 [049 130]
12 TUDCA versus no
treatment
1 33 Risk Ratio (M-H Fixed 95 CI) 159 [030 833]
2 All-cause mortality worst-best
case and best-worst case
scenarios
5 Risk Ratio (M-H Fixed 95 CI) Subtotals only
21 Worst-best case scenario 5 257 Risk Ratio (M-H Fixed 95 CI) 130 [086 196]
22 Best-worst case scenario 5 257 Risk Ratio (M-H Fixed 95 CI) 058 [038 090]
3 Subgroup analyses all-cause
mortality at maximum
follow-up according to time of
start of bile acids
5 257 Risk Ratio (M-H Fixed 95 CI) 085 [053 136]
31 Less than three days after
transplantation
1 102 Risk Ratio (M-H Fixed 95 CI) 124 [061 254]
32 Three days or more after
transplantation
4 155 Risk Ratio (M-H Fixed 95 CI) 063 [033 120]
4 Subgroup analyses all cause
mortality at maximum
follow-up according to
treatment duration
5 257 Risk Ratio (M-H Fixed 95 CI) 085 [053 136]
41 Less than six months 3 184 Risk Ratio (M-H Fixed 95 CI) 078 [045 138]
42 Six months or more 2 73 Risk Ratio (M-H Fixed 95 CI) 102 [043 240]
5 Number of deaths related
to rejection at maximum
follow-up
1 102 Risk Ratio (M-H Fixed 95 CI) 030 [001 712]
51 UDCA versus placebo 1 102 Risk Ratio (M-H Fixed 95 CI) 030 [001 712]
6 Number of retransplantations at
maximum follow-up
2 132 Risk Ratio (M-H Fixed 95 CI) 076 [020 286]
7 Number of patients with acute
cellular rejection at maximum
follow-up
7 339 Risk Ratio (M-H Fixed 95 CI) 089 [074 106]
71 UDCA versus placebo or
no treatment
6 306 Risk Ratio (M-H Fixed 95 CI) 089 [074 108]
72 TUDCA versus no
treatment
1 33 Risk Ratio (M-H Fixed 95 CI) 085 [045 160]
8 Subgroup analysis number of
patients with acute cellular
rejection according to time of
start of bile acid
7 339 Risk Ratio (M-H Fixed 95 CI) 089 [074 106]
32Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
81 Less than three days after
transplantation
2 134 Risk Ratio (M-H Fixed 95 CI) 084 [063 111]
82 Three days or more after
liver transplantation
5 205 Risk Ratio (M-H Fixed 95 CI) 092 [072 117]
9 Subgroup analysis number
of patients with acute
cellular rejection according to
treatment duration
7 339 Risk Ratio (M-H Fixed 95 CI) 089 [074 106]
91 Less than six months 5 266 Risk Ratio (M-H Fixed 95 CI) 087 [071 107]
92 Six months or more 2 73 Risk Ratio (M-H Fixed 95 CI) 094 [065 136]
10 Number of patients with
chronic rejection at maximum
follow-up
3 184 Risk Ratio (M-H Fixed 95 CI) 028 [008 095]
11 Number of patients with
steroid-resistant rejection at
maximum follow-up
4 234 Risk Ratio (M-H Fixed 95 CI) 077 [047 127]
12 Serum bilirubin (mgdl) at the
end of treatment
1 30 Mean Difference (IV Fixed 95 CI) 26 [-096 616]
13 Number of days of
hospitalisation after liver
transplantation
1 52 Mean Difference (IV Fixed 95 CI) -85 [-1667 -033]
14 Adverse events 3 187 Risk Ratio (M-H Fixed 95 CI) 088 [030 260]
Analysis 11 Comparison 1 Bile acids for liver-transplanted patients Outcome 1 All-cause mortality at
maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 1 All-cause mortality at maximum follow-up
Study or subgroup Favours bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 UDCA versus placebo or no treatment
Barnes 1997 228 724 253 024 [ 006 107 ]
Fleckenstein 1998 214 416 125 057 [ 012 266 ]
Keiding 1997 1454 1048 355 124 [ 061 254 ]
Sama 1991 520 620 201 083 [ 030 229 ]
Subtotal (95 CI) 116 108 935 080 [ 049 130 ]
Total events 23 (Favours bile acids) 27 (Control)
Heterogeneity Chi2 = 416 df = 3 (P = 025) I2 =28
Test for overall effect Z = 091 (P = 036)
01 02 05 1 2 5 10
Favours bile acids Favours control
(Continued )
33Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Favours bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
2 TUDCA versus no treatment
Angelico 1999 316 217 65 159 [ 030 833 ]
Subtotal (95 CI) 16 17 65 159 [ 030 833 ]
Total events 3 (Favours bile acids) 2 (Control)
Heterogeneity not applicable
Test for overall effect Z = 055 (P = 058)
Total (95 CI) 132 125 1000 085 [ 053 136 ]
Total events 26 (Favours bile acids) 29 (Control)
Heterogeneity Chi2 = 466 df = 4 (P = 032) I2 =14
Test for overall effect Z = 069 (P = 049)
01 02 05 1 2 5 10
Favours bile acids Favours control
Analysis 12 Comparison 1 Bile acids for liver-transplanted patients Outcome 2 All-cause mortality worst-
best case and best-worst case scenarios
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 2 All-cause mortality worst-best case and best-worst case scenarios
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 Worst-best case scenario
Angelico 1999 516 217 65 266 [ 060 1180 ]
Barnes 1997 828 724 253 098 [ 042 230 ]
Fleckenstein 1998 314 416 125 086 [ 023 319 ]
Keiding 1997 1954 1048 355 169 [ 087 327 ]
Sama 1991 520 620 201 083 [ 030 229 ]
Subtotal (95 CI) 132 125 1000 130 [ 086 196 ]
Total events 40 (Bile acids) 29 (Control)
Heterogeneity Chi2 = 303 df = 4 (P = 055) I2 =00
Test for overall effect Z = 123 (P = 022)
2 Best-worst case scenario
005 02 1 5 20
Favours bile acids Favours control
(Continued )
34Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Angelico 1999 316 417 90 080 [ 021 302 ]
Barnes 1997 228 1124 274 016 [ 004 063 ]
Fleckenstein 1998 214 616 130 038 [ 009 159 ]
Keiding 1997 1454 1548 368 083 [ 045 154 ]
Sama 1991 520 620 139 083 [ 030 229 ]
Subtotal (95 CI) 132 125 1000 058 [ 038 090 ]
Total events 26 (Bile acids) 42 (Control)
Heterogeneity Chi2 = 567 df = 4 (P = 023) I2 =29
Test for overall effect Z = 247 (P = 0014)
005 02 1 5 20
Favours bile acids Favours control
Analysis 13 Comparison 1 Bile acids for liver-transplanted patients Outcome 3 Subgroup analyses all-
cause mortality at maximum follow-up according to time of start of bile acids
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 3 Subgroup analyses all-cause mortality at maximum follow-up according to time of start of bile acids
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 Less than three days after transplantation
Keiding 1997 1454 1048 355 124 [ 061 254 ]
Subtotal (95 CI) 54 48 355 124 [ 061 254 ]
Total events 14 (Bile acids) 10 (Control)
Heterogeneity not applicable
Test for overall effect Z = 060 (P = 055)
2 Three days or more after transplantation
Angelico 1999 316 217 65 159 [ 030 833 ]
Barnes 1997 228 724 253 024 [ 006 107 ]
Fleckenstein 1998 214 416 125 057 [ 012 266 ]
Sama 1991 520 620 201 083 [ 030 229 ]
005 02 1 5 20
Favours bile acids Favours control
(Continued )
35Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Subtotal (95 CI) 78 77 645 063 [ 033 120 ]
Total events 12 (Bile acids) 19 (Control)
Heterogeneity Chi2 = 310 df = 3 (P = 038) I2 =3
Test for overall effect Z = 141 (P = 016)
Total (95 CI) 132 125 1000 085 [ 053 136 ]
Total events 26 (Bile acids) 29 (Control)
Heterogeneity Chi2 = 466 df = 4 (P = 032) I2 =14
Test for overall effect Z = 069 (P = 049)
005 02 1 5 20
Favours bile acids Favours control
Analysis 14 Comparison 1 Bile acids for liver-transplanted patients Outcome 4 Subgroup analyses all
cause mortality at maximum follow-up according to treatment duration
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 4 Subgroup analyses all cause mortality at maximum follow-up according to treatment duration
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 Less than six months
Barnes 1997 228 724 253 024 [ 006 107 ]
Fleckenstein 1998 214 416 125 057 [ 012 266 ]
Keiding 1997 1454 1048 355 124 [ 061 254 ]
Subtotal (95 CI) 96 88 734 078 [ 045 138 ]
Total events 18 (Bile acids) 21 (Control)
Heterogeneity Chi2 = 417 df = 2 (P = 012) I2 =52
Test for overall effect Z = 084 (P = 040)
2 Six months or more
Angelico 1999 316 217 65 159 [ 030 833 ]
Sama 1991 520 620 201 083 [ 030 229 ]
Subtotal (95 CI) 36 37 266 102 [ 043 240 ]
Total events 8 (Bile acids) 8 (Control)
Heterogeneity Chi2 = 043 df = 1 (P = 051) I2 =00
005 02 1 5 20
Favours bile acids Favours control
(Continued )
36Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Test for overall effect Z = 004 (P = 097)
Total (95 CI) 132 125 1000 085 [ 053 136 ]
Total events 26 (Bile acids) 29 (Control)
Heterogeneity Chi2 = 466 df = 4 (P = 032) I2 =14
Test for overall effect Z = 069 (P = 049)
005 02 1 5 20
Favours bile acids Favours control
Analysis 15 Comparison 1 Bile acids for liver-transplanted patients Outcome 5 Number of deaths related
to rejection at maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 5 Number of deaths related to rejection at maximum follow-up
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 UDCA versus placebo
Keiding 1997 054 148 1000 030 [ 001 712 ]
Total (95 CI) 54 48 1000 030 [ 001 712 ]
Total events 0 (Bile acids) 1 (Control)
Heterogeneity not applicable
Test for overall effect Z = 075 (P = 045)
0001 001 01 1 10 100 1000
Favours bile acids Favours control
37Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 16 Comparison 1 Bile acids for liver-transplanted patients Outcome 6 Number of
retransplantations at maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 6 Number of retransplantations at maximum follow-up
Study or subgroup Bile acids Placebo Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Fleckenstein 1998 214 016 100 567 [ 029 10891 ]
Keiding 1997 154 448 900 022 [ 003 192 ]
Total (95 CI) 68 64 1000 076 [ 020 286 ]
Total events 3 (Bile acids) 4 (Placebo)
Heterogeneity Chi2 = 303 df = 1 (P = 008) I2 =67
Test for overall effect Z = 040 (P = 069)
0001 001 01 1 10 100 1000
Favours bile acids Favours placebo
Analysis 17 Comparison 1 Bile acids for liver-transplanted patients Outcome 7 Number of patients with
acute cellular rejection at maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 7 Number of patients with acute cellular rejection at maximum follow-up
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 UDCA versus placebo or no treatment
Barnes 1997 1728 1724 180 086 [ 058 127 ]
Fleckenstein 1998 814 916 83 102 [ 054 190 ]
Keiding 1997 3554 3248 333 097 [ 073 129 ]
Koneru 1993 316 916 89 033 [ 011 101 ]
Pageaux 1995 926 924 92 092 [ 044 193 ]
Sama 1991 1320 1320 128 100 [ 063 158 ]
Subtotal (95 CI) 158 148 905 089 [ 074 108 ]
01 02 05 1 2 5 10
Favours bile acids Favours control
(Continued )
38Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Total events 85 (Bile acids) 89 (Control)
Heterogeneity Chi2 = 387 df = 5 (P = 057) I2 =00
Test for overall effect Z = 120 (P = 023)
2 TUDCA versus no treatment
Angelico 1999 816 1017 95 085 [ 045 160 ]
Subtotal (95 CI) 16 17 95 085 [ 045 160 ]
Total events 8 (Bile acids) 10 (Control)
Heterogeneity not applicable
Test for overall effect Z = 050 (P = 061)
Total (95 CI) 174 165 1000 089 [ 074 106 ]
Total events 93 (Bile acids) 99 (Control)
Heterogeneity Chi2 = 392 df = 6 (P = 069) I2 =00
Test for overall effect Z = 130 (P = 019)
01 02 05 1 2 5 10
Favours bile acids Favours control
Analysis 18 Comparison 1 Bile acids for liver-transplanted patients Outcome 8 Subgroup analysis
number of patients with acute cellular rejection according to time of start of bile acid
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 8 Subgroup analysis number of patients with acute cellular rejection according to time of start of bile acid
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 Less than three days after transplantation
Keiding 1997 3554 3248 333 097 [ 073 129 ]
Koneru 1993 316 916 89 033 [ 011 101 ]
Subtotal (95 CI) 70 64 422 084 [ 063 111 ]
Total events 38 (Bile acids) 41 (Control)
Heterogeneity Chi2 = 374 df = 1 (P = 005) I2 =73
Test for overall effect Z = 124 (P = 022)
2 Three days or more after liver transplantation
Angelico 1999 816 1017 95 085 [ 045 160 ]
01 02 05 1 2 5 10
Favours bile acids Favours control
(Continued )
39Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Barnes 1997 1728 1724 180 086 [ 058 127 ]
Fleckenstein 1998 814 916 83 102 [ 054 190 ]
Pageaux 1995 926 924 92 092 [ 044 193 ]
Sama 1991 1320 1320 128 100 [ 063 158 ]
Subtotal (95 CI) 104 101 578 092 [ 072 117 ]
Total events 55 (Bile acids) 58 (Control)
Heterogeneity Chi2 = 041 df = 4 (P = 098) I2 =00
Test for overall effect Z = 067 (P = 050)
Total (95 CI) 174 165 1000 089 [ 074 106 ]
Total events 93 (Bile acids) 99 (Control)
Heterogeneity Chi2 = 392 df = 6 (P = 069) I2 =00
Test for overall effect Z = 130 (P = 019)
01 02 05 1 2 5 10
Favours bile acids Favours control
40Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 19 Comparison 1 Bile acids for liver-transplanted patients Outcome 9 Subgroup analysis
number of patients with acute cellular rejection according to treatment duration
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 9 Subgroup analysis number of patients with acute cellular rejection according to treatment duration
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 Less than six months
Barnes 1997 1728 1724 180 086 [ 058 127 ]
Fleckenstein 1998 814 916 83 102 [ 054 190 ]
Keiding 1997 3554 3248 333 097 [ 073 129 ]
Koneru 1993 316 916 89 033 [ 011 101 ]
Pageaux 1995 926 924 92 092 [ 044 193 ]
Subtotal (95 CI) 138 128 777 087 [ 071 107 ]
Total events 72 (Bile acids) 76 (Control)
Heterogeneity Chi2 = 374 df = 4 (P = 044) I2 =00
Test for overall effect Z = 129 (P = 020)
2 Six months or more
Angelico 1999 816 1017 95 085 [ 045 160 ]
Sama 1991 1320 1320 128 100 [ 063 158 ]
Subtotal (95 CI) 36 37 223 094 [ 065 136 ]
Total events 21 (Bile acids) 23 (Control)
Heterogeneity Chi2 = 017 df = 1 (P = 068) I2 =00
Test for overall effect Z = 035 (P = 073)
Total (95 CI) 174 165 1000 089 [ 074 106 ]
Total events 93 (Bile acids) 99 (Control)
Heterogeneity Chi2 = 392 df = 6 (P = 069) I2 =00
Test for overall effect Z = 130 (P = 019)
01 02 05 1 2 5 10
Favours bile acids Favours control
41Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 110 Comparison 1 Bile acids for liver-transplanted patients Outcome 10 Number of patients
with chronic rejection at maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 10 Number of patients with chronic rejection at maximum follow-up
Study or subgroup Bile acids Placebo Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Barnes 1997 128 624 611 014 [ 002 110 ]
Fleckenstein 1998 114 116 88 114 [ 008 1663 ]
Keiding 1997 154 348 300 030 [ 003 275 ]
Total (95 CI) 96 88 1000 028 [ 008 095 ]
Total events 3 (Bile acids) 10 (Placebo)
Heterogeneity Chi2 = 148 df = 2 (P = 048) I2 =00
Test for overall effect Z = 204 (P = 0041)
0001 001 01 1 10 100 1000
Favours bile acids Favours placebo
Analysis 111 Comparison 1 Bile acids for liver-transplanted patients Outcome 11 Number of patients
with steroid-resistant rejection at maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 11 Number of patients with steroid-resistant rejection at maximum follow-up
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Barnes 1997 328 724 277 037 [ 011 127 ]
Fleckenstein 1998 314 316 103 114 [ 027 478 ]
Keiding 1997 1454 1548 583 083 [ 045 154 ]
Pageaux 1995 226 124 38 185 [ 018 1908 ]
Total (95 CI) 122 112 1000 077 [ 047 127 ]
Total events 22 (Bile acids) 26 (Control)
Heterogeneity Chi2 = 226 df = 3 (P = 052) I2 =00
Test for overall effect Z = 102 (P = 031)
001 01 1 10 100
Favours bile acids Favours placebo
42Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 112 Comparison 1 Bile acids for liver-transplanted patients Outcome 12 Serum bilirubin (mgdl)
at the end of treatment
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 12 Serum bilirubin (mgdl) at the end of treatment
Study or subgroup Bile acids Placebo Mean Difference Weight Mean Difference
N Mean(SD) N Mean(SD) IVFixed95 CI IVFixed95 CI
Fleckenstein 1998 14 319 (68) 16 059 (022) 1000 260 [ -096 616 ]
Total (95 CI) 14 16 1000 260 [ -096 616 ]
Heterogeneity not applicable
Test for overall effect Z = 143 (P = 015)
-10 -5 0 5 10
Favours bile acids Favours placebo
Analysis 113 Comparison 1 Bile acids for liver-transplanted patients Outcome 13 Number of days of
hospitalisation after liver transplantation
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 13 Number of days of hospitalisation after liver transplantation
Study or subgroup Bile acids Placebo Mean Difference Weight Mean Difference
N Mean(SD) N Mean(SD) IVFixed95 CI IVFixed95 CI
Barnes 1997 28 25 (17) 24 335 (13) 1000 -850 [ -1667 -033 ]
Total (95 CI) 28 24 1000 -850 [ -1667 -033 ]
Heterogeneity not applicable
Test for overall effect Z = 204 (P = 0041)
-100 -50 0 50 100
Favours bile acids Favours placebo
43Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 114 Comparison 1 Bile acids for liver-transplanted patients Outcome 14 Adverse events
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 14 Adverse events
Study or subgroup Bile acids Placebo Risk Ratio Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Angelico 1999 016 017 00 [ 00 00 ]
Barnes 1997 128 124 086 [ 006 1298 ]
Keiding 1997 554 548 089 [ 027 288 ]
Total (95 CI) 98 89 088 [ 030 260 ]
Total events 6 (Bile acids) 6 (Placebo)
Heterogeneity Chi2 = 000 df = 1 (P = 098) I2 =00
Test for overall effect Z = 022 (P = 082)
001 01 1 10 100
Favours bile acids Favours placebo
A P P E N D I C E S
Appendix 1 Search strategies
Data Base Date of Search Search Strategy
The Cochrane Hepato-Biliary Group Con-
trolled Trials Register
September 2009 1 rsquoliver transplantationrsquo and rsquochenodeoxy-
cholicrsquo
2 rsquoliver transplantationrsquo and rsquocholicrsquo
3 rsquoliver transplantationrsquo and rsquodeoxycholicrsquo
4 rsquoliver transplantationrsquo and rsquoglycochen-
odeoxycholicrsquo
5 rsquoliver transplantationrsquo and rsquoglycocholicrsquo
6 rsquoliver transplantationrsquo and rsquoglycodeoxy-
cholicrsquo
7 rsquoliver transplantationrsquo and rsquoglycolitho-
cholicrsquo
8 rsquoliver transplantationrsquo and rsquohyodeoxy-
cholicrsquo
9 rsquoliver transplantationrsquo and rsquolithocholicrsquo
10 rsquoliver transplantationrsquo and rsquotaurochen-
odeoxycholicrsquo
44Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
11 rsquoliver transplantationrsquo and rsquotauro-
cholicrsquo
12 rsquoliver transplantationrsquo and rsquotaurodehy-
drocholicrsquo
13 rsquoliver transplantationrsquo and rsquotau-
rodeoxycholicrsquo
14 rsquoliver transplantationrsquo and rsquotauroglyco-
cholicrsquo
15 rsquoliver transplantationrsquo and rsquotaurolitho-
cholicrsquo
16 rsquoliver transplantationrsquo and rsquotaurosel-
cholicrsquo
17 rsquoliver transplantationrsquo and rsquotaurourso-
cholicrsquo
18 rsquoliver transplantationrsquo and rsquotaurour-
sodeoxycholicrsquo
19 rsquoliver transplantationrsquo and rsquoursocholicrsquo
20 rsquoliver transplantationrsquo and rsquoursodeoxy-
cholicrsquo
The Cochrane Central Register of Con-
trolled Trials in The Cochrane Library
Issue 3 2009 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
6 3 or 4
7 5 and 6
MEDLINE September 2009 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
45Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
6 3 or 4
7 5 and 6
8 RANDOMIZED-CONTROLLED-
TRIAL ME
9 RANDOM
10 8 or 9
11 7 and 10
EMBASE September 2009 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
6 3 or 4
7 5 and 6
8 RANDOMIZED-CONTROLLED-
TRIAL ME
9 RANDOM
10 8 or 9
11 7 and 10
46Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
Science Citation Index Expanded September 2009 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
6 3 or 4
7 5 and 6
8 RANDOMIZED-CONTROLLED-
TRIAL ME
9 RANDOM
10 8 or 9
11 7 and 10
The Chinese Biomedical Database Searched from January 1980 to April 2002 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
47Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
6 3 or 4
7 5 and 6
8 RANDOMIZED-CONTROLLED-
TRIAL ME
9 RANDOM
10 8 or 9
11 7 and 10
W H A T rsquo S N E W
Last assessed as up-to-date 8 February 2010
18 September 2009 New citation required but conclusions have not
changed
This review is an updated version of a review that was
published for the first time in Issue 3 2005 of TheCochrane Library by Chen 2003b
18 September 2009 New search has been performed No new studies fulfilled the inclusion criteria
H I S T O R Y
Protocol first published Issue 3 2003
Review first published Issue 3 2005
C O N T R I B U T I O N S O F A U T H O R S
GP and VG independently performed searches of relevant databases GP validated the search selected trials for inclusion contacted
the authors of the trials performed data extraction and data analysis and drafted the systematic review VG revised the review update
CG and DS revised the review update solved discrepancies of data extraction validated data analyses and provided consultation
D E C L A R A T I O N S O F I N T E R E S T
None known
48Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
S O U R C E S O F S U P P O R T
Internal sources
bull Copenhagen Trial Unit Denmark
External sources
bull Danish Medical Research Councilrsquos Grant on Getting Research into Practice (GRIP) Denmark
D I F F E R E N C E S B E T W E E N P R O T O C O L A N D R E V I E W
We assessed the risk of bias in the included studies for another four domains that were added to the review protocol (incomplete
outcome data selective outcome reporting baseline imbalance and early stopping of trial) In general the text of the risk of bias
domains were updated following Higgins 2008 Trials were considered at low risk of bias when judged as adequate in all domains
Quasi-randomised studies observational and case-control studies were included for the report of adverse events
We performed trial sequential analysis for outcomes demonstrating a statistically significant result
I N D E X T E R M S
Medical Subject Headings (MeSH)
lowastLiver Transplantation Cholagogues and Choleretics [lowasttherapeutic use] Graft Rejection [lowastprevention amp control] Randomized Con-
trolled Trials as Topic Taurochenodeoxycholic Acid [lowasttherapeutic use] Ursodeoxycholic Acid [lowasttherapeutic use]
MeSH check words
Humans
49Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Barnes 1997 (Continued)
B 13
and C 8
Origins of liver diseases Laennecrsquos cirrhosis 4
PBC 3
cryptogenic cirrhosis 6
hepatitis Ccirrhosis 4
hepatitis Bcirrhosis 3
autoimmune hepatitis with cirrhosis 3
PSC 2
other 3
- Placebo group (n = 24)
Mean age (years +- SD)
507 +- 93
Ratio of sex (malefemale) 159
Child class A 6
B 14
and C 4
Origins of liver diseases Laennecrsquos cirrhosis 9
PBC 5
cryptogenic cirrhosis 1
hepatitis Ccirrhosis 1
hepatitis Bcirrhosis 1
autoimmune hepatitis with cirrhosis 1
PSC 2
other 4
Interventions UDCA group
- Dose 10-15 mgkg body weightday in divided doses
- Route orally
- Duration immediately after intestinal transit recovery usually between postoperative
days three and five and continue for three months
Placebo group
- identical-appearing capsules administered in the same quantity and manner
Co-interventions all patients received standard triple-drug regimens (steroids azathio-
prine and cyclosporine or tacrolimus)
Outcomes All cause mortality
Number of patients with acute cellular rejection
Number of patients with chronic rejection
Number of patients with steroid-resistant rejection
Number of days of hospitalisation
Adverse events
Notes Letter was sent to the authors in September 2009 A reply with additional information
was received shortly after
Risk of bias
Item Authorsrsquo judgement Description
21Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Barnes 1997 (Continued)
Adequate sequence generation Yes Computer generated table
Allocation concealment Unclear No information provided
Blinding Yes Quote ldquorandomised to receive either
UDCA or an identical placebo capsulerdquo
Incomplete outcome data addressed
All outcomes
Yes Mean follow-up time 18 months Ten pa-
tients withdrawn from study 6 in UDCA
group and 4 in placebo group Reasons
for withdrawal were reported Four patients
died in the placebo group
Free of selective reporting Yes All expected outcomes reported
Sample size calculation Unclear The trial reported the method of sample
size calculation but the actual number of
patients needed was not reported
Intention-to-treat analysis Yes Stated and used
Baseline imbalance Unclear Not enough information provided
Early stopping of trial Unclear The number of patients needed to gain the
actual power was not reported Whether
the trial was terminated early is not clear
Fleckenstein 1998
Methods Study design prospective randomised double-blind trial
Participants Country United States
Publication language English
Inclusion criteria
- patients who underwent liver transplantation at the Johns Hopkins Hospital
Exclusion criteria
- patients who were under 18 years old undergoing repeat transplantation had primary
graft nonfunction or refused consent
Participants
- UDCA group (n = 14)
Mean age (years +- SD)
443 +- 127
Ratio of sex (malefemale) 68
Origins of liver diseases hepatitis C 6
alcohol 2
autoimmune 1
PBC 2
22Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Fleckenstein 1998 (Continued)
PSC 1
autoimmune cholangiopathy 1
hepatitis B 1
- Placebo group (n = 16)
Mean age (years +- SD)
496 +- 109
Ratio of sex (malefemale) 124
Origins of liver diseases hepatitis C 3
alcohol 3
autoimmune 3
PBC 1
PSC 2
cryptogenic 2
hepatitis B 1
alpha1-antitrypsin deficiency 1
Interventions UDCA group
- Dose 15 mgkg body weightday in divided doses
- Route orally
- Duration immediately after intestinal transit recovery usually between postoperative
days three and five and continue for three months
Placebo group
- Identical-appearing capsules administered in the same quantity and manner
Co-interventions all patients received standard triple-drug regimens (steroids azathio-
prine and cyclosporine or tacrolimus)
Outcomes All cause mortality
Number with retransplantation
Number of patients with acute cellular rejection
Number of patients with chronic rejection
Serum bilirubin levels at the end of treatment
Notes Follow-up time nine months
Letter was sent to the authors in September 2009 No reply was received
Risk of bias
Item Authorsrsquo judgement Description
Adequate sequence generation Unclear No information provided
Allocation concealment Unclear No information provided
Blinding Yes Method of blinding not described but
probably adequate
Incomplete outcome data addressed
All outcomes
Yes Withdrawal one patient from the UDCA
group and two patients from the placebo
group because of capsule size
23Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Fleckenstein 1998 (Continued)
Free of selective reporting Unclear Outcomes were not completely described
Sample size calculation No Not reported
Intention-to-treat analysis Yes Quote ldquoThree patients withdrew after in-
clusionThey were included in the statis-
tical analysisrdquo
Baseline imbalance Unclear Not enough information provided
Early stopping of trial Unclear Not enough information provided
Keiding 1997
Methods Study design prospective randomised placebo-controlled multicenter study
Participants Country Denmark Finland Norway and Sweden
Publication language English
Inclusion criteria
- patients who underwent liver transplantation in Denmark Finland Norway and Swe-
den from September 1 1992 to May 31 1994
Exclusion criteria
- patients with malignant diseases
Participants
The age of the children ranged from 0 to 13 years (median 15) and the age of adults
ranged from 14 to 59 years old (median 44) MaleFemale ratio was 96 for children and
4344 for adults
- UDCA group (n = 54)
Origins of liver diseases
paracetamol intoxication 1 hepatitis B 1 autoimmune hepatitis 0 biliary atresia 2
metabolic diseases 7 neonatal hepatitis 2 PBC 13 post hepatitis cirrhosis 8 PSC 3
cryptogenic cirrhosis 7 alcoholic cirrhosis 2 other reasons 8
- Placebo group (n = 48)
Origins of liver diseases paracetamol intoxication 1 hepatitis B 0 autoimmune hepatitis
1 biliary atresia 3 metabolic diseases 11 neonatal hepatitis 0 PBC 7 post hepatitis
cirrhosis 5 PSC 7 cryptogenic cirrhosis 2 alcoholic cirrhosis 6 other reasons 5
Interventions UDCA group
- Dose 15 mgkg body weightday in two or three divided doses
- Route orally
- Duration immediately after intestinal transit recovery usually between postoperative
days three and five and continue for three months
Placebo group
- Identical-appearing capsules administered in the same quantity and manner
Co-interventions all patients received standard triple-drug regimens (steroids azathio-
prine and cyclosporine or tacrolimus)
24Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Keiding 1997 (Continued)
Outcomes All cause mortality
Number of deaths related to rejection
Number of patients with acute cellular rejection
Number of patients with chronic rejection
Number of patients with steroid-resistant rejection
Adverse events
Notes Letter was sent to the authors in September 2009 No reply was received
Risk of bias
Item Authorsrsquo judgement Description
Adequate sequence generation Unclear Patients were randomised at a ratio of 11
Allocation concealment Yes Quote ldquo The allocation was performed in
blocks of 10 patients using the sealed serial
envelope methodrdquo
Blinding Yes Quote ldquoThe UDCA and the placebo cap-
sules had identical appearance and tasterdquo
Incomplete outcome data addressed
All outcomes
Yes Follow-up time 12 months Five UDCA
patients and five placebo patients withdrew
from study Reasons were reported
Free of selective reporting Unclear Insufficient information
Sample size calculation Yes Performed and allowed for a difference in
the incidence of at least one episode of
acute rejection of 50 between the treat-
ment and placebo groups with 90 statisti-
cal power and a significance level of P value
less than 005 The calculated sample size
was 80 patients
Intention-to-treat analysis Yes Stated and used
Baseline imbalance Yes The study seems to be free of baseline im-
balance
Early stopping of trial Yes Study attained the pre-specified sample
size
25Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Koneru 1993
Methods Study design randomised controlled trial
Participants Country United States
Publication language English
Inclusion criteria
- patients who underwent liver transplantation
Exclusion criteria
- not mentioned
Participants
- UDCA group (n = 16)
Mean age (years +- SD)
no information
Ratio of sex (malefemale) no information
Origins of liver diseases
no information
- Control group (n = 16)
Mean age (years +- SD)
no information
Ratio of sex (malefemale) no information
Origins of liver diseases
no information
Interventions UDCA group
- Dose 900 mgday
- Route orally
- Duration immediately after intestinal transit recovery usually between postoperative
days three and five and continue for three months
Control group
- no treatment
Co-interventions all patients received standard triple-drug regimens (steroids azathio-
prine and cyclosporine)
Outcomes Number of patients with retransplantation due to rejection
Number of patients with rejection episodes
Notes Abstract
Letter was sent to the authors in September 2009 No reply was received
Risk of bias
Item Authorsrsquo judgement Description
Adequate sequence generation Unclear No information provided
Allocation concealment Unclear No information provided
Blinding No Not performed
26Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Koneru 1993 (Continued)
Incomplete outcome data addressed
All outcomes
Unclear The study gives the impression that there
were no withdrawals but this was not ex-
plicitly stated
Free of selective reporting Unclear Insufficient information provided
Sample size calculation No Not performed
Intention-to-treat analysis Unclear No information provided
Baseline imbalance Unclear Not enough information provided
Early stopping of trial Unclear Not enough information provided
Pageaux 1995
Methods Study design double-blind randomised study
Participants Country France
Publication language English
Inclusion criteria
- patients who underwent liver transplantation
Exclusion criteria
- not mentioned
Participants
- UDCA group (n=26)
Mean age (years +- SD)
47 +- 10
Ratio of sex (malefemale) 179
Origins of liver diseases alcoholic cirrhosis 14
post-hepatic B cirrhosis 2
post-hepatitis C cirrhosis 4
PBC 2
liver cancer 2
fulminant hepatitis 1
miscellaneous 1
- Placebo group (n = 24)
Mean age (years +- SD)
51+- 9
Ratio of sex (malefemale) 159
Origins of liver diseases alcoholic cirrhosis 10
post-hepatic B cirrhosis 0
post-hepatic C cirrhosis 6
PBC 3
liver cancer 4
fulminant hepatitis 0
miscellaneous 1
27Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Pageaux 1995 (Continued)
Interventions UDCA group
- Dose 600 mgday in three divided doses
- Route orally
- Duration immediately after intestinal transit recovery usually between postoperative
days three and five and continue for two months
Placebo group
- identical-appearing capsules administered in the same quantity and manner
Co-interventions all patients received standard triple-drug regimens (steroids azathio-
prine and cyclosporine or tacrolimus)
Outcomes Number of patients with acute cellular rejection
Number of patients with steroid-resistant rejection
Notes Letter was sent to the authors in September 2009 No reply was received
Risk of bias
Item Authorsrsquo judgement Description
Adequate sequence generation Unclear No information provided
Allocation concealment Unclear No information provided
Blinding Unclear Method of blinding not described
Incomplete outcome data addressed
All outcomes
Yes Five patients died from non-immunologi-
cal causes before the end of the first month
and were excluded from the study Reasons
were reported
Free of selective reporting Unclear Not enough information provided
Sample size calculation No Not performed
Intention-to-treat analysis No Not stated and not used
Baseline imbalance Unclear Not enough information provided
Early stopping of trial Unclear Not enough information provided
Sama 1991
Methods Study design randomised controlled trial
Participants Country Italy
Publication language English
Inclusion criteria
28Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Sama 1991 (Continued)
- patients who underwent liver transplantation
Exclusion criteria
- not mentioned
Participants
- UDCA group (n = 20)
Mean age (years +- SD)
no information
Ratio of sex (malefemale) no information
Origins of liver diseases
no information
- Control group (n = 20)
Mean age (years +- SD)
no information
Ratio of sex (malefemale) no information
Origins of liver diseases
no information
Interventions UDCA group
- Dose 600 mgday in two divided doses
- Route orally
- Duration immediately after intestinal transit recovery usually between postoperative
day five and day seven and continue for six months
Control group
- no treatment
Co-interventions all patients received standard immunosuppressive treatment (steroids
and cyclosporine)
Outcomes All cause mortality
Number of patients with acute cellular rejection
Notes Abstract
Letter was sent to the authors in September 2009 No reply was received
Risk of bias
Item Authorsrsquo judgement Description
Adequate sequence generation Unclear A randomisation list was performed before
patients were admitted to the trial (infor-
mation from principal author)
Allocation concealment Unclear No information provided
Blinding Unclear The principle author provided information
that the study was made according to a
single-blind randomised protocol The pri-
mary outcome was the occurrence of biopsy
proven rejection episodes The pathologists
were blind but the patients were not
29Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Sama 1991 (Continued)
Incomplete outcome data addressed
All outcomes
Unclear Five patients from the UDCA group and
six patients from the placebo group were
excluded Reasons for exclusion were not
fully stated
Free of selective reporting No Data about survival of patients were not
adequately reported
Sample size calculation No Not performed
Intention-to-treat analysis No Not stated and not used
Baseline imbalance Unclear Basic characteristics of patients not re-
ported
Early stopping of trial Unclear Not enough information provided
UDCA = ursodeoxycholic acid
TUDCA = tauroursodeoxycholic acid
PBC = primary biliary cirrhosis
PSC = primary sclerosing cholangitis
OKT3 = anti-CD3 monoclonal antibody
Characteristics of excluded studies [ordered by study ID]
Assy 2007 A randomised controlled trial that included only recipients of liver transplantation with stable graft function and
no episodes of rejection for at least 2 years that were then offered total immunosuppression withdrawal Fourteen
patients received UDCA (15 mgkg body weightday) and 12 received placebo Rejection occurred in 43 and
75 of patients respectively (no significant difference) None developed chronic rejection After follow-up two
patients were free of immunosuppression 80 were steroid free and 50 were able to reduce their dose of
cyclosporine
Clavien 1996 Case series Fifty consecutive liver-transplanted patients were treated with a standard cyclosporine immunosup-
pressive regimen Twenty three of the 43 survivors developed an episode of rejection and UDCA (10 mgkg
weightday) was initiated Only one patient had a second episode of rejection
Friman 1992 Observational study Thirty-three liver-transplanted patients received 10 mg UDCAkg body weightday for
median of 10 months (range four to 21 months) Eight historical liver-transplanted patients served as control
group The rejection incidence was significantly lower in the patients who received the treatment with UDCA
Biochemistry one month after transplantation demonstrated significantly lower average values of aminotrans-
ferases and alkaline phosphatases in patients treated with UDCA than in the control group
30Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
Heathcote 1999 Observational study From 1987 to 1996 37 UDCA treated and 53 placebo treated patients with primary biliary
cirrhosis were referred for transplantation Posttransplantation survival rates at one month were 939 in the
UDCA group and 884 in the placebo group and one year survival rates were 903 and 784 respectively
(no significant differences) However rejection (type not defined - a secondary outcome measure) occurred
significantly less often in the UDCA group (429) than in placebo group (688)
Henriksson 1991 Observational study All patients in this study were given sequential quadruple immunosuppression with anti-
lymphocyte globulin azathioprine steroids and cyclosporine All patients with primary graft function (n = 11)
were treated with 10 mg UDCAkg body weightday starting during the first postoperative week Patients who
received liver transplantation in the first 6 months of 1989 (n = 8) served as controls In the control group one
patient died after 9 months with chronic graft dysfunction and six patients had rejection episodes during the
first postoperative month All patients in the UDCA group were alive without rejection episodes
Persson 1990 Observational study All 11 adult patients transplanted between August 1989 and January 1990 with primary
graft function were treated with 10 mg UDCA kg body weightday Eight patients transplanted during the first
half of 1989 served as control UDCA was started during the first postoperative week and the treatment was
continued for six months All patients in the UDCA treated group survived with satisfactory graft function In
the control group six patients had at least one rejection episode needing treatment during the first postoperative
month
Rafael 1995 Observational study Seventeen patients who underwent liver transplantation between February 1990 and April
1993 and developed biliary complications after transplantation were retrospectively analysed regarding treatment
with UDCA UDCA was given in a dose of 500 to 1000 mgday Ten patients were treated for at least one year while
seven patients were treated for 14 to 250 days UDCA significantly improved gammaglutamyl transpeptidase in
liver graft recipients with biliary complications There was also a trend towards improvement in serum bilirubin
and alanine transaminase values
Sama 1998 Observational study Thirty-four patients who underwent liver transplantation between January 1995 and June
1996 were included in the study Seventeen were treated with UDCA 10 mgkg body weightday during 6
months while 17 served as controls on the basis of having undergone liver transplantation closest to UDCA
patients A significant decrease in serum bilirubin levels was observed in UDCA patients There was a significantly
higher incidence of recurrent hepatitis in the control group
UDCA ursodeoxycholic acid
31Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
D A T A A N D A N A L Y S E S
Comparison 1 Bile acids for liver-transplanted patients
Outcome or subgroup titleNo of
studies
No of
participants Statistical method Effect size
1 All-cause mortality at maximum
follow-up
5 257 Risk Ratio (M-H Fixed 95 CI) 085 [053 136]
11 UDCA versus placebo or
no treatment
4 224 Risk Ratio (M-H Fixed 95 CI) 080 [049 130]
12 TUDCA versus no
treatment
1 33 Risk Ratio (M-H Fixed 95 CI) 159 [030 833]
2 All-cause mortality worst-best
case and best-worst case
scenarios
5 Risk Ratio (M-H Fixed 95 CI) Subtotals only
21 Worst-best case scenario 5 257 Risk Ratio (M-H Fixed 95 CI) 130 [086 196]
22 Best-worst case scenario 5 257 Risk Ratio (M-H Fixed 95 CI) 058 [038 090]
3 Subgroup analyses all-cause
mortality at maximum
follow-up according to time of
start of bile acids
5 257 Risk Ratio (M-H Fixed 95 CI) 085 [053 136]
31 Less than three days after
transplantation
1 102 Risk Ratio (M-H Fixed 95 CI) 124 [061 254]
32 Three days or more after
transplantation
4 155 Risk Ratio (M-H Fixed 95 CI) 063 [033 120]
4 Subgroup analyses all cause
mortality at maximum
follow-up according to
treatment duration
5 257 Risk Ratio (M-H Fixed 95 CI) 085 [053 136]
41 Less than six months 3 184 Risk Ratio (M-H Fixed 95 CI) 078 [045 138]
42 Six months or more 2 73 Risk Ratio (M-H Fixed 95 CI) 102 [043 240]
5 Number of deaths related
to rejection at maximum
follow-up
1 102 Risk Ratio (M-H Fixed 95 CI) 030 [001 712]
51 UDCA versus placebo 1 102 Risk Ratio (M-H Fixed 95 CI) 030 [001 712]
6 Number of retransplantations at
maximum follow-up
2 132 Risk Ratio (M-H Fixed 95 CI) 076 [020 286]
7 Number of patients with acute
cellular rejection at maximum
follow-up
7 339 Risk Ratio (M-H Fixed 95 CI) 089 [074 106]
71 UDCA versus placebo or
no treatment
6 306 Risk Ratio (M-H Fixed 95 CI) 089 [074 108]
72 TUDCA versus no
treatment
1 33 Risk Ratio (M-H Fixed 95 CI) 085 [045 160]
8 Subgroup analysis number of
patients with acute cellular
rejection according to time of
start of bile acid
7 339 Risk Ratio (M-H Fixed 95 CI) 089 [074 106]
32Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
81 Less than three days after
transplantation
2 134 Risk Ratio (M-H Fixed 95 CI) 084 [063 111]
82 Three days or more after
liver transplantation
5 205 Risk Ratio (M-H Fixed 95 CI) 092 [072 117]
9 Subgroup analysis number
of patients with acute
cellular rejection according to
treatment duration
7 339 Risk Ratio (M-H Fixed 95 CI) 089 [074 106]
91 Less than six months 5 266 Risk Ratio (M-H Fixed 95 CI) 087 [071 107]
92 Six months or more 2 73 Risk Ratio (M-H Fixed 95 CI) 094 [065 136]
10 Number of patients with
chronic rejection at maximum
follow-up
3 184 Risk Ratio (M-H Fixed 95 CI) 028 [008 095]
11 Number of patients with
steroid-resistant rejection at
maximum follow-up
4 234 Risk Ratio (M-H Fixed 95 CI) 077 [047 127]
12 Serum bilirubin (mgdl) at the
end of treatment
1 30 Mean Difference (IV Fixed 95 CI) 26 [-096 616]
13 Number of days of
hospitalisation after liver
transplantation
1 52 Mean Difference (IV Fixed 95 CI) -85 [-1667 -033]
14 Adverse events 3 187 Risk Ratio (M-H Fixed 95 CI) 088 [030 260]
Analysis 11 Comparison 1 Bile acids for liver-transplanted patients Outcome 1 All-cause mortality at
maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 1 All-cause mortality at maximum follow-up
Study or subgroup Favours bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 UDCA versus placebo or no treatment
Barnes 1997 228 724 253 024 [ 006 107 ]
Fleckenstein 1998 214 416 125 057 [ 012 266 ]
Keiding 1997 1454 1048 355 124 [ 061 254 ]
Sama 1991 520 620 201 083 [ 030 229 ]
Subtotal (95 CI) 116 108 935 080 [ 049 130 ]
Total events 23 (Favours bile acids) 27 (Control)
Heterogeneity Chi2 = 416 df = 3 (P = 025) I2 =28
Test for overall effect Z = 091 (P = 036)
01 02 05 1 2 5 10
Favours bile acids Favours control
(Continued )
33Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Favours bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
2 TUDCA versus no treatment
Angelico 1999 316 217 65 159 [ 030 833 ]
Subtotal (95 CI) 16 17 65 159 [ 030 833 ]
Total events 3 (Favours bile acids) 2 (Control)
Heterogeneity not applicable
Test for overall effect Z = 055 (P = 058)
Total (95 CI) 132 125 1000 085 [ 053 136 ]
Total events 26 (Favours bile acids) 29 (Control)
Heterogeneity Chi2 = 466 df = 4 (P = 032) I2 =14
Test for overall effect Z = 069 (P = 049)
01 02 05 1 2 5 10
Favours bile acids Favours control
Analysis 12 Comparison 1 Bile acids for liver-transplanted patients Outcome 2 All-cause mortality worst-
best case and best-worst case scenarios
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 2 All-cause mortality worst-best case and best-worst case scenarios
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 Worst-best case scenario
Angelico 1999 516 217 65 266 [ 060 1180 ]
Barnes 1997 828 724 253 098 [ 042 230 ]
Fleckenstein 1998 314 416 125 086 [ 023 319 ]
Keiding 1997 1954 1048 355 169 [ 087 327 ]
Sama 1991 520 620 201 083 [ 030 229 ]
Subtotal (95 CI) 132 125 1000 130 [ 086 196 ]
Total events 40 (Bile acids) 29 (Control)
Heterogeneity Chi2 = 303 df = 4 (P = 055) I2 =00
Test for overall effect Z = 123 (P = 022)
2 Best-worst case scenario
005 02 1 5 20
Favours bile acids Favours control
(Continued )
34Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Angelico 1999 316 417 90 080 [ 021 302 ]
Barnes 1997 228 1124 274 016 [ 004 063 ]
Fleckenstein 1998 214 616 130 038 [ 009 159 ]
Keiding 1997 1454 1548 368 083 [ 045 154 ]
Sama 1991 520 620 139 083 [ 030 229 ]
Subtotal (95 CI) 132 125 1000 058 [ 038 090 ]
Total events 26 (Bile acids) 42 (Control)
Heterogeneity Chi2 = 567 df = 4 (P = 023) I2 =29
Test for overall effect Z = 247 (P = 0014)
005 02 1 5 20
Favours bile acids Favours control
Analysis 13 Comparison 1 Bile acids for liver-transplanted patients Outcome 3 Subgroup analyses all-
cause mortality at maximum follow-up according to time of start of bile acids
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 3 Subgroup analyses all-cause mortality at maximum follow-up according to time of start of bile acids
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 Less than three days after transplantation
Keiding 1997 1454 1048 355 124 [ 061 254 ]
Subtotal (95 CI) 54 48 355 124 [ 061 254 ]
Total events 14 (Bile acids) 10 (Control)
Heterogeneity not applicable
Test for overall effect Z = 060 (P = 055)
2 Three days or more after transplantation
Angelico 1999 316 217 65 159 [ 030 833 ]
Barnes 1997 228 724 253 024 [ 006 107 ]
Fleckenstein 1998 214 416 125 057 [ 012 266 ]
Sama 1991 520 620 201 083 [ 030 229 ]
005 02 1 5 20
Favours bile acids Favours control
(Continued )
35Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Subtotal (95 CI) 78 77 645 063 [ 033 120 ]
Total events 12 (Bile acids) 19 (Control)
Heterogeneity Chi2 = 310 df = 3 (P = 038) I2 =3
Test for overall effect Z = 141 (P = 016)
Total (95 CI) 132 125 1000 085 [ 053 136 ]
Total events 26 (Bile acids) 29 (Control)
Heterogeneity Chi2 = 466 df = 4 (P = 032) I2 =14
Test for overall effect Z = 069 (P = 049)
005 02 1 5 20
Favours bile acids Favours control
Analysis 14 Comparison 1 Bile acids for liver-transplanted patients Outcome 4 Subgroup analyses all
cause mortality at maximum follow-up according to treatment duration
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 4 Subgroup analyses all cause mortality at maximum follow-up according to treatment duration
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 Less than six months
Barnes 1997 228 724 253 024 [ 006 107 ]
Fleckenstein 1998 214 416 125 057 [ 012 266 ]
Keiding 1997 1454 1048 355 124 [ 061 254 ]
Subtotal (95 CI) 96 88 734 078 [ 045 138 ]
Total events 18 (Bile acids) 21 (Control)
Heterogeneity Chi2 = 417 df = 2 (P = 012) I2 =52
Test for overall effect Z = 084 (P = 040)
2 Six months or more
Angelico 1999 316 217 65 159 [ 030 833 ]
Sama 1991 520 620 201 083 [ 030 229 ]
Subtotal (95 CI) 36 37 266 102 [ 043 240 ]
Total events 8 (Bile acids) 8 (Control)
Heterogeneity Chi2 = 043 df = 1 (P = 051) I2 =00
005 02 1 5 20
Favours bile acids Favours control
(Continued )
36Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Test for overall effect Z = 004 (P = 097)
Total (95 CI) 132 125 1000 085 [ 053 136 ]
Total events 26 (Bile acids) 29 (Control)
Heterogeneity Chi2 = 466 df = 4 (P = 032) I2 =14
Test for overall effect Z = 069 (P = 049)
005 02 1 5 20
Favours bile acids Favours control
Analysis 15 Comparison 1 Bile acids for liver-transplanted patients Outcome 5 Number of deaths related
to rejection at maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 5 Number of deaths related to rejection at maximum follow-up
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 UDCA versus placebo
Keiding 1997 054 148 1000 030 [ 001 712 ]
Total (95 CI) 54 48 1000 030 [ 001 712 ]
Total events 0 (Bile acids) 1 (Control)
Heterogeneity not applicable
Test for overall effect Z = 075 (P = 045)
0001 001 01 1 10 100 1000
Favours bile acids Favours control
37Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 16 Comparison 1 Bile acids for liver-transplanted patients Outcome 6 Number of
retransplantations at maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 6 Number of retransplantations at maximum follow-up
Study or subgroup Bile acids Placebo Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Fleckenstein 1998 214 016 100 567 [ 029 10891 ]
Keiding 1997 154 448 900 022 [ 003 192 ]
Total (95 CI) 68 64 1000 076 [ 020 286 ]
Total events 3 (Bile acids) 4 (Placebo)
Heterogeneity Chi2 = 303 df = 1 (P = 008) I2 =67
Test for overall effect Z = 040 (P = 069)
0001 001 01 1 10 100 1000
Favours bile acids Favours placebo
Analysis 17 Comparison 1 Bile acids for liver-transplanted patients Outcome 7 Number of patients with
acute cellular rejection at maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 7 Number of patients with acute cellular rejection at maximum follow-up
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 UDCA versus placebo or no treatment
Barnes 1997 1728 1724 180 086 [ 058 127 ]
Fleckenstein 1998 814 916 83 102 [ 054 190 ]
Keiding 1997 3554 3248 333 097 [ 073 129 ]
Koneru 1993 316 916 89 033 [ 011 101 ]
Pageaux 1995 926 924 92 092 [ 044 193 ]
Sama 1991 1320 1320 128 100 [ 063 158 ]
Subtotal (95 CI) 158 148 905 089 [ 074 108 ]
01 02 05 1 2 5 10
Favours bile acids Favours control
(Continued )
38Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Total events 85 (Bile acids) 89 (Control)
Heterogeneity Chi2 = 387 df = 5 (P = 057) I2 =00
Test for overall effect Z = 120 (P = 023)
2 TUDCA versus no treatment
Angelico 1999 816 1017 95 085 [ 045 160 ]
Subtotal (95 CI) 16 17 95 085 [ 045 160 ]
Total events 8 (Bile acids) 10 (Control)
Heterogeneity not applicable
Test for overall effect Z = 050 (P = 061)
Total (95 CI) 174 165 1000 089 [ 074 106 ]
Total events 93 (Bile acids) 99 (Control)
Heterogeneity Chi2 = 392 df = 6 (P = 069) I2 =00
Test for overall effect Z = 130 (P = 019)
01 02 05 1 2 5 10
Favours bile acids Favours control
Analysis 18 Comparison 1 Bile acids for liver-transplanted patients Outcome 8 Subgroup analysis
number of patients with acute cellular rejection according to time of start of bile acid
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 8 Subgroup analysis number of patients with acute cellular rejection according to time of start of bile acid
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 Less than three days after transplantation
Keiding 1997 3554 3248 333 097 [ 073 129 ]
Koneru 1993 316 916 89 033 [ 011 101 ]
Subtotal (95 CI) 70 64 422 084 [ 063 111 ]
Total events 38 (Bile acids) 41 (Control)
Heterogeneity Chi2 = 374 df = 1 (P = 005) I2 =73
Test for overall effect Z = 124 (P = 022)
2 Three days or more after liver transplantation
Angelico 1999 816 1017 95 085 [ 045 160 ]
01 02 05 1 2 5 10
Favours bile acids Favours control
(Continued )
39Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Barnes 1997 1728 1724 180 086 [ 058 127 ]
Fleckenstein 1998 814 916 83 102 [ 054 190 ]
Pageaux 1995 926 924 92 092 [ 044 193 ]
Sama 1991 1320 1320 128 100 [ 063 158 ]
Subtotal (95 CI) 104 101 578 092 [ 072 117 ]
Total events 55 (Bile acids) 58 (Control)
Heterogeneity Chi2 = 041 df = 4 (P = 098) I2 =00
Test for overall effect Z = 067 (P = 050)
Total (95 CI) 174 165 1000 089 [ 074 106 ]
Total events 93 (Bile acids) 99 (Control)
Heterogeneity Chi2 = 392 df = 6 (P = 069) I2 =00
Test for overall effect Z = 130 (P = 019)
01 02 05 1 2 5 10
Favours bile acids Favours control
40Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 19 Comparison 1 Bile acids for liver-transplanted patients Outcome 9 Subgroup analysis
number of patients with acute cellular rejection according to treatment duration
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 9 Subgroup analysis number of patients with acute cellular rejection according to treatment duration
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 Less than six months
Barnes 1997 1728 1724 180 086 [ 058 127 ]
Fleckenstein 1998 814 916 83 102 [ 054 190 ]
Keiding 1997 3554 3248 333 097 [ 073 129 ]
Koneru 1993 316 916 89 033 [ 011 101 ]
Pageaux 1995 926 924 92 092 [ 044 193 ]
Subtotal (95 CI) 138 128 777 087 [ 071 107 ]
Total events 72 (Bile acids) 76 (Control)
Heterogeneity Chi2 = 374 df = 4 (P = 044) I2 =00
Test for overall effect Z = 129 (P = 020)
2 Six months or more
Angelico 1999 816 1017 95 085 [ 045 160 ]
Sama 1991 1320 1320 128 100 [ 063 158 ]
Subtotal (95 CI) 36 37 223 094 [ 065 136 ]
Total events 21 (Bile acids) 23 (Control)
Heterogeneity Chi2 = 017 df = 1 (P = 068) I2 =00
Test for overall effect Z = 035 (P = 073)
Total (95 CI) 174 165 1000 089 [ 074 106 ]
Total events 93 (Bile acids) 99 (Control)
Heterogeneity Chi2 = 392 df = 6 (P = 069) I2 =00
Test for overall effect Z = 130 (P = 019)
01 02 05 1 2 5 10
Favours bile acids Favours control
41Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 110 Comparison 1 Bile acids for liver-transplanted patients Outcome 10 Number of patients
with chronic rejection at maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 10 Number of patients with chronic rejection at maximum follow-up
Study or subgroup Bile acids Placebo Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Barnes 1997 128 624 611 014 [ 002 110 ]
Fleckenstein 1998 114 116 88 114 [ 008 1663 ]
Keiding 1997 154 348 300 030 [ 003 275 ]
Total (95 CI) 96 88 1000 028 [ 008 095 ]
Total events 3 (Bile acids) 10 (Placebo)
Heterogeneity Chi2 = 148 df = 2 (P = 048) I2 =00
Test for overall effect Z = 204 (P = 0041)
0001 001 01 1 10 100 1000
Favours bile acids Favours placebo
Analysis 111 Comparison 1 Bile acids for liver-transplanted patients Outcome 11 Number of patients
with steroid-resistant rejection at maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 11 Number of patients with steroid-resistant rejection at maximum follow-up
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Barnes 1997 328 724 277 037 [ 011 127 ]
Fleckenstein 1998 314 316 103 114 [ 027 478 ]
Keiding 1997 1454 1548 583 083 [ 045 154 ]
Pageaux 1995 226 124 38 185 [ 018 1908 ]
Total (95 CI) 122 112 1000 077 [ 047 127 ]
Total events 22 (Bile acids) 26 (Control)
Heterogeneity Chi2 = 226 df = 3 (P = 052) I2 =00
Test for overall effect Z = 102 (P = 031)
001 01 1 10 100
Favours bile acids Favours placebo
42Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 112 Comparison 1 Bile acids for liver-transplanted patients Outcome 12 Serum bilirubin (mgdl)
at the end of treatment
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 12 Serum bilirubin (mgdl) at the end of treatment
Study or subgroup Bile acids Placebo Mean Difference Weight Mean Difference
N Mean(SD) N Mean(SD) IVFixed95 CI IVFixed95 CI
Fleckenstein 1998 14 319 (68) 16 059 (022) 1000 260 [ -096 616 ]
Total (95 CI) 14 16 1000 260 [ -096 616 ]
Heterogeneity not applicable
Test for overall effect Z = 143 (P = 015)
-10 -5 0 5 10
Favours bile acids Favours placebo
Analysis 113 Comparison 1 Bile acids for liver-transplanted patients Outcome 13 Number of days of
hospitalisation after liver transplantation
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 13 Number of days of hospitalisation after liver transplantation
Study or subgroup Bile acids Placebo Mean Difference Weight Mean Difference
N Mean(SD) N Mean(SD) IVFixed95 CI IVFixed95 CI
Barnes 1997 28 25 (17) 24 335 (13) 1000 -850 [ -1667 -033 ]
Total (95 CI) 28 24 1000 -850 [ -1667 -033 ]
Heterogeneity not applicable
Test for overall effect Z = 204 (P = 0041)
-100 -50 0 50 100
Favours bile acids Favours placebo
43Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 114 Comparison 1 Bile acids for liver-transplanted patients Outcome 14 Adverse events
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 14 Adverse events
Study or subgroup Bile acids Placebo Risk Ratio Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Angelico 1999 016 017 00 [ 00 00 ]
Barnes 1997 128 124 086 [ 006 1298 ]
Keiding 1997 554 548 089 [ 027 288 ]
Total (95 CI) 98 89 088 [ 030 260 ]
Total events 6 (Bile acids) 6 (Placebo)
Heterogeneity Chi2 = 000 df = 1 (P = 098) I2 =00
Test for overall effect Z = 022 (P = 082)
001 01 1 10 100
Favours bile acids Favours placebo
A P P E N D I C E S
Appendix 1 Search strategies
Data Base Date of Search Search Strategy
The Cochrane Hepato-Biliary Group Con-
trolled Trials Register
September 2009 1 rsquoliver transplantationrsquo and rsquochenodeoxy-
cholicrsquo
2 rsquoliver transplantationrsquo and rsquocholicrsquo
3 rsquoliver transplantationrsquo and rsquodeoxycholicrsquo
4 rsquoliver transplantationrsquo and rsquoglycochen-
odeoxycholicrsquo
5 rsquoliver transplantationrsquo and rsquoglycocholicrsquo
6 rsquoliver transplantationrsquo and rsquoglycodeoxy-
cholicrsquo
7 rsquoliver transplantationrsquo and rsquoglycolitho-
cholicrsquo
8 rsquoliver transplantationrsquo and rsquohyodeoxy-
cholicrsquo
9 rsquoliver transplantationrsquo and rsquolithocholicrsquo
10 rsquoliver transplantationrsquo and rsquotaurochen-
odeoxycholicrsquo
44Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
11 rsquoliver transplantationrsquo and rsquotauro-
cholicrsquo
12 rsquoliver transplantationrsquo and rsquotaurodehy-
drocholicrsquo
13 rsquoliver transplantationrsquo and rsquotau-
rodeoxycholicrsquo
14 rsquoliver transplantationrsquo and rsquotauroglyco-
cholicrsquo
15 rsquoliver transplantationrsquo and rsquotaurolitho-
cholicrsquo
16 rsquoliver transplantationrsquo and rsquotaurosel-
cholicrsquo
17 rsquoliver transplantationrsquo and rsquotaurourso-
cholicrsquo
18 rsquoliver transplantationrsquo and rsquotaurour-
sodeoxycholicrsquo
19 rsquoliver transplantationrsquo and rsquoursocholicrsquo
20 rsquoliver transplantationrsquo and rsquoursodeoxy-
cholicrsquo
The Cochrane Central Register of Con-
trolled Trials in The Cochrane Library
Issue 3 2009 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
6 3 or 4
7 5 and 6
MEDLINE September 2009 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
45Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
6 3 or 4
7 5 and 6
8 RANDOMIZED-CONTROLLED-
TRIAL ME
9 RANDOM
10 8 or 9
11 7 and 10
EMBASE September 2009 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
6 3 or 4
7 5 and 6
8 RANDOMIZED-CONTROLLED-
TRIAL ME
9 RANDOM
10 8 or 9
11 7 and 10
46Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
Science Citation Index Expanded September 2009 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
6 3 or 4
7 5 and 6
8 RANDOMIZED-CONTROLLED-
TRIAL ME
9 RANDOM
10 8 or 9
11 7 and 10
The Chinese Biomedical Database Searched from January 1980 to April 2002 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
47Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
6 3 or 4
7 5 and 6
8 RANDOMIZED-CONTROLLED-
TRIAL ME
9 RANDOM
10 8 or 9
11 7 and 10
W H A T rsquo S N E W
Last assessed as up-to-date 8 February 2010
18 September 2009 New citation required but conclusions have not
changed
This review is an updated version of a review that was
published for the first time in Issue 3 2005 of TheCochrane Library by Chen 2003b
18 September 2009 New search has been performed No new studies fulfilled the inclusion criteria
H I S T O R Y
Protocol first published Issue 3 2003
Review first published Issue 3 2005
C O N T R I B U T I O N S O F A U T H O R S
GP and VG independently performed searches of relevant databases GP validated the search selected trials for inclusion contacted
the authors of the trials performed data extraction and data analysis and drafted the systematic review VG revised the review update
CG and DS revised the review update solved discrepancies of data extraction validated data analyses and provided consultation
D E C L A R A T I O N S O F I N T E R E S T
None known
48Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
S O U R C E S O F S U P P O R T
Internal sources
bull Copenhagen Trial Unit Denmark
External sources
bull Danish Medical Research Councilrsquos Grant on Getting Research into Practice (GRIP) Denmark
D I F F E R E N C E S B E T W E E N P R O T O C O L A N D R E V I E W
We assessed the risk of bias in the included studies for another four domains that were added to the review protocol (incomplete
outcome data selective outcome reporting baseline imbalance and early stopping of trial) In general the text of the risk of bias
domains were updated following Higgins 2008 Trials were considered at low risk of bias when judged as adequate in all domains
Quasi-randomised studies observational and case-control studies were included for the report of adverse events
We performed trial sequential analysis for outcomes demonstrating a statistically significant result
I N D E X T E R M S
Medical Subject Headings (MeSH)
lowastLiver Transplantation Cholagogues and Choleretics [lowasttherapeutic use] Graft Rejection [lowastprevention amp control] Randomized Con-
trolled Trials as Topic Taurochenodeoxycholic Acid [lowasttherapeutic use] Ursodeoxycholic Acid [lowasttherapeutic use]
MeSH check words
Humans
49Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Barnes 1997 (Continued)
Adequate sequence generation Yes Computer generated table
Allocation concealment Unclear No information provided
Blinding Yes Quote ldquorandomised to receive either
UDCA or an identical placebo capsulerdquo
Incomplete outcome data addressed
All outcomes
Yes Mean follow-up time 18 months Ten pa-
tients withdrawn from study 6 in UDCA
group and 4 in placebo group Reasons
for withdrawal were reported Four patients
died in the placebo group
Free of selective reporting Yes All expected outcomes reported
Sample size calculation Unclear The trial reported the method of sample
size calculation but the actual number of
patients needed was not reported
Intention-to-treat analysis Yes Stated and used
Baseline imbalance Unclear Not enough information provided
Early stopping of trial Unclear The number of patients needed to gain the
actual power was not reported Whether
the trial was terminated early is not clear
Fleckenstein 1998
Methods Study design prospective randomised double-blind trial
Participants Country United States
Publication language English
Inclusion criteria
- patients who underwent liver transplantation at the Johns Hopkins Hospital
Exclusion criteria
- patients who were under 18 years old undergoing repeat transplantation had primary
graft nonfunction or refused consent
Participants
- UDCA group (n = 14)
Mean age (years +- SD)
443 +- 127
Ratio of sex (malefemale) 68
Origins of liver diseases hepatitis C 6
alcohol 2
autoimmune 1
PBC 2
22Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Fleckenstein 1998 (Continued)
PSC 1
autoimmune cholangiopathy 1
hepatitis B 1
- Placebo group (n = 16)
Mean age (years +- SD)
496 +- 109
Ratio of sex (malefemale) 124
Origins of liver diseases hepatitis C 3
alcohol 3
autoimmune 3
PBC 1
PSC 2
cryptogenic 2
hepatitis B 1
alpha1-antitrypsin deficiency 1
Interventions UDCA group
- Dose 15 mgkg body weightday in divided doses
- Route orally
- Duration immediately after intestinal transit recovery usually between postoperative
days three and five and continue for three months
Placebo group
- Identical-appearing capsules administered in the same quantity and manner
Co-interventions all patients received standard triple-drug regimens (steroids azathio-
prine and cyclosporine or tacrolimus)
Outcomes All cause mortality
Number with retransplantation
Number of patients with acute cellular rejection
Number of patients with chronic rejection
Serum bilirubin levels at the end of treatment
Notes Follow-up time nine months
Letter was sent to the authors in September 2009 No reply was received
Risk of bias
Item Authorsrsquo judgement Description
Adequate sequence generation Unclear No information provided
Allocation concealment Unclear No information provided
Blinding Yes Method of blinding not described but
probably adequate
Incomplete outcome data addressed
All outcomes
Yes Withdrawal one patient from the UDCA
group and two patients from the placebo
group because of capsule size
23Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Fleckenstein 1998 (Continued)
Free of selective reporting Unclear Outcomes were not completely described
Sample size calculation No Not reported
Intention-to-treat analysis Yes Quote ldquoThree patients withdrew after in-
clusionThey were included in the statis-
tical analysisrdquo
Baseline imbalance Unclear Not enough information provided
Early stopping of trial Unclear Not enough information provided
Keiding 1997
Methods Study design prospective randomised placebo-controlled multicenter study
Participants Country Denmark Finland Norway and Sweden
Publication language English
Inclusion criteria
- patients who underwent liver transplantation in Denmark Finland Norway and Swe-
den from September 1 1992 to May 31 1994
Exclusion criteria
- patients with malignant diseases
Participants
The age of the children ranged from 0 to 13 years (median 15) and the age of adults
ranged from 14 to 59 years old (median 44) MaleFemale ratio was 96 for children and
4344 for adults
- UDCA group (n = 54)
Origins of liver diseases
paracetamol intoxication 1 hepatitis B 1 autoimmune hepatitis 0 biliary atresia 2
metabolic diseases 7 neonatal hepatitis 2 PBC 13 post hepatitis cirrhosis 8 PSC 3
cryptogenic cirrhosis 7 alcoholic cirrhosis 2 other reasons 8
- Placebo group (n = 48)
Origins of liver diseases paracetamol intoxication 1 hepatitis B 0 autoimmune hepatitis
1 biliary atresia 3 metabolic diseases 11 neonatal hepatitis 0 PBC 7 post hepatitis
cirrhosis 5 PSC 7 cryptogenic cirrhosis 2 alcoholic cirrhosis 6 other reasons 5
Interventions UDCA group
- Dose 15 mgkg body weightday in two or three divided doses
- Route orally
- Duration immediately after intestinal transit recovery usually between postoperative
days three and five and continue for three months
Placebo group
- Identical-appearing capsules administered in the same quantity and manner
Co-interventions all patients received standard triple-drug regimens (steroids azathio-
prine and cyclosporine or tacrolimus)
24Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Keiding 1997 (Continued)
Outcomes All cause mortality
Number of deaths related to rejection
Number of patients with acute cellular rejection
Number of patients with chronic rejection
Number of patients with steroid-resistant rejection
Adverse events
Notes Letter was sent to the authors in September 2009 No reply was received
Risk of bias
Item Authorsrsquo judgement Description
Adequate sequence generation Unclear Patients were randomised at a ratio of 11
Allocation concealment Yes Quote ldquo The allocation was performed in
blocks of 10 patients using the sealed serial
envelope methodrdquo
Blinding Yes Quote ldquoThe UDCA and the placebo cap-
sules had identical appearance and tasterdquo
Incomplete outcome data addressed
All outcomes
Yes Follow-up time 12 months Five UDCA
patients and five placebo patients withdrew
from study Reasons were reported
Free of selective reporting Unclear Insufficient information
Sample size calculation Yes Performed and allowed for a difference in
the incidence of at least one episode of
acute rejection of 50 between the treat-
ment and placebo groups with 90 statisti-
cal power and a significance level of P value
less than 005 The calculated sample size
was 80 patients
Intention-to-treat analysis Yes Stated and used
Baseline imbalance Yes The study seems to be free of baseline im-
balance
Early stopping of trial Yes Study attained the pre-specified sample
size
25Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Koneru 1993
Methods Study design randomised controlled trial
Participants Country United States
Publication language English
Inclusion criteria
- patients who underwent liver transplantation
Exclusion criteria
- not mentioned
Participants
- UDCA group (n = 16)
Mean age (years +- SD)
no information
Ratio of sex (malefemale) no information
Origins of liver diseases
no information
- Control group (n = 16)
Mean age (years +- SD)
no information
Ratio of sex (malefemale) no information
Origins of liver diseases
no information
Interventions UDCA group
- Dose 900 mgday
- Route orally
- Duration immediately after intestinal transit recovery usually between postoperative
days three and five and continue for three months
Control group
- no treatment
Co-interventions all patients received standard triple-drug regimens (steroids azathio-
prine and cyclosporine)
Outcomes Number of patients with retransplantation due to rejection
Number of patients with rejection episodes
Notes Abstract
Letter was sent to the authors in September 2009 No reply was received
Risk of bias
Item Authorsrsquo judgement Description
Adequate sequence generation Unclear No information provided
Allocation concealment Unclear No information provided
Blinding No Not performed
26Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Koneru 1993 (Continued)
Incomplete outcome data addressed
All outcomes
Unclear The study gives the impression that there
were no withdrawals but this was not ex-
plicitly stated
Free of selective reporting Unclear Insufficient information provided
Sample size calculation No Not performed
Intention-to-treat analysis Unclear No information provided
Baseline imbalance Unclear Not enough information provided
Early stopping of trial Unclear Not enough information provided
Pageaux 1995
Methods Study design double-blind randomised study
Participants Country France
Publication language English
Inclusion criteria
- patients who underwent liver transplantation
Exclusion criteria
- not mentioned
Participants
- UDCA group (n=26)
Mean age (years +- SD)
47 +- 10
Ratio of sex (malefemale) 179
Origins of liver diseases alcoholic cirrhosis 14
post-hepatic B cirrhosis 2
post-hepatitis C cirrhosis 4
PBC 2
liver cancer 2
fulminant hepatitis 1
miscellaneous 1
- Placebo group (n = 24)
Mean age (years +- SD)
51+- 9
Ratio of sex (malefemale) 159
Origins of liver diseases alcoholic cirrhosis 10
post-hepatic B cirrhosis 0
post-hepatic C cirrhosis 6
PBC 3
liver cancer 4
fulminant hepatitis 0
miscellaneous 1
27Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Pageaux 1995 (Continued)
Interventions UDCA group
- Dose 600 mgday in three divided doses
- Route orally
- Duration immediately after intestinal transit recovery usually between postoperative
days three and five and continue for two months
Placebo group
- identical-appearing capsules administered in the same quantity and manner
Co-interventions all patients received standard triple-drug regimens (steroids azathio-
prine and cyclosporine or tacrolimus)
Outcomes Number of patients with acute cellular rejection
Number of patients with steroid-resistant rejection
Notes Letter was sent to the authors in September 2009 No reply was received
Risk of bias
Item Authorsrsquo judgement Description
Adequate sequence generation Unclear No information provided
Allocation concealment Unclear No information provided
Blinding Unclear Method of blinding not described
Incomplete outcome data addressed
All outcomes
Yes Five patients died from non-immunologi-
cal causes before the end of the first month
and were excluded from the study Reasons
were reported
Free of selective reporting Unclear Not enough information provided
Sample size calculation No Not performed
Intention-to-treat analysis No Not stated and not used
Baseline imbalance Unclear Not enough information provided
Early stopping of trial Unclear Not enough information provided
Sama 1991
Methods Study design randomised controlled trial
Participants Country Italy
Publication language English
Inclusion criteria
28Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Sama 1991 (Continued)
- patients who underwent liver transplantation
Exclusion criteria
- not mentioned
Participants
- UDCA group (n = 20)
Mean age (years +- SD)
no information
Ratio of sex (malefemale) no information
Origins of liver diseases
no information
- Control group (n = 20)
Mean age (years +- SD)
no information
Ratio of sex (malefemale) no information
Origins of liver diseases
no information
Interventions UDCA group
- Dose 600 mgday in two divided doses
- Route orally
- Duration immediately after intestinal transit recovery usually between postoperative
day five and day seven and continue for six months
Control group
- no treatment
Co-interventions all patients received standard immunosuppressive treatment (steroids
and cyclosporine)
Outcomes All cause mortality
Number of patients with acute cellular rejection
Notes Abstract
Letter was sent to the authors in September 2009 No reply was received
Risk of bias
Item Authorsrsquo judgement Description
Adequate sequence generation Unclear A randomisation list was performed before
patients were admitted to the trial (infor-
mation from principal author)
Allocation concealment Unclear No information provided
Blinding Unclear The principle author provided information
that the study was made according to a
single-blind randomised protocol The pri-
mary outcome was the occurrence of biopsy
proven rejection episodes The pathologists
were blind but the patients were not
29Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Sama 1991 (Continued)
Incomplete outcome data addressed
All outcomes
Unclear Five patients from the UDCA group and
six patients from the placebo group were
excluded Reasons for exclusion were not
fully stated
Free of selective reporting No Data about survival of patients were not
adequately reported
Sample size calculation No Not performed
Intention-to-treat analysis No Not stated and not used
Baseline imbalance Unclear Basic characteristics of patients not re-
ported
Early stopping of trial Unclear Not enough information provided
UDCA = ursodeoxycholic acid
TUDCA = tauroursodeoxycholic acid
PBC = primary biliary cirrhosis
PSC = primary sclerosing cholangitis
OKT3 = anti-CD3 monoclonal antibody
Characteristics of excluded studies [ordered by study ID]
Assy 2007 A randomised controlled trial that included only recipients of liver transplantation with stable graft function and
no episodes of rejection for at least 2 years that were then offered total immunosuppression withdrawal Fourteen
patients received UDCA (15 mgkg body weightday) and 12 received placebo Rejection occurred in 43 and
75 of patients respectively (no significant difference) None developed chronic rejection After follow-up two
patients were free of immunosuppression 80 were steroid free and 50 were able to reduce their dose of
cyclosporine
Clavien 1996 Case series Fifty consecutive liver-transplanted patients were treated with a standard cyclosporine immunosup-
pressive regimen Twenty three of the 43 survivors developed an episode of rejection and UDCA (10 mgkg
weightday) was initiated Only one patient had a second episode of rejection
Friman 1992 Observational study Thirty-three liver-transplanted patients received 10 mg UDCAkg body weightday for
median of 10 months (range four to 21 months) Eight historical liver-transplanted patients served as control
group The rejection incidence was significantly lower in the patients who received the treatment with UDCA
Biochemistry one month after transplantation demonstrated significantly lower average values of aminotrans-
ferases and alkaline phosphatases in patients treated with UDCA than in the control group
30Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
Heathcote 1999 Observational study From 1987 to 1996 37 UDCA treated and 53 placebo treated patients with primary biliary
cirrhosis were referred for transplantation Posttransplantation survival rates at one month were 939 in the
UDCA group and 884 in the placebo group and one year survival rates were 903 and 784 respectively
(no significant differences) However rejection (type not defined - a secondary outcome measure) occurred
significantly less often in the UDCA group (429) than in placebo group (688)
Henriksson 1991 Observational study All patients in this study were given sequential quadruple immunosuppression with anti-
lymphocyte globulin azathioprine steroids and cyclosporine All patients with primary graft function (n = 11)
were treated with 10 mg UDCAkg body weightday starting during the first postoperative week Patients who
received liver transplantation in the first 6 months of 1989 (n = 8) served as controls In the control group one
patient died after 9 months with chronic graft dysfunction and six patients had rejection episodes during the
first postoperative month All patients in the UDCA group were alive without rejection episodes
Persson 1990 Observational study All 11 adult patients transplanted between August 1989 and January 1990 with primary
graft function were treated with 10 mg UDCA kg body weightday Eight patients transplanted during the first
half of 1989 served as control UDCA was started during the first postoperative week and the treatment was
continued for six months All patients in the UDCA treated group survived with satisfactory graft function In
the control group six patients had at least one rejection episode needing treatment during the first postoperative
month
Rafael 1995 Observational study Seventeen patients who underwent liver transplantation between February 1990 and April
1993 and developed biliary complications after transplantation were retrospectively analysed regarding treatment
with UDCA UDCA was given in a dose of 500 to 1000 mgday Ten patients were treated for at least one year while
seven patients were treated for 14 to 250 days UDCA significantly improved gammaglutamyl transpeptidase in
liver graft recipients with biliary complications There was also a trend towards improvement in serum bilirubin
and alanine transaminase values
Sama 1998 Observational study Thirty-four patients who underwent liver transplantation between January 1995 and June
1996 were included in the study Seventeen were treated with UDCA 10 mgkg body weightday during 6
months while 17 served as controls on the basis of having undergone liver transplantation closest to UDCA
patients A significant decrease in serum bilirubin levels was observed in UDCA patients There was a significantly
higher incidence of recurrent hepatitis in the control group
UDCA ursodeoxycholic acid
31Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
D A T A A N D A N A L Y S E S
Comparison 1 Bile acids for liver-transplanted patients
Outcome or subgroup titleNo of
studies
No of
participants Statistical method Effect size
1 All-cause mortality at maximum
follow-up
5 257 Risk Ratio (M-H Fixed 95 CI) 085 [053 136]
11 UDCA versus placebo or
no treatment
4 224 Risk Ratio (M-H Fixed 95 CI) 080 [049 130]
12 TUDCA versus no
treatment
1 33 Risk Ratio (M-H Fixed 95 CI) 159 [030 833]
2 All-cause mortality worst-best
case and best-worst case
scenarios
5 Risk Ratio (M-H Fixed 95 CI) Subtotals only
21 Worst-best case scenario 5 257 Risk Ratio (M-H Fixed 95 CI) 130 [086 196]
22 Best-worst case scenario 5 257 Risk Ratio (M-H Fixed 95 CI) 058 [038 090]
3 Subgroup analyses all-cause
mortality at maximum
follow-up according to time of
start of bile acids
5 257 Risk Ratio (M-H Fixed 95 CI) 085 [053 136]
31 Less than three days after
transplantation
1 102 Risk Ratio (M-H Fixed 95 CI) 124 [061 254]
32 Three days or more after
transplantation
4 155 Risk Ratio (M-H Fixed 95 CI) 063 [033 120]
4 Subgroup analyses all cause
mortality at maximum
follow-up according to
treatment duration
5 257 Risk Ratio (M-H Fixed 95 CI) 085 [053 136]
41 Less than six months 3 184 Risk Ratio (M-H Fixed 95 CI) 078 [045 138]
42 Six months or more 2 73 Risk Ratio (M-H Fixed 95 CI) 102 [043 240]
5 Number of deaths related
to rejection at maximum
follow-up
1 102 Risk Ratio (M-H Fixed 95 CI) 030 [001 712]
51 UDCA versus placebo 1 102 Risk Ratio (M-H Fixed 95 CI) 030 [001 712]
6 Number of retransplantations at
maximum follow-up
2 132 Risk Ratio (M-H Fixed 95 CI) 076 [020 286]
7 Number of patients with acute
cellular rejection at maximum
follow-up
7 339 Risk Ratio (M-H Fixed 95 CI) 089 [074 106]
71 UDCA versus placebo or
no treatment
6 306 Risk Ratio (M-H Fixed 95 CI) 089 [074 108]
72 TUDCA versus no
treatment
1 33 Risk Ratio (M-H Fixed 95 CI) 085 [045 160]
8 Subgroup analysis number of
patients with acute cellular
rejection according to time of
start of bile acid
7 339 Risk Ratio (M-H Fixed 95 CI) 089 [074 106]
32Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
81 Less than three days after
transplantation
2 134 Risk Ratio (M-H Fixed 95 CI) 084 [063 111]
82 Three days or more after
liver transplantation
5 205 Risk Ratio (M-H Fixed 95 CI) 092 [072 117]
9 Subgroup analysis number
of patients with acute
cellular rejection according to
treatment duration
7 339 Risk Ratio (M-H Fixed 95 CI) 089 [074 106]
91 Less than six months 5 266 Risk Ratio (M-H Fixed 95 CI) 087 [071 107]
92 Six months or more 2 73 Risk Ratio (M-H Fixed 95 CI) 094 [065 136]
10 Number of patients with
chronic rejection at maximum
follow-up
3 184 Risk Ratio (M-H Fixed 95 CI) 028 [008 095]
11 Number of patients with
steroid-resistant rejection at
maximum follow-up
4 234 Risk Ratio (M-H Fixed 95 CI) 077 [047 127]
12 Serum bilirubin (mgdl) at the
end of treatment
1 30 Mean Difference (IV Fixed 95 CI) 26 [-096 616]
13 Number of days of
hospitalisation after liver
transplantation
1 52 Mean Difference (IV Fixed 95 CI) -85 [-1667 -033]
14 Adverse events 3 187 Risk Ratio (M-H Fixed 95 CI) 088 [030 260]
Analysis 11 Comparison 1 Bile acids for liver-transplanted patients Outcome 1 All-cause mortality at
maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 1 All-cause mortality at maximum follow-up
Study or subgroup Favours bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 UDCA versus placebo or no treatment
Barnes 1997 228 724 253 024 [ 006 107 ]
Fleckenstein 1998 214 416 125 057 [ 012 266 ]
Keiding 1997 1454 1048 355 124 [ 061 254 ]
Sama 1991 520 620 201 083 [ 030 229 ]
Subtotal (95 CI) 116 108 935 080 [ 049 130 ]
Total events 23 (Favours bile acids) 27 (Control)
Heterogeneity Chi2 = 416 df = 3 (P = 025) I2 =28
Test for overall effect Z = 091 (P = 036)
01 02 05 1 2 5 10
Favours bile acids Favours control
(Continued )
33Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Favours bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
2 TUDCA versus no treatment
Angelico 1999 316 217 65 159 [ 030 833 ]
Subtotal (95 CI) 16 17 65 159 [ 030 833 ]
Total events 3 (Favours bile acids) 2 (Control)
Heterogeneity not applicable
Test for overall effect Z = 055 (P = 058)
Total (95 CI) 132 125 1000 085 [ 053 136 ]
Total events 26 (Favours bile acids) 29 (Control)
Heterogeneity Chi2 = 466 df = 4 (P = 032) I2 =14
Test for overall effect Z = 069 (P = 049)
01 02 05 1 2 5 10
Favours bile acids Favours control
Analysis 12 Comparison 1 Bile acids for liver-transplanted patients Outcome 2 All-cause mortality worst-
best case and best-worst case scenarios
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 2 All-cause mortality worst-best case and best-worst case scenarios
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 Worst-best case scenario
Angelico 1999 516 217 65 266 [ 060 1180 ]
Barnes 1997 828 724 253 098 [ 042 230 ]
Fleckenstein 1998 314 416 125 086 [ 023 319 ]
Keiding 1997 1954 1048 355 169 [ 087 327 ]
Sama 1991 520 620 201 083 [ 030 229 ]
Subtotal (95 CI) 132 125 1000 130 [ 086 196 ]
Total events 40 (Bile acids) 29 (Control)
Heterogeneity Chi2 = 303 df = 4 (P = 055) I2 =00
Test for overall effect Z = 123 (P = 022)
2 Best-worst case scenario
005 02 1 5 20
Favours bile acids Favours control
(Continued )
34Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Angelico 1999 316 417 90 080 [ 021 302 ]
Barnes 1997 228 1124 274 016 [ 004 063 ]
Fleckenstein 1998 214 616 130 038 [ 009 159 ]
Keiding 1997 1454 1548 368 083 [ 045 154 ]
Sama 1991 520 620 139 083 [ 030 229 ]
Subtotal (95 CI) 132 125 1000 058 [ 038 090 ]
Total events 26 (Bile acids) 42 (Control)
Heterogeneity Chi2 = 567 df = 4 (P = 023) I2 =29
Test for overall effect Z = 247 (P = 0014)
005 02 1 5 20
Favours bile acids Favours control
Analysis 13 Comparison 1 Bile acids for liver-transplanted patients Outcome 3 Subgroup analyses all-
cause mortality at maximum follow-up according to time of start of bile acids
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 3 Subgroup analyses all-cause mortality at maximum follow-up according to time of start of bile acids
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 Less than three days after transplantation
Keiding 1997 1454 1048 355 124 [ 061 254 ]
Subtotal (95 CI) 54 48 355 124 [ 061 254 ]
Total events 14 (Bile acids) 10 (Control)
Heterogeneity not applicable
Test for overall effect Z = 060 (P = 055)
2 Three days or more after transplantation
Angelico 1999 316 217 65 159 [ 030 833 ]
Barnes 1997 228 724 253 024 [ 006 107 ]
Fleckenstein 1998 214 416 125 057 [ 012 266 ]
Sama 1991 520 620 201 083 [ 030 229 ]
005 02 1 5 20
Favours bile acids Favours control
(Continued )
35Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Subtotal (95 CI) 78 77 645 063 [ 033 120 ]
Total events 12 (Bile acids) 19 (Control)
Heterogeneity Chi2 = 310 df = 3 (P = 038) I2 =3
Test for overall effect Z = 141 (P = 016)
Total (95 CI) 132 125 1000 085 [ 053 136 ]
Total events 26 (Bile acids) 29 (Control)
Heterogeneity Chi2 = 466 df = 4 (P = 032) I2 =14
Test for overall effect Z = 069 (P = 049)
005 02 1 5 20
Favours bile acids Favours control
Analysis 14 Comparison 1 Bile acids for liver-transplanted patients Outcome 4 Subgroup analyses all
cause mortality at maximum follow-up according to treatment duration
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 4 Subgroup analyses all cause mortality at maximum follow-up according to treatment duration
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 Less than six months
Barnes 1997 228 724 253 024 [ 006 107 ]
Fleckenstein 1998 214 416 125 057 [ 012 266 ]
Keiding 1997 1454 1048 355 124 [ 061 254 ]
Subtotal (95 CI) 96 88 734 078 [ 045 138 ]
Total events 18 (Bile acids) 21 (Control)
Heterogeneity Chi2 = 417 df = 2 (P = 012) I2 =52
Test for overall effect Z = 084 (P = 040)
2 Six months or more
Angelico 1999 316 217 65 159 [ 030 833 ]
Sama 1991 520 620 201 083 [ 030 229 ]
Subtotal (95 CI) 36 37 266 102 [ 043 240 ]
Total events 8 (Bile acids) 8 (Control)
Heterogeneity Chi2 = 043 df = 1 (P = 051) I2 =00
005 02 1 5 20
Favours bile acids Favours control
(Continued )
36Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Test for overall effect Z = 004 (P = 097)
Total (95 CI) 132 125 1000 085 [ 053 136 ]
Total events 26 (Bile acids) 29 (Control)
Heterogeneity Chi2 = 466 df = 4 (P = 032) I2 =14
Test for overall effect Z = 069 (P = 049)
005 02 1 5 20
Favours bile acids Favours control
Analysis 15 Comparison 1 Bile acids for liver-transplanted patients Outcome 5 Number of deaths related
to rejection at maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 5 Number of deaths related to rejection at maximum follow-up
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 UDCA versus placebo
Keiding 1997 054 148 1000 030 [ 001 712 ]
Total (95 CI) 54 48 1000 030 [ 001 712 ]
Total events 0 (Bile acids) 1 (Control)
Heterogeneity not applicable
Test for overall effect Z = 075 (P = 045)
0001 001 01 1 10 100 1000
Favours bile acids Favours control
37Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 16 Comparison 1 Bile acids for liver-transplanted patients Outcome 6 Number of
retransplantations at maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 6 Number of retransplantations at maximum follow-up
Study or subgroup Bile acids Placebo Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Fleckenstein 1998 214 016 100 567 [ 029 10891 ]
Keiding 1997 154 448 900 022 [ 003 192 ]
Total (95 CI) 68 64 1000 076 [ 020 286 ]
Total events 3 (Bile acids) 4 (Placebo)
Heterogeneity Chi2 = 303 df = 1 (P = 008) I2 =67
Test for overall effect Z = 040 (P = 069)
0001 001 01 1 10 100 1000
Favours bile acids Favours placebo
Analysis 17 Comparison 1 Bile acids for liver-transplanted patients Outcome 7 Number of patients with
acute cellular rejection at maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 7 Number of patients with acute cellular rejection at maximum follow-up
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 UDCA versus placebo or no treatment
Barnes 1997 1728 1724 180 086 [ 058 127 ]
Fleckenstein 1998 814 916 83 102 [ 054 190 ]
Keiding 1997 3554 3248 333 097 [ 073 129 ]
Koneru 1993 316 916 89 033 [ 011 101 ]
Pageaux 1995 926 924 92 092 [ 044 193 ]
Sama 1991 1320 1320 128 100 [ 063 158 ]
Subtotal (95 CI) 158 148 905 089 [ 074 108 ]
01 02 05 1 2 5 10
Favours bile acids Favours control
(Continued )
38Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Total events 85 (Bile acids) 89 (Control)
Heterogeneity Chi2 = 387 df = 5 (P = 057) I2 =00
Test for overall effect Z = 120 (P = 023)
2 TUDCA versus no treatment
Angelico 1999 816 1017 95 085 [ 045 160 ]
Subtotal (95 CI) 16 17 95 085 [ 045 160 ]
Total events 8 (Bile acids) 10 (Control)
Heterogeneity not applicable
Test for overall effect Z = 050 (P = 061)
Total (95 CI) 174 165 1000 089 [ 074 106 ]
Total events 93 (Bile acids) 99 (Control)
Heterogeneity Chi2 = 392 df = 6 (P = 069) I2 =00
Test for overall effect Z = 130 (P = 019)
01 02 05 1 2 5 10
Favours bile acids Favours control
Analysis 18 Comparison 1 Bile acids for liver-transplanted patients Outcome 8 Subgroup analysis
number of patients with acute cellular rejection according to time of start of bile acid
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 8 Subgroup analysis number of patients with acute cellular rejection according to time of start of bile acid
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 Less than three days after transplantation
Keiding 1997 3554 3248 333 097 [ 073 129 ]
Koneru 1993 316 916 89 033 [ 011 101 ]
Subtotal (95 CI) 70 64 422 084 [ 063 111 ]
Total events 38 (Bile acids) 41 (Control)
Heterogeneity Chi2 = 374 df = 1 (P = 005) I2 =73
Test for overall effect Z = 124 (P = 022)
2 Three days or more after liver transplantation
Angelico 1999 816 1017 95 085 [ 045 160 ]
01 02 05 1 2 5 10
Favours bile acids Favours control
(Continued )
39Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Barnes 1997 1728 1724 180 086 [ 058 127 ]
Fleckenstein 1998 814 916 83 102 [ 054 190 ]
Pageaux 1995 926 924 92 092 [ 044 193 ]
Sama 1991 1320 1320 128 100 [ 063 158 ]
Subtotal (95 CI) 104 101 578 092 [ 072 117 ]
Total events 55 (Bile acids) 58 (Control)
Heterogeneity Chi2 = 041 df = 4 (P = 098) I2 =00
Test for overall effect Z = 067 (P = 050)
Total (95 CI) 174 165 1000 089 [ 074 106 ]
Total events 93 (Bile acids) 99 (Control)
Heterogeneity Chi2 = 392 df = 6 (P = 069) I2 =00
Test for overall effect Z = 130 (P = 019)
01 02 05 1 2 5 10
Favours bile acids Favours control
40Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 19 Comparison 1 Bile acids for liver-transplanted patients Outcome 9 Subgroup analysis
number of patients with acute cellular rejection according to treatment duration
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 9 Subgroup analysis number of patients with acute cellular rejection according to treatment duration
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 Less than six months
Barnes 1997 1728 1724 180 086 [ 058 127 ]
Fleckenstein 1998 814 916 83 102 [ 054 190 ]
Keiding 1997 3554 3248 333 097 [ 073 129 ]
Koneru 1993 316 916 89 033 [ 011 101 ]
Pageaux 1995 926 924 92 092 [ 044 193 ]
Subtotal (95 CI) 138 128 777 087 [ 071 107 ]
Total events 72 (Bile acids) 76 (Control)
Heterogeneity Chi2 = 374 df = 4 (P = 044) I2 =00
Test for overall effect Z = 129 (P = 020)
2 Six months or more
Angelico 1999 816 1017 95 085 [ 045 160 ]
Sama 1991 1320 1320 128 100 [ 063 158 ]
Subtotal (95 CI) 36 37 223 094 [ 065 136 ]
Total events 21 (Bile acids) 23 (Control)
Heterogeneity Chi2 = 017 df = 1 (P = 068) I2 =00
Test for overall effect Z = 035 (P = 073)
Total (95 CI) 174 165 1000 089 [ 074 106 ]
Total events 93 (Bile acids) 99 (Control)
Heterogeneity Chi2 = 392 df = 6 (P = 069) I2 =00
Test for overall effect Z = 130 (P = 019)
01 02 05 1 2 5 10
Favours bile acids Favours control
41Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 110 Comparison 1 Bile acids for liver-transplanted patients Outcome 10 Number of patients
with chronic rejection at maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 10 Number of patients with chronic rejection at maximum follow-up
Study or subgroup Bile acids Placebo Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Barnes 1997 128 624 611 014 [ 002 110 ]
Fleckenstein 1998 114 116 88 114 [ 008 1663 ]
Keiding 1997 154 348 300 030 [ 003 275 ]
Total (95 CI) 96 88 1000 028 [ 008 095 ]
Total events 3 (Bile acids) 10 (Placebo)
Heterogeneity Chi2 = 148 df = 2 (P = 048) I2 =00
Test for overall effect Z = 204 (P = 0041)
0001 001 01 1 10 100 1000
Favours bile acids Favours placebo
Analysis 111 Comparison 1 Bile acids for liver-transplanted patients Outcome 11 Number of patients
with steroid-resistant rejection at maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 11 Number of patients with steroid-resistant rejection at maximum follow-up
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Barnes 1997 328 724 277 037 [ 011 127 ]
Fleckenstein 1998 314 316 103 114 [ 027 478 ]
Keiding 1997 1454 1548 583 083 [ 045 154 ]
Pageaux 1995 226 124 38 185 [ 018 1908 ]
Total (95 CI) 122 112 1000 077 [ 047 127 ]
Total events 22 (Bile acids) 26 (Control)
Heterogeneity Chi2 = 226 df = 3 (P = 052) I2 =00
Test for overall effect Z = 102 (P = 031)
001 01 1 10 100
Favours bile acids Favours placebo
42Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 112 Comparison 1 Bile acids for liver-transplanted patients Outcome 12 Serum bilirubin (mgdl)
at the end of treatment
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 12 Serum bilirubin (mgdl) at the end of treatment
Study or subgroup Bile acids Placebo Mean Difference Weight Mean Difference
N Mean(SD) N Mean(SD) IVFixed95 CI IVFixed95 CI
Fleckenstein 1998 14 319 (68) 16 059 (022) 1000 260 [ -096 616 ]
Total (95 CI) 14 16 1000 260 [ -096 616 ]
Heterogeneity not applicable
Test for overall effect Z = 143 (P = 015)
-10 -5 0 5 10
Favours bile acids Favours placebo
Analysis 113 Comparison 1 Bile acids for liver-transplanted patients Outcome 13 Number of days of
hospitalisation after liver transplantation
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 13 Number of days of hospitalisation after liver transplantation
Study or subgroup Bile acids Placebo Mean Difference Weight Mean Difference
N Mean(SD) N Mean(SD) IVFixed95 CI IVFixed95 CI
Barnes 1997 28 25 (17) 24 335 (13) 1000 -850 [ -1667 -033 ]
Total (95 CI) 28 24 1000 -850 [ -1667 -033 ]
Heterogeneity not applicable
Test for overall effect Z = 204 (P = 0041)
-100 -50 0 50 100
Favours bile acids Favours placebo
43Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 114 Comparison 1 Bile acids for liver-transplanted patients Outcome 14 Adverse events
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 14 Adverse events
Study or subgroup Bile acids Placebo Risk Ratio Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Angelico 1999 016 017 00 [ 00 00 ]
Barnes 1997 128 124 086 [ 006 1298 ]
Keiding 1997 554 548 089 [ 027 288 ]
Total (95 CI) 98 89 088 [ 030 260 ]
Total events 6 (Bile acids) 6 (Placebo)
Heterogeneity Chi2 = 000 df = 1 (P = 098) I2 =00
Test for overall effect Z = 022 (P = 082)
001 01 1 10 100
Favours bile acids Favours placebo
A P P E N D I C E S
Appendix 1 Search strategies
Data Base Date of Search Search Strategy
The Cochrane Hepato-Biliary Group Con-
trolled Trials Register
September 2009 1 rsquoliver transplantationrsquo and rsquochenodeoxy-
cholicrsquo
2 rsquoliver transplantationrsquo and rsquocholicrsquo
3 rsquoliver transplantationrsquo and rsquodeoxycholicrsquo
4 rsquoliver transplantationrsquo and rsquoglycochen-
odeoxycholicrsquo
5 rsquoliver transplantationrsquo and rsquoglycocholicrsquo
6 rsquoliver transplantationrsquo and rsquoglycodeoxy-
cholicrsquo
7 rsquoliver transplantationrsquo and rsquoglycolitho-
cholicrsquo
8 rsquoliver transplantationrsquo and rsquohyodeoxy-
cholicrsquo
9 rsquoliver transplantationrsquo and rsquolithocholicrsquo
10 rsquoliver transplantationrsquo and rsquotaurochen-
odeoxycholicrsquo
44Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
11 rsquoliver transplantationrsquo and rsquotauro-
cholicrsquo
12 rsquoliver transplantationrsquo and rsquotaurodehy-
drocholicrsquo
13 rsquoliver transplantationrsquo and rsquotau-
rodeoxycholicrsquo
14 rsquoliver transplantationrsquo and rsquotauroglyco-
cholicrsquo
15 rsquoliver transplantationrsquo and rsquotaurolitho-
cholicrsquo
16 rsquoliver transplantationrsquo and rsquotaurosel-
cholicrsquo
17 rsquoliver transplantationrsquo and rsquotaurourso-
cholicrsquo
18 rsquoliver transplantationrsquo and rsquotaurour-
sodeoxycholicrsquo
19 rsquoliver transplantationrsquo and rsquoursocholicrsquo
20 rsquoliver transplantationrsquo and rsquoursodeoxy-
cholicrsquo
The Cochrane Central Register of Con-
trolled Trials in The Cochrane Library
Issue 3 2009 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
6 3 or 4
7 5 and 6
MEDLINE September 2009 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
45Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
6 3 or 4
7 5 and 6
8 RANDOMIZED-CONTROLLED-
TRIAL ME
9 RANDOM
10 8 or 9
11 7 and 10
EMBASE September 2009 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
6 3 or 4
7 5 and 6
8 RANDOMIZED-CONTROLLED-
TRIAL ME
9 RANDOM
10 8 or 9
11 7 and 10
46Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
Science Citation Index Expanded September 2009 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
6 3 or 4
7 5 and 6
8 RANDOMIZED-CONTROLLED-
TRIAL ME
9 RANDOM
10 8 or 9
11 7 and 10
The Chinese Biomedical Database Searched from January 1980 to April 2002 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
47Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
6 3 or 4
7 5 and 6
8 RANDOMIZED-CONTROLLED-
TRIAL ME
9 RANDOM
10 8 or 9
11 7 and 10
W H A T rsquo S N E W
Last assessed as up-to-date 8 February 2010
18 September 2009 New citation required but conclusions have not
changed
This review is an updated version of a review that was
published for the first time in Issue 3 2005 of TheCochrane Library by Chen 2003b
18 September 2009 New search has been performed No new studies fulfilled the inclusion criteria
H I S T O R Y
Protocol first published Issue 3 2003
Review first published Issue 3 2005
C O N T R I B U T I O N S O F A U T H O R S
GP and VG independently performed searches of relevant databases GP validated the search selected trials for inclusion contacted
the authors of the trials performed data extraction and data analysis and drafted the systematic review VG revised the review update
CG and DS revised the review update solved discrepancies of data extraction validated data analyses and provided consultation
D E C L A R A T I O N S O F I N T E R E S T
None known
48Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
S O U R C E S O F S U P P O R T
Internal sources
bull Copenhagen Trial Unit Denmark
External sources
bull Danish Medical Research Councilrsquos Grant on Getting Research into Practice (GRIP) Denmark
D I F F E R E N C E S B E T W E E N P R O T O C O L A N D R E V I E W
We assessed the risk of bias in the included studies for another four domains that were added to the review protocol (incomplete
outcome data selective outcome reporting baseline imbalance and early stopping of trial) In general the text of the risk of bias
domains were updated following Higgins 2008 Trials were considered at low risk of bias when judged as adequate in all domains
Quasi-randomised studies observational and case-control studies were included for the report of adverse events
We performed trial sequential analysis for outcomes demonstrating a statistically significant result
I N D E X T E R M S
Medical Subject Headings (MeSH)
lowastLiver Transplantation Cholagogues and Choleretics [lowasttherapeutic use] Graft Rejection [lowastprevention amp control] Randomized Con-
trolled Trials as Topic Taurochenodeoxycholic Acid [lowasttherapeutic use] Ursodeoxycholic Acid [lowasttherapeutic use]
MeSH check words
Humans
49Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Fleckenstein 1998 (Continued)
PSC 1
autoimmune cholangiopathy 1
hepatitis B 1
- Placebo group (n = 16)
Mean age (years +- SD)
496 +- 109
Ratio of sex (malefemale) 124
Origins of liver diseases hepatitis C 3
alcohol 3
autoimmune 3
PBC 1
PSC 2
cryptogenic 2
hepatitis B 1
alpha1-antitrypsin deficiency 1
Interventions UDCA group
- Dose 15 mgkg body weightday in divided doses
- Route orally
- Duration immediately after intestinal transit recovery usually between postoperative
days three and five and continue for three months
Placebo group
- Identical-appearing capsules administered in the same quantity and manner
Co-interventions all patients received standard triple-drug regimens (steroids azathio-
prine and cyclosporine or tacrolimus)
Outcomes All cause mortality
Number with retransplantation
Number of patients with acute cellular rejection
Number of patients with chronic rejection
Serum bilirubin levels at the end of treatment
Notes Follow-up time nine months
Letter was sent to the authors in September 2009 No reply was received
Risk of bias
Item Authorsrsquo judgement Description
Adequate sequence generation Unclear No information provided
Allocation concealment Unclear No information provided
Blinding Yes Method of blinding not described but
probably adequate
Incomplete outcome data addressed
All outcomes
Yes Withdrawal one patient from the UDCA
group and two patients from the placebo
group because of capsule size
23Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Fleckenstein 1998 (Continued)
Free of selective reporting Unclear Outcomes were not completely described
Sample size calculation No Not reported
Intention-to-treat analysis Yes Quote ldquoThree patients withdrew after in-
clusionThey were included in the statis-
tical analysisrdquo
Baseline imbalance Unclear Not enough information provided
Early stopping of trial Unclear Not enough information provided
Keiding 1997
Methods Study design prospective randomised placebo-controlled multicenter study
Participants Country Denmark Finland Norway and Sweden
Publication language English
Inclusion criteria
- patients who underwent liver transplantation in Denmark Finland Norway and Swe-
den from September 1 1992 to May 31 1994
Exclusion criteria
- patients with malignant diseases
Participants
The age of the children ranged from 0 to 13 years (median 15) and the age of adults
ranged from 14 to 59 years old (median 44) MaleFemale ratio was 96 for children and
4344 for adults
- UDCA group (n = 54)
Origins of liver diseases
paracetamol intoxication 1 hepatitis B 1 autoimmune hepatitis 0 biliary atresia 2
metabolic diseases 7 neonatal hepatitis 2 PBC 13 post hepatitis cirrhosis 8 PSC 3
cryptogenic cirrhosis 7 alcoholic cirrhosis 2 other reasons 8
- Placebo group (n = 48)
Origins of liver diseases paracetamol intoxication 1 hepatitis B 0 autoimmune hepatitis
1 biliary atresia 3 metabolic diseases 11 neonatal hepatitis 0 PBC 7 post hepatitis
cirrhosis 5 PSC 7 cryptogenic cirrhosis 2 alcoholic cirrhosis 6 other reasons 5
Interventions UDCA group
- Dose 15 mgkg body weightday in two or three divided doses
- Route orally
- Duration immediately after intestinal transit recovery usually between postoperative
days three and five and continue for three months
Placebo group
- Identical-appearing capsules administered in the same quantity and manner
Co-interventions all patients received standard triple-drug regimens (steroids azathio-
prine and cyclosporine or tacrolimus)
24Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Keiding 1997 (Continued)
Outcomes All cause mortality
Number of deaths related to rejection
Number of patients with acute cellular rejection
Number of patients with chronic rejection
Number of patients with steroid-resistant rejection
Adverse events
Notes Letter was sent to the authors in September 2009 No reply was received
Risk of bias
Item Authorsrsquo judgement Description
Adequate sequence generation Unclear Patients were randomised at a ratio of 11
Allocation concealment Yes Quote ldquo The allocation was performed in
blocks of 10 patients using the sealed serial
envelope methodrdquo
Blinding Yes Quote ldquoThe UDCA and the placebo cap-
sules had identical appearance and tasterdquo
Incomplete outcome data addressed
All outcomes
Yes Follow-up time 12 months Five UDCA
patients and five placebo patients withdrew
from study Reasons were reported
Free of selective reporting Unclear Insufficient information
Sample size calculation Yes Performed and allowed for a difference in
the incidence of at least one episode of
acute rejection of 50 between the treat-
ment and placebo groups with 90 statisti-
cal power and a significance level of P value
less than 005 The calculated sample size
was 80 patients
Intention-to-treat analysis Yes Stated and used
Baseline imbalance Yes The study seems to be free of baseline im-
balance
Early stopping of trial Yes Study attained the pre-specified sample
size
25Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Koneru 1993
Methods Study design randomised controlled trial
Participants Country United States
Publication language English
Inclusion criteria
- patients who underwent liver transplantation
Exclusion criteria
- not mentioned
Participants
- UDCA group (n = 16)
Mean age (years +- SD)
no information
Ratio of sex (malefemale) no information
Origins of liver diseases
no information
- Control group (n = 16)
Mean age (years +- SD)
no information
Ratio of sex (malefemale) no information
Origins of liver diseases
no information
Interventions UDCA group
- Dose 900 mgday
- Route orally
- Duration immediately after intestinal transit recovery usually between postoperative
days three and five and continue for three months
Control group
- no treatment
Co-interventions all patients received standard triple-drug regimens (steroids azathio-
prine and cyclosporine)
Outcomes Number of patients with retransplantation due to rejection
Number of patients with rejection episodes
Notes Abstract
Letter was sent to the authors in September 2009 No reply was received
Risk of bias
Item Authorsrsquo judgement Description
Adequate sequence generation Unclear No information provided
Allocation concealment Unclear No information provided
Blinding No Not performed
26Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Koneru 1993 (Continued)
Incomplete outcome data addressed
All outcomes
Unclear The study gives the impression that there
were no withdrawals but this was not ex-
plicitly stated
Free of selective reporting Unclear Insufficient information provided
Sample size calculation No Not performed
Intention-to-treat analysis Unclear No information provided
Baseline imbalance Unclear Not enough information provided
Early stopping of trial Unclear Not enough information provided
Pageaux 1995
Methods Study design double-blind randomised study
Participants Country France
Publication language English
Inclusion criteria
- patients who underwent liver transplantation
Exclusion criteria
- not mentioned
Participants
- UDCA group (n=26)
Mean age (years +- SD)
47 +- 10
Ratio of sex (malefemale) 179
Origins of liver diseases alcoholic cirrhosis 14
post-hepatic B cirrhosis 2
post-hepatitis C cirrhosis 4
PBC 2
liver cancer 2
fulminant hepatitis 1
miscellaneous 1
- Placebo group (n = 24)
Mean age (years +- SD)
51+- 9
Ratio of sex (malefemale) 159
Origins of liver diseases alcoholic cirrhosis 10
post-hepatic B cirrhosis 0
post-hepatic C cirrhosis 6
PBC 3
liver cancer 4
fulminant hepatitis 0
miscellaneous 1
27Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Pageaux 1995 (Continued)
Interventions UDCA group
- Dose 600 mgday in three divided doses
- Route orally
- Duration immediately after intestinal transit recovery usually between postoperative
days three and five and continue for two months
Placebo group
- identical-appearing capsules administered in the same quantity and manner
Co-interventions all patients received standard triple-drug regimens (steroids azathio-
prine and cyclosporine or tacrolimus)
Outcomes Number of patients with acute cellular rejection
Number of patients with steroid-resistant rejection
Notes Letter was sent to the authors in September 2009 No reply was received
Risk of bias
Item Authorsrsquo judgement Description
Adequate sequence generation Unclear No information provided
Allocation concealment Unclear No information provided
Blinding Unclear Method of blinding not described
Incomplete outcome data addressed
All outcomes
Yes Five patients died from non-immunologi-
cal causes before the end of the first month
and were excluded from the study Reasons
were reported
Free of selective reporting Unclear Not enough information provided
Sample size calculation No Not performed
Intention-to-treat analysis No Not stated and not used
Baseline imbalance Unclear Not enough information provided
Early stopping of trial Unclear Not enough information provided
Sama 1991
Methods Study design randomised controlled trial
Participants Country Italy
Publication language English
Inclusion criteria
28Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Sama 1991 (Continued)
- patients who underwent liver transplantation
Exclusion criteria
- not mentioned
Participants
- UDCA group (n = 20)
Mean age (years +- SD)
no information
Ratio of sex (malefemale) no information
Origins of liver diseases
no information
- Control group (n = 20)
Mean age (years +- SD)
no information
Ratio of sex (malefemale) no information
Origins of liver diseases
no information
Interventions UDCA group
- Dose 600 mgday in two divided doses
- Route orally
- Duration immediately after intestinal transit recovery usually between postoperative
day five and day seven and continue for six months
Control group
- no treatment
Co-interventions all patients received standard immunosuppressive treatment (steroids
and cyclosporine)
Outcomes All cause mortality
Number of patients with acute cellular rejection
Notes Abstract
Letter was sent to the authors in September 2009 No reply was received
Risk of bias
Item Authorsrsquo judgement Description
Adequate sequence generation Unclear A randomisation list was performed before
patients were admitted to the trial (infor-
mation from principal author)
Allocation concealment Unclear No information provided
Blinding Unclear The principle author provided information
that the study was made according to a
single-blind randomised protocol The pri-
mary outcome was the occurrence of biopsy
proven rejection episodes The pathologists
were blind but the patients were not
29Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Sama 1991 (Continued)
Incomplete outcome data addressed
All outcomes
Unclear Five patients from the UDCA group and
six patients from the placebo group were
excluded Reasons for exclusion were not
fully stated
Free of selective reporting No Data about survival of patients were not
adequately reported
Sample size calculation No Not performed
Intention-to-treat analysis No Not stated and not used
Baseline imbalance Unclear Basic characteristics of patients not re-
ported
Early stopping of trial Unclear Not enough information provided
UDCA = ursodeoxycholic acid
TUDCA = tauroursodeoxycholic acid
PBC = primary biliary cirrhosis
PSC = primary sclerosing cholangitis
OKT3 = anti-CD3 monoclonal antibody
Characteristics of excluded studies [ordered by study ID]
Assy 2007 A randomised controlled trial that included only recipients of liver transplantation with stable graft function and
no episodes of rejection for at least 2 years that were then offered total immunosuppression withdrawal Fourteen
patients received UDCA (15 mgkg body weightday) and 12 received placebo Rejection occurred in 43 and
75 of patients respectively (no significant difference) None developed chronic rejection After follow-up two
patients were free of immunosuppression 80 were steroid free and 50 were able to reduce their dose of
cyclosporine
Clavien 1996 Case series Fifty consecutive liver-transplanted patients were treated with a standard cyclosporine immunosup-
pressive regimen Twenty three of the 43 survivors developed an episode of rejection and UDCA (10 mgkg
weightday) was initiated Only one patient had a second episode of rejection
Friman 1992 Observational study Thirty-three liver-transplanted patients received 10 mg UDCAkg body weightday for
median of 10 months (range four to 21 months) Eight historical liver-transplanted patients served as control
group The rejection incidence was significantly lower in the patients who received the treatment with UDCA
Biochemistry one month after transplantation demonstrated significantly lower average values of aminotrans-
ferases and alkaline phosphatases in patients treated with UDCA than in the control group
30Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
Heathcote 1999 Observational study From 1987 to 1996 37 UDCA treated and 53 placebo treated patients with primary biliary
cirrhosis were referred for transplantation Posttransplantation survival rates at one month were 939 in the
UDCA group and 884 in the placebo group and one year survival rates were 903 and 784 respectively
(no significant differences) However rejection (type not defined - a secondary outcome measure) occurred
significantly less often in the UDCA group (429) than in placebo group (688)
Henriksson 1991 Observational study All patients in this study were given sequential quadruple immunosuppression with anti-
lymphocyte globulin azathioprine steroids and cyclosporine All patients with primary graft function (n = 11)
were treated with 10 mg UDCAkg body weightday starting during the first postoperative week Patients who
received liver transplantation in the first 6 months of 1989 (n = 8) served as controls In the control group one
patient died after 9 months with chronic graft dysfunction and six patients had rejection episodes during the
first postoperative month All patients in the UDCA group were alive without rejection episodes
Persson 1990 Observational study All 11 adult patients transplanted between August 1989 and January 1990 with primary
graft function were treated with 10 mg UDCA kg body weightday Eight patients transplanted during the first
half of 1989 served as control UDCA was started during the first postoperative week and the treatment was
continued for six months All patients in the UDCA treated group survived with satisfactory graft function In
the control group six patients had at least one rejection episode needing treatment during the first postoperative
month
Rafael 1995 Observational study Seventeen patients who underwent liver transplantation between February 1990 and April
1993 and developed biliary complications after transplantation were retrospectively analysed regarding treatment
with UDCA UDCA was given in a dose of 500 to 1000 mgday Ten patients were treated for at least one year while
seven patients were treated for 14 to 250 days UDCA significantly improved gammaglutamyl transpeptidase in
liver graft recipients with biliary complications There was also a trend towards improvement in serum bilirubin
and alanine transaminase values
Sama 1998 Observational study Thirty-four patients who underwent liver transplantation between January 1995 and June
1996 were included in the study Seventeen were treated with UDCA 10 mgkg body weightday during 6
months while 17 served as controls on the basis of having undergone liver transplantation closest to UDCA
patients A significant decrease in serum bilirubin levels was observed in UDCA patients There was a significantly
higher incidence of recurrent hepatitis in the control group
UDCA ursodeoxycholic acid
31Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
D A T A A N D A N A L Y S E S
Comparison 1 Bile acids for liver-transplanted patients
Outcome or subgroup titleNo of
studies
No of
participants Statistical method Effect size
1 All-cause mortality at maximum
follow-up
5 257 Risk Ratio (M-H Fixed 95 CI) 085 [053 136]
11 UDCA versus placebo or
no treatment
4 224 Risk Ratio (M-H Fixed 95 CI) 080 [049 130]
12 TUDCA versus no
treatment
1 33 Risk Ratio (M-H Fixed 95 CI) 159 [030 833]
2 All-cause mortality worst-best
case and best-worst case
scenarios
5 Risk Ratio (M-H Fixed 95 CI) Subtotals only
21 Worst-best case scenario 5 257 Risk Ratio (M-H Fixed 95 CI) 130 [086 196]
22 Best-worst case scenario 5 257 Risk Ratio (M-H Fixed 95 CI) 058 [038 090]
3 Subgroup analyses all-cause
mortality at maximum
follow-up according to time of
start of bile acids
5 257 Risk Ratio (M-H Fixed 95 CI) 085 [053 136]
31 Less than three days after
transplantation
1 102 Risk Ratio (M-H Fixed 95 CI) 124 [061 254]
32 Three days or more after
transplantation
4 155 Risk Ratio (M-H Fixed 95 CI) 063 [033 120]
4 Subgroup analyses all cause
mortality at maximum
follow-up according to
treatment duration
5 257 Risk Ratio (M-H Fixed 95 CI) 085 [053 136]
41 Less than six months 3 184 Risk Ratio (M-H Fixed 95 CI) 078 [045 138]
42 Six months or more 2 73 Risk Ratio (M-H Fixed 95 CI) 102 [043 240]
5 Number of deaths related
to rejection at maximum
follow-up
1 102 Risk Ratio (M-H Fixed 95 CI) 030 [001 712]
51 UDCA versus placebo 1 102 Risk Ratio (M-H Fixed 95 CI) 030 [001 712]
6 Number of retransplantations at
maximum follow-up
2 132 Risk Ratio (M-H Fixed 95 CI) 076 [020 286]
7 Number of patients with acute
cellular rejection at maximum
follow-up
7 339 Risk Ratio (M-H Fixed 95 CI) 089 [074 106]
71 UDCA versus placebo or
no treatment
6 306 Risk Ratio (M-H Fixed 95 CI) 089 [074 108]
72 TUDCA versus no
treatment
1 33 Risk Ratio (M-H Fixed 95 CI) 085 [045 160]
8 Subgroup analysis number of
patients with acute cellular
rejection according to time of
start of bile acid
7 339 Risk Ratio (M-H Fixed 95 CI) 089 [074 106]
32Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
81 Less than three days after
transplantation
2 134 Risk Ratio (M-H Fixed 95 CI) 084 [063 111]
82 Three days or more after
liver transplantation
5 205 Risk Ratio (M-H Fixed 95 CI) 092 [072 117]
9 Subgroup analysis number
of patients with acute
cellular rejection according to
treatment duration
7 339 Risk Ratio (M-H Fixed 95 CI) 089 [074 106]
91 Less than six months 5 266 Risk Ratio (M-H Fixed 95 CI) 087 [071 107]
92 Six months or more 2 73 Risk Ratio (M-H Fixed 95 CI) 094 [065 136]
10 Number of patients with
chronic rejection at maximum
follow-up
3 184 Risk Ratio (M-H Fixed 95 CI) 028 [008 095]
11 Number of patients with
steroid-resistant rejection at
maximum follow-up
4 234 Risk Ratio (M-H Fixed 95 CI) 077 [047 127]
12 Serum bilirubin (mgdl) at the
end of treatment
1 30 Mean Difference (IV Fixed 95 CI) 26 [-096 616]
13 Number of days of
hospitalisation after liver
transplantation
1 52 Mean Difference (IV Fixed 95 CI) -85 [-1667 -033]
14 Adverse events 3 187 Risk Ratio (M-H Fixed 95 CI) 088 [030 260]
Analysis 11 Comparison 1 Bile acids for liver-transplanted patients Outcome 1 All-cause mortality at
maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 1 All-cause mortality at maximum follow-up
Study or subgroup Favours bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 UDCA versus placebo or no treatment
Barnes 1997 228 724 253 024 [ 006 107 ]
Fleckenstein 1998 214 416 125 057 [ 012 266 ]
Keiding 1997 1454 1048 355 124 [ 061 254 ]
Sama 1991 520 620 201 083 [ 030 229 ]
Subtotal (95 CI) 116 108 935 080 [ 049 130 ]
Total events 23 (Favours bile acids) 27 (Control)
Heterogeneity Chi2 = 416 df = 3 (P = 025) I2 =28
Test for overall effect Z = 091 (P = 036)
01 02 05 1 2 5 10
Favours bile acids Favours control
(Continued )
33Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Favours bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
2 TUDCA versus no treatment
Angelico 1999 316 217 65 159 [ 030 833 ]
Subtotal (95 CI) 16 17 65 159 [ 030 833 ]
Total events 3 (Favours bile acids) 2 (Control)
Heterogeneity not applicable
Test for overall effect Z = 055 (P = 058)
Total (95 CI) 132 125 1000 085 [ 053 136 ]
Total events 26 (Favours bile acids) 29 (Control)
Heterogeneity Chi2 = 466 df = 4 (P = 032) I2 =14
Test for overall effect Z = 069 (P = 049)
01 02 05 1 2 5 10
Favours bile acids Favours control
Analysis 12 Comparison 1 Bile acids for liver-transplanted patients Outcome 2 All-cause mortality worst-
best case and best-worst case scenarios
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 2 All-cause mortality worst-best case and best-worst case scenarios
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 Worst-best case scenario
Angelico 1999 516 217 65 266 [ 060 1180 ]
Barnes 1997 828 724 253 098 [ 042 230 ]
Fleckenstein 1998 314 416 125 086 [ 023 319 ]
Keiding 1997 1954 1048 355 169 [ 087 327 ]
Sama 1991 520 620 201 083 [ 030 229 ]
Subtotal (95 CI) 132 125 1000 130 [ 086 196 ]
Total events 40 (Bile acids) 29 (Control)
Heterogeneity Chi2 = 303 df = 4 (P = 055) I2 =00
Test for overall effect Z = 123 (P = 022)
2 Best-worst case scenario
005 02 1 5 20
Favours bile acids Favours control
(Continued )
34Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Angelico 1999 316 417 90 080 [ 021 302 ]
Barnes 1997 228 1124 274 016 [ 004 063 ]
Fleckenstein 1998 214 616 130 038 [ 009 159 ]
Keiding 1997 1454 1548 368 083 [ 045 154 ]
Sama 1991 520 620 139 083 [ 030 229 ]
Subtotal (95 CI) 132 125 1000 058 [ 038 090 ]
Total events 26 (Bile acids) 42 (Control)
Heterogeneity Chi2 = 567 df = 4 (P = 023) I2 =29
Test for overall effect Z = 247 (P = 0014)
005 02 1 5 20
Favours bile acids Favours control
Analysis 13 Comparison 1 Bile acids for liver-transplanted patients Outcome 3 Subgroup analyses all-
cause mortality at maximum follow-up according to time of start of bile acids
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 3 Subgroup analyses all-cause mortality at maximum follow-up according to time of start of bile acids
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 Less than three days after transplantation
Keiding 1997 1454 1048 355 124 [ 061 254 ]
Subtotal (95 CI) 54 48 355 124 [ 061 254 ]
Total events 14 (Bile acids) 10 (Control)
Heterogeneity not applicable
Test for overall effect Z = 060 (P = 055)
2 Three days or more after transplantation
Angelico 1999 316 217 65 159 [ 030 833 ]
Barnes 1997 228 724 253 024 [ 006 107 ]
Fleckenstein 1998 214 416 125 057 [ 012 266 ]
Sama 1991 520 620 201 083 [ 030 229 ]
005 02 1 5 20
Favours bile acids Favours control
(Continued )
35Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Subtotal (95 CI) 78 77 645 063 [ 033 120 ]
Total events 12 (Bile acids) 19 (Control)
Heterogeneity Chi2 = 310 df = 3 (P = 038) I2 =3
Test for overall effect Z = 141 (P = 016)
Total (95 CI) 132 125 1000 085 [ 053 136 ]
Total events 26 (Bile acids) 29 (Control)
Heterogeneity Chi2 = 466 df = 4 (P = 032) I2 =14
Test for overall effect Z = 069 (P = 049)
005 02 1 5 20
Favours bile acids Favours control
Analysis 14 Comparison 1 Bile acids for liver-transplanted patients Outcome 4 Subgroup analyses all
cause mortality at maximum follow-up according to treatment duration
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 4 Subgroup analyses all cause mortality at maximum follow-up according to treatment duration
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 Less than six months
Barnes 1997 228 724 253 024 [ 006 107 ]
Fleckenstein 1998 214 416 125 057 [ 012 266 ]
Keiding 1997 1454 1048 355 124 [ 061 254 ]
Subtotal (95 CI) 96 88 734 078 [ 045 138 ]
Total events 18 (Bile acids) 21 (Control)
Heterogeneity Chi2 = 417 df = 2 (P = 012) I2 =52
Test for overall effect Z = 084 (P = 040)
2 Six months or more
Angelico 1999 316 217 65 159 [ 030 833 ]
Sama 1991 520 620 201 083 [ 030 229 ]
Subtotal (95 CI) 36 37 266 102 [ 043 240 ]
Total events 8 (Bile acids) 8 (Control)
Heterogeneity Chi2 = 043 df = 1 (P = 051) I2 =00
005 02 1 5 20
Favours bile acids Favours control
(Continued )
36Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Test for overall effect Z = 004 (P = 097)
Total (95 CI) 132 125 1000 085 [ 053 136 ]
Total events 26 (Bile acids) 29 (Control)
Heterogeneity Chi2 = 466 df = 4 (P = 032) I2 =14
Test for overall effect Z = 069 (P = 049)
005 02 1 5 20
Favours bile acids Favours control
Analysis 15 Comparison 1 Bile acids for liver-transplanted patients Outcome 5 Number of deaths related
to rejection at maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 5 Number of deaths related to rejection at maximum follow-up
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 UDCA versus placebo
Keiding 1997 054 148 1000 030 [ 001 712 ]
Total (95 CI) 54 48 1000 030 [ 001 712 ]
Total events 0 (Bile acids) 1 (Control)
Heterogeneity not applicable
Test for overall effect Z = 075 (P = 045)
0001 001 01 1 10 100 1000
Favours bile acids Favours control
37Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 16 Comparison 1 Bile acids for liver-transplanted patients Outcome 6 Number of
retransplantations at maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 6 Number of retransplantations at maximum follow-up
Study or subgroup Bile acids Placebo Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Fleckenstein 1998 214 016 100 567 [ 029 10891 ]
Keiding 1997 154 448 900 022 [ 003 192 ]
Total (95 CI) 68 64 1000 076 [ 020 286 ]
Total events 3 (Bile acids) 4 (Placebo)
Heterogeneity Chi2 = 303 df = 1 (P = 008) I2 =67
Test for overall effect Z = 040 (P = 069)
0001 001 01 1 10 100 1000
Favours bile acids Favours placebo
Analysis 17 Comparison 1 Bile acids for liver-transplanted patients Outcome 7 Number of patients with
acute cellular rejection at maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 7 Number of patients with acute cellular rejection at maximum follow-up
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 UDCA versus placebo or no treatment
Barnes 1997 1728 1724 180 086 [ 058 127 ]
Fleckenstein 1998 814 916 83 102 [ 054 190 ]
Keiding 1997 3554 3248 333 097 [ 073 129 ]
Koneru 1993 316 916 89 033 [ 011 101 ]
Pageaux 1995 926 924 92 092 [ 044 193 ]
Sama 1991 1320 1320 128 100 [ 063 158 ]
Subtotal (95 CI) 158 148 905 089 [ 074 108 ]
01 02 05 1 2 5 10
Favours bile acids Favours control
(Continued )
38Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Total events 85 (Bile acids) 89 (Control)
Heterogeneity Chi2 = 387 df = 5 (P = 057) I2 =00
Test for overall effect Z = 120 (P = 023)
2 TUDCA versus no treatment
Angelico 1999 816 1017 95 085 [ 045 160 ]
Subtotal (95 CI) 16 17 95 085 [ 045 160 ]
Total events 8 (Bile acids) 10 (Control)
Heterogeneity not applicable
Test for overall effect Z = 050 (P = 061)
Total (95 CI) 174 165 1000 089 [ 074 106 ]
Total events 93 (Bile acids) 99 (Control)
Heterogeneity Chi2 = 392 df = 6 (P = 069) I2 =00
Test for overall effect Z = 130 (P = 019)
01 02 05 1 2 5 10
Favours bile acids Favours control
Analysis 18 Comparison 1 Bile acids for liver-transplanted patients Outcome 8 Subgroup analysis
number of patients with acute cellular rejection according to time of start of bile acid
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 8 Subgroup analysis number of patients with acute cellular rejection according to time of start of bile acid
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 Less than three days after transplantation
Keiding 1997 3554 3248 333 097 [ 073 129 ]
Koneru 1993 316 916 89 033 [ 011 101 ]
Subtotal (95 CI) 70 64 422 084 [ 063 111 ]
Total events 38 (Bile acids) 41 (Control)
Heterogeneity Chi2 = 374 df = 1 (P = 005) I2 =73
Test for overall effect Z = 124 (P = 022)
2 Three days or more after liver transplantation
Angelico 1999 816 1017 95 085 [ 045 160 ]
01 02 05 1 2 5 10
Favours bile acids Favours control
(Continued )
39Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Barnes 1997 1728 1724 180 086 [ 058 127 ]
Fleckenstein 1998 814 916 83 102 [ 054 190 ]
Pageaux 1995 926 924 92 092 [ 044 193 ]
Sama 1991 1320 1320 128 100 [ 063 158 ]
Subtotal (95 CI) 104 101 578 092 [ 072 117 ]
Total events 55 (Bile acids) 58 (Control)
Heterogeneity Chi2 = 041 df = 4 (P = 098) I2 =00
Test for overall effect Z = 067 (P = 050)
Total (95 CI) 174 165 1000 089 [ 074 106 ]
Total events 93 (Bile acids) 99 (Control)
Heterogeneity Chi2 = 392 df = 6 (P = 069) I2 =00
Test for overall effect Z = 130 (P = 019)
01 02 05 1 2 5 10
Favours bile acids Favours control
40Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 19 Comparison 1 Bile acids for liver-transplanted patients Outcome 9 Subgroup analysis
number of patients with acute cellular rejection according to treatment duration
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 9 Subgroup analysis number of patients with acute cellular rejection according to treatment duration
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 Less than six months
Barnes 1997 1728 1724 180 086 [ 058 127 ]
Fleckenstein 1998 814 916 83 102 [ 054 190 ]
Keiding 1997 3554 3248 333 097 [ 073 129 ]
Koneru 1993 316 916 89 033 [ 011 101 ]
Pageaux 1995 926 924 92 092 [ 044 193 ]
Subtotal (95 CI) 138 128 777 087 [ 071 107 ]
Total events 72 (Bile acids) 76 (Control)
Heterogeneity Chi2 = 374 df = 4 (P = 044) I2 =00
Test for overall effect Z = 129 (P = 020)
2 Six months or more
Angelico 1999 816 1017 95 085 [ 045 160 ]
Sama 1991 1320 1320 128 100 [ 063 158 ]
Subtotal (95 CI) 36 37 223 094 [ 065 136 ]
Total events 21 (Bile acids) 23 (Control)
Heterogeneity Chi2 = 017 df = 1 (P = 068) I2 =00
Test for overall effect Z = 035 (P = 073)
Total (95 CI) 174 165 1000 089 [ 074 106 ]
Total events 93 (Bile acids) 99 (Control)
Heterogeneity Chi2 = 392 df = 6 (P = 069) I2 =00
Test for overall effect Z = 130 (P = 019)
01 02 05 1 2 5 10
Favours bile acids Favours control
41Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 110 Comparison 1 Bile acids for liver-transplanted patients Outcome 10 Number of patients
with chronic rejection at maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 10 Number of patients with chronic rejection at maximum follow-up
Study or subgroup Bile acids Placebo Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Barnes 1997 128 624 611 014 [ 002 110 ]
Fleckenstein 1998 114 116 88 114 [ 008 1663 ]
Keiding 1997 154 348 300 030 [ 003 275 ]
Total (95 CI) 96 88 1000 028 [ 008 095 ]
Total events 3 (Bile acids) 10 (Placebo)
Heterogeneity Chi2 = 148 df = 2 (P = 048) I2 =00
Test for overall effect Z = 204 (P = 0041)
0001 001 01 1 10 100 1000
Favours bile acids Favours placebo
Analysis 111 Comparison 1 Bile acids for liver-transplanted patients Outcome 11 Number of patients
with steroid-resistant rejection at maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 11 Number of patients with steroid-resistant rejection at maximum follow-up
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Barnes 1997 328 724 277 037 [ 011 127 ]
Fleckenstein 1998 314 316 103 114 [ 027 478 ]
Keiding 1997 1454 1548 583 083 [ 045 154 ]
Pageaux 1995 226 124 38 185 [ 018 1908 ]
Total (95 CI) 122 112 1000 077 [ 047 127 ]
Total events 22 (Bile acids) 26 (Control)
Heterogeneity Chi2 = 226 df = 3 (P = 052) I2 =00
Test for overall effect Z = 102 (P = 031)
001 01 1 10 100
Favours bile acids Favours placebo
42Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 112 Comparison 1 Bile acids for liver-transplanted patients Outcome 12 Serum bilirubin (mgdl)
at the end of treatment
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 12 Serum bilirubin (mgdl) at the end of treatment
Study or subgroup Bile acids Placebo Mean Difference Weight Mean Difference
N Mean(SD) N Mean(SD) IVFixed95 CI IVFixed95 CI
Fleckenstein 1998 14 319 (68) 16 059 (022) 1000 260 [ -096 616 ]
Total (95 CI) 14 16 1000 260 [ -096 616 ]
Heterogeneity not applicable
Test for overall effect Z = 143 (P = 015)
-10 -5 0 5 10
Favours bile acids Favours placebo
Analysis 113 Comparison 1 Bile acids for liver-transplanted patients Outcome 13 Number of days of
hospitalisation after liver transplantation
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 13 Number of days of hospitalisation after liver transplantation
Study or subgroup Bile acids Placebo Mean Difference Weight Mean Difference
N Mean(SD) N Mean(SD) IVFixed95 CI IVFixed95 CI
Barnes 1997 28 25 (17) 24 335 (13) 1000 -850 [ -1667 -033 ]
Total (95 CI) 28 24 1000 -850 [ -1667 -033 ]
Heterogeneity not applicable
Test for overall effect Z = 204 (P = 0041)
-100 -50 0 50 100
Favours bile acids Favours placebo
43Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 114 Comparison 1 Bile acids for liver-transplanted patients Outcome 14 Adverse events
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 14 Adverse events
Study or subgroup Bile acids Placebo Risk Ratio Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Angelico 1999 016 017 00 [ 00 00 ]
Barnes 1997 128 124 086 [ 006 1298 ]
Keiding 1997 554 548 089 [ 027 288 ]
Total (95 CI) 98 89 088 [ 030 260 ]
Total events 6 (Bile acids) 6 (Placebo)
Heterogeneity Chi2 = 000 df = 1 (P = 098) I2 =00
Test for overall effect Z = 022 (P = 082)
001 01 1 10 100
Favours bile acids Favours placebo
A P P E N D I C E S
Appendix 1 Search strategies
Data Base Date of Search Search Strategy
The Cochrane Hepato-Biliary Group Con-
trolled Trials Register
September 2009 1 rsquoliver transplantationrsquo and rsquochenodeoxy-
cholicrsquo
2 rsquoliver transplantationrsquo and rsquocholicrsquo
3 rsquoliver transplantationrsquo and rsquodeoxycholicrsquo
4 rsquoliver transplantationrsquo and rsquoglycochen-
odeoxycholicrsquo
5 rsquoliver transplantationrsquo and rsquoglycocholicrsquo
6 rsquoliver transplantationrsquo and rsquoglycodeoxy-
cholicrsquo
7 rsquoliver transplantationrsquo and rsquoglycolitho-
cholicrsquo
8 rsquoliver transplantationrsquo and rsquohyodeoxy-
cholicrsquo
9 rsquoliver transplantationrsquo and rsquolithocholicrsquo
10 rsquoliver transplantationrsquo and rsquotaurochen-
odeoxycholicrsquo
44Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
11 rsquoliver transplantationrsquo and rsquotauro-
cholicrsquo
12 rsquoliver transplantationrsquo and rsquotaurodehy-
drocholicrsquo
13 rsquoliver transplantationrsquo and rsquotau-
rodeoxycholicrsquo
14 rsquoliver transplantationrsquo and rsquotauroglyco-
cholicrsquo
15 rsquoliver transplantationrsquo and rsquotaurolitho-
cholicrsquo
16 rsquoliver transplantationrsquo and rsquotaurosel-
cholicrsquo
17 rsquoliver transplantationrsquo and rsquotaurourso-
cholicrsquo
18 rsquoliver transplantationrsquo and rsquotaurour-
sodeoxycholicrsquo
19 rsquoliver transplantationrsquo and rsquoursocholicrsquo
20 rsquoliver transplantationrsquo and rsquoursodeoxy-
cholicrsquo
The Cochrane Central Register of Con-
trolled Trials in The Cochrane Library
Issue 3 2009 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
6 3 or 4
7 5 and 6
MEDLINE September 2009 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
45Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
6 3 or 4
7 5 and 6
8 RANDOMIZED-CONTROLLED-
TRIAL ME
9 RANDOM
10 8 or 9
11 7 and 10
EMBASE September 2009 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
6 3 or 4
7 5 and 6
8 RANDOMIZED-CONTROLLED-
TRIAL ME
9 RANDOM
10 8 or 9
11 7 and 10
46Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
Science Citation Index Expanded September 2009 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
6 3 or 4
7 5 and 6
8 RANDOMIZED-CONTROLLED-
TRIAL ME
9 RANDOM
10 8 or 9
11 7 and 10
The Chinese Biomedical Database Searched from January 1980 to April 2002 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
47Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
6 3 or 4
7 5 and 6
8 RANDOMIZED-CONTROLLED-
TRIAL ME
9 RANDOM
10 8 or 9
11 7 and 10
W H A T rsquo S N E W
Last assessed as up-to-date 8 February 2010
18 September 2009 New citation required but conclusions have not
changed
This review is an updated version of a review that was
published for the first time in Issue 3 2005 of TheCochrane Library by Chen 2003b
18 September 2009 New search has been performed No new studies fulfilled the inclusion criteria
H I S T O R Y
Protocol first published Issue 3 2003
Review first published Issue 3 2005
C O N T R I B U T I O N S O F A U T H O R S
GP and VG independently performed searches of relevant databases GP validated the search selected trials for inclusion contacted
the authors of the trials performed data extraction and data analysis and drafted the systematic review VG revised the review update
CG and DS revised the review update solved discrepancies of data extraction validated data analyses and provided consultation
D E C L A R A T I O N S O F I N T E R E S T
None known
48Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
S O U R C E S O F S U P P O R T
Internal sources
bull Copenhagen Trial Unit Denmark
External sources
bull Danish Medical Research Councilrsquos Grant on Getting Research into Practice (GRIP) Denmark
D I F F E R E N C E S B E T W E E N P R O T O C O L A N D R E V I E W
We assessed the risk of bias in the included studies for another four domains that were added to the review protocol (incomplete
outcome data selective outcome reporting baseline imbalance and early stopping of trial) In general the text of the risk of bias
domains were updated following Higgins 2008 Trials were considered at low risk of bias when judged as adequate in all domains
Quasi-randomised studies observational and case-control studies were included for the report of adverse events
We performed trial sequential analysis for outcomes demonstrating a statistically significant result
I N D E X T E R M S
Medical Subject Headings (MeSH)
lowastLiver Transplantation Cholagogues and Choleretics [lowasttherapeutic use] Graft Rejection [lowastprevention amp control] Randomized Con-
trolled Trials as Topic Taurochenodeoxycholic Acid [lowasttherapeutic use] Ursodeoxycholic Acid [lowasttherapeutic use]
MeSH check words
Humans
49Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Fleckenstein 1998 (Continued)
Free of selective reporting Unclear Outcomes were not completely described
Sample size calculation No Not reported
Intention-to-treat analysis Yes Quote ldquoThree patients withdrew after in-
clusionThey were included in the statis-
tical analysisrdquo
Baseline imbalance Unclear Not enough information provided
Early stopping of trial Unclear Not enough information provided
Keiding 1997
Methods Study design prospective randomised placebo-controlled multicenter study
Participants Country Denmark Finland Norway and Sweden
Publication language English
Inclusion criteria
- patients who underwent liver transplantation in Denmark Finland Norway and Swe-
den from September 1 1992 to May 31 1994
Exclusion criteria
- patients with malignant diseases
Participants
The age of the children ranged from 0 to 13 years (median 15) and the age of adults
ranged from 14 to 59 years old (median 44) MaleFemale ratio was 96 for children and
4344 for adults
- UDCA group (n = 54)
Origins of liver diseases
paracetamol intoxication 1 hepatitis B 1 autoimmune hepatitis 0 biliary atresia 2
metabolic diseases 7 neonatal hepatitis 2 PBC 13 post hepatitis cirrhosis 8 PSC 3
cryptogenic cirrhosis 7 alcoholic cirrhosis 2 other reasons 8
- Placebo group (n = 48)
Origins of liver diseases paracetamol intoxication 1 hepatitis B 0 autoimmune hepatitis
1 biliary atresia 3 metabolic diseases 11 neonatal hepatitis 0 PBC 7 post hepatitis
cirrhosis 5 PSC 7 cryptogenic cirrhosis 2 alcoholic cirrhosis 6 other reasons 5
Interventions UDCA group
- Dose 15 mgkg body weightday in two or three divided doses
- Route orally
- Duration immediately after intestinal transit recovery usually between postoperative
days three and five and continue for three months
Placebo group
- Identical-appearing capsules administered in the same quantity and manner
Co-interventions all patients received standard triple-drug regimens (steroids azathio-
prine and cyclosporine or tacrolimus)
24Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Keiding 1997 (Continued)
Outcomes All cause mortality
Number of deaths related to rejection
Number of patients with acute cellular rejection
Number of patients with chronic rejection
Number of patients with steroid-resistant rejection
Adverse events
Notes Letter was sent to the authors in September 2009 No reply was received
Risk of bias
Item Authorsrsquo judgement Description
Adequate sequence generation Unclear Patients were randomised at a ratio of 11
Allocation concealment Yes Quote ldquo The allocation was performed in
blocks of 10 patients using the sealed serial
envelope methodrdquo
Blinding Yes Quote ldquoThe UDCA and the placebo cap-
sules had identical appearance and tasterdquo
Incomplete outcome data addressed
All outcomes
Yes Follow-up time 12 months Five UDCA
patients and five placebo patients withdrew
from study Reasons were reported
Free of selective reporting Unclear Insufficient information
Sample size calculation Yes Performed and allowed for a difference in
the incidence of at least one episode of
acute rejection of 50 between the treat-
ment and placebo groups with 90 statisti-
cal power and a significance level of P value
less than 005 The calculated sample size
was 80 patients
Intention-to-treat analysis Yes Stated and used
Baseline imbalance Yes The study seems to be free of baseline im-
balance
Early stopping of trial Yes Study attained the pre-specified sample
size
25Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Koneru 1993
Methods Study design randomised controlled trial
Participants Country United States
Publication language English
Inclusion criteria
- patients who underwent liver transplantation
Exclusion criteria
- not mentioned
Participants
- UDCA group (n = 16)
Mean age (years +- SD)
no information
Ratio of sex (malefemale) no information
Origins of liver diseases
no information
- Control group (n = 16)
Mean age (years +- SD)
no information
Ratio of sex (malefemale) no information
Origins of liver diseases
no information
Interventions UDCA group
- Dose 900 mgday
- Route orally
- Duration immediately after intestinal transit recovery usually between postoperative
days three and five and continue for three months
Control group
- no treatment
Co-interventions all patients received standard triple-drug regimens (steroids azathio-
prine and cyclosporine)
Outcomes Number of patients with retransplantation due to rejection
Number of patients with rejection episodes
Notes Abstract
Letter was sent to the authors in September 2009 No reply was received
Risk of bias
Item Authorsrsquo judgement Description
Adequate sequence generation Unclear No information provided
Allocation concealment Unclear No information provided
Blinding No Not performed
26Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Koneru 1993 (Continued)
Incomplete outcome data addressed
All outcomes
Unclear The study gives the impression that there
were no withdrawals but this was not ex-
plicitly stated
Free of selective reporting Unclear Insufficient information provided
Sample size calculation No Not performed
Intention-to-treat analysis Unclear No information provided
Baseline imbalance Unclear Not enough information provided
Early stopping of trial Unclear Not enough information provided
Pageaux 1995
Methods Study design double-blind randomised study
Participants Country France
Publication language English
Inclusion criteria
- patients who underwent liver transplantation
Exclusion criteria
- not mentioned
Participants
- UDCA group (n=26)
Mean age (years +- SD)
47 +- 10
Ratio of sex (malefemale) 179
Origins of liver diseases alcoholic cirrhosis 14
post-hepatic B cirrhosis 2
post-hepatitis C cirrhosis 4
PBC 2
liver cancer 2
fulminant hepatitis 1
miscellaneous 1
- Placebo group (n = 24)
Mean age (years +- SD)
51+- 9
Ratio of sex (malefemale) 159
Origins of liver diseases alcoholic cirrhosis 10
post-hepatic B cirrhosis 0
post-hepatic C cirrhosis 6
PBC 3
liver cancer 4
fulminant hepatitis 0
miscellaneous 1
27Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Pageaux 1995 (Continued)
Interventions UDCA group
- Dose 600 mgday in three divided doses
- Route orally
- Duration immediately after intestinal transit recovery usually between postoperative
days three and five and continue for two months
Placebo group
- identical-appearing capsules administered in the same quantity and manner
Co-interventions all patients received standard triple-drug regimens (steroids azathio-
prine and cyclosporine or tacrolimus)
Outcomes Number of patients with acute cellular rejection
Number of patients with steroid-resistant rejection
Notes Letter was sent to the authors in September 2009 No reply was received
Risk of bias
Item Authorsrsquo judgement Description
Adequate sequence generation Unclear No information provided
Allocation concealment Unclear No information provided
Blinding Unclear Method of blinding not described
Incomplete outcome data addressed
All outcomes
Yes Five patients died from non-immunologi-
cal causes before the end of the first month
and were excluded from the study Reasons
were reported
Free of selective reporting Unclear Not enough information provided
Sample size calculation No Not performed
Intention-to-treat analysis No Not stated and not used
Baseline imbalance Unclear Not enough information provided
Early stopping of trial Unclear Not enough information provided
Sama 1991
Methods Study design randomised controlled trial
Participants Country Italy
Publication language English
Inclusion criteria
28Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Sama 1991 (Continued)
- patients who underwent liver transplantation
Exclusion criteria
- not mentioned
Participants
- UDCA group (n = 20)
Mean age (years +- SD)
no information
Ratio of sex (malefemale) no information
Origins of liver diseases
no information
- Control group (n = 20)
Mean age (years +- SD)
no information
Ratio of sex (malefemale) no information
Origins of liver diseases
no information
Interventions UDCA group
- Dose 600 mgday in two divided doses
- Route orally
- Duration immediately after intestinal transit recovery usually between postoperative
day five and day seven and continue for six months
Control group
- no treatment
Co-interventions all patients received standard immunosuppressive treatment (steroids
and cyclosporine)
Outcomes All cause mortality
Number of patients with acute cellular rejection
Notes Abstract
Letter was sent to the authors in September 2009 No reply was received
Risk of bias
Item Authorsrsquo judgement Description
Adequate sequence generation Unclear A randomisation list was performed before
patients were admitted to the trial (infor-
mation from principal author)
Allocation concealment Unclear No information provided
Blinding Unclear The principle author provided information
that the study was made according to a
single-blind randomised protocol The pri-
mary outcome was the occurrence of biopsy
proven rejection episodes The pathologists
were blind but the patients were not
29Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Sama 1991 (Continued)
Incomplete outcome data addressed
All outcomes
Unclear Five patients from the UDCA group and
six patients from the placebo group were
excluded Reasons for exclusion were not
fully stated
Free of selective reporting No Data about survival of patients were not
adequately reported
Sample size calculation No Not performed
Intention-to-treat analysis No Not stated and not used
Baseline imbalance Unclear Basic characteristics of patients not re-
ported
Early stopping of trial Unclear Not enough information provided
UDCA = ursodeoxycholic acid
TUDCA = tauroursodeoxycholic acid
PBC = primary biliary cirrhosis
PSC = primary sclerosing cholangitis
OKT3 = anti-CD3 monoclonal antibody
Characteristics of excluded studies [ordered by study ID]
Assy 2007 A randomised controlled trial that included only recipients of liver transplantation with stable graft function and
no episodes of rejection for at least 2 years that were then offered total immunosuppression withdrawal Fourteen
patients received UDCA (15 mgkg body weightday) and 12 received placebo Rejection occurred in 43 and
75 of patients respectively (no significant difference) None developed chronic rejection After follow-up two
patients were free of immunosuppression 80 were steroid free and 50 were able to reduce their dose of
cyclosporine
Clavien 1996 Case series Fifty consecutive liver-transplanted patients were treated with a standard cyclosporine immunosup-
pressive regimen Twenty three of the 43 survivors developed an episode of rejection and UDCA (10 mgkg
weightday) was initiated Only one patient had a second episode of rejection
Friman 1992 Observational study Thirty-three liver-transplanted patients received 10 mg UDCAkg body weightday for
median of 10 months (range four to 21 months) Eight historical liver-transplanted patients served as control
group The rejection incidence was significantly lower in the patients who received the treatment with UDCA
Biochemistry one month after transplantation demonstrated significantly lower average values of aminotrans-
ferases and alkaline phosphatases in patients treated with UDCA than in the control group
30Bile acids for liver-transplanted patients (Review)
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(Continued)
Heathcote 1999 Observational study From 1987 to 1996 37 UDCA treated and 53 placebo treated patients with primary biliary
cirrhosis were referred for transplantation Posttransplantation survival rates at one month were 939 in the
UDCA group and 884 in the placebo group and one year survival rates were 903 and 784 respectively
(no significant differences) However rejection (type not defined - a secondary outcome measure) occurred
significantly less often in the UDCA group (429) than in placebo group (688)
Henriksson 1991 Observational study All patients in this study were given sequential quadruple immunosuppression with anti-
lymphocyte globulin azathioprine steroids and cyclosporine All patients with primary graft function (n = 11)
were treated with 10 mg UDCAkg body weightday starting during the first postoperative week Patients who
received liver transplantation in the first 6 months of 1989 (n = 8) served as controls In the control group one
patient died after 9 months with chronic graft dysfunction and six patients had rejection episodes during the
first postoperative month All patients in the UDCA group were alive without rejection episodes
Persson 1990 Observational study All 11 adult patients transplanted between August 1989 and January 1990 with primary
graft function were treated with 10 mg UDCA kg body weightday Eight patients transplanted during the first
half of 1989 served as control UDCA was started during the first postoperative week and the treatment was
continued for six months All patients in the UDCA treated group survived with satisfactory graft function In
the control group six patients had at least one rejection episode needing treatment during the first postoperative
month
Rafael 1995 Observational study Seventeen patients who underwent liver transplantation between February 1990 and April
1993 and developed biliary complications after transplantation were retrospectively analysed regarding treatment
with UDCA UDCA was given in a dose of 500 to 1000 mgday Ten patients were treated for at least one year while
seven patients were treated for 14 to 250 days UDCA significantly improved gammaglutamyl transpeptidase in
liver graft recipients with biliary complications There was also a trend towards improvement in serum bilirubin
and alanine transaminase values
Sama 1998 Observational study Thirty-four patients who underwent liver transplantation between January 1995 and June
1996 were included in the study Seventeen were treated with UDCA 10 mgkg body weightday during 6
months while 17 served as controls on the basis of having undergone liver transplantation closest to UDCA
patients A significant decrease in serum bilirubin levels was observed in UDCA patients There was a significantly
higher incidence of recurrent hepatitis in the control group
UDCA ursodeoxycholic acid
31Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
D A T A A N D A N A L Y S E S
Comparison 1 Bile acids for liver-transplanted patients
Outcome or subgroup titleNo of
studies
No of
participants Statistical method Effect size
1 All-cause mortality at maximum
follow-up
5 257 Risk Ratio (M-H Fixed 95 CI) 085 [053 136]
11 UDCA versus placebo or
no treatment
4 224 Risk Ratio (M-H Fixed 95 CI) 080 [049 130]
12 TUDCA versus no
treatment
1 33 Risk Ratio (M-H Fixed 95 CI) 159 [030 833]
2 All-cause mortality worst-best
case and best-worst case
scenarios
5 Risk Ratio (M-H Fixed 95 CI) Subtotals only
21 Worst-best case scenario 5 257 Risk Ratio (M-H Fixed 95 CI) 130 [086 196]
22 Best-worst case scenario 5 257 Risk Ratio (M-H Fixed 95 CI) 058 [038 090]
3 Subgroup analyses all-cause
mortality at maximum
follow-up according to time of
start of bile acids
5 257 Risk Ratio (M-H Fixed 95 CI) 085 [053 136]
31 Less than three days after
transplantation
1 102 Risk Ratio (M-H Fixed 95 CI) 124 [061 254]
32 Three days or more after
transplantation
4 155 Risk Ratio (M-H Fixed 95 CI) 063 [033 120]
4 Subgroup analyses all cause
mortality at maximum
follow-up according to
treatment duration
5 257 Risk Ratio (M-H Fixed 95 CI) 085 [053 136]
41 Less than six months 3 184 Risk Ratio (M-H Fixed 95 CI) 078 [045 138]
42 Six months or more 2 73 Risk Ratio (M-H Fixed 95 CI) 102 [043 240]
5 Number of deaths related
to rejection at maximum
follow-up
1 102 Risk Ratio (M-H Fixed 95 CI) 030 [001 712]
51 UDCA versus placebo 1 102 Risk Ratio (M-H Fixed 95 CI) 030 [001 712]
6 Number of retransplantations at
maximum follow-up
2 132 Risk Ratio (M-H Fixed 95 CI) 076 [020 286]
7 Number of patients with acute
cellular rejection at maximum
follow-up
7 339 Risk Ratio (M-H Fixed 95 CI) 089 [074 106]
71 UDCA versus placebo or
no treatment
6 306 Risk Ratio (M-H Fixed 95 CI) 089 [074 108]
72 TUDCA versus no
treatment
1 33 Risk Ratio (M-H Fixed 95 CI) 085 [045 160]
8 Subgroup analysis number of
patients with acute cellular
rejection according to time of
start of bile acid
7 339 Risk Ratio (M-H Fixed 95 CI) 089 [074 106]
32Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
81 Less than three days after
transplantation
2 134 Risk Ratio (M-H Fixed 95 CI) 084 [063 111]
82 Three days or more after
liver transplantation
5 205 Risk Ratio (M-H Fixed 95 CI) 092 [072 117]
9 Subgroup analysis number
of patients with acute
cellular rejection according to
treatment duration
7 339 Risk Ratio (M-H Fixed 95 CI) 089 [074 106]
91 Less than six months 5 266 Risk Ratio (M-H Fixed 95 CI) 087 [071 107]
92 Six months or more 2 73 Risk Ratio (M-H Fixed 95 CI) 094 [065 136]
10 Number of patients with
chronic rejection at maximum
follow-up
3 184 Risk Ratio (M-H Fixed 95 CI) 028 [008 095]
11 Number of patients with
steroid-resistant rejection at
maximum follow-up
4 234 Risk Ratio (M-H Fixed 95 CI) 077 [047 127]
12 Serum bilirubin (mgdl) at the
end of treatment
1 30 Mean Difference (IV Fixed 95 CI) 26 [-096 616]
13 Number of days of
hospitalisation after liver
transplantation
1 52 Mean Difference (IV Fixed 95 CI) -85 [-1667 -033]
14 Adverse events 3 187 Risk Ratio (M-H Fixed 95 CI) 088 [030 260]
Analysis 11 Comparison 1 Bile acids for liver-transplanted patients Outcome 1 All-cause mortality at
maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 1 All-cause mortality at maximum follow-up
Study or subgroup Favours bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 UDCA versus placebo or no treatment
Barnes 1997 228 724 253 024 [ 006 107 ]
Fleckenstein 1998 214 416 125 057 [ 012 266 ]
Keiding 1997 1454 1048 355 124 [ 061 254 ]
Sama 1991 520 620 201 083 [ 030 229 ]
Subtotal (95 CI) 116 108 935 080 [ 049 130 ]
Total events 23 (Favours bile acids) 27 (Control)
Heterogeneity Chi2 = 416 df = 3 (P = 025) I2 =28
Test for overall effect Z = 091 (P = 036)
01 02 05 1 2 5 10
Favours bile acids Favours control
(Continued )
33Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Favours bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
2 TUDCA versus no treatment
Angelico 1999 316 217 65 159 [ 030 833 ]
Subtotal (95 CI) 16 17 65 159 [ 030 833 ]
Total events 3 (Favours bile acids) 2 (Control)
Heterogeneity not applicable
Test for overall effect Z = 055 (P = 058)
Total (95 CI) 132 125 1000 085 [ 053 136 ]
Total events 26 (Favours bile acids) 29 (Control)
Heterogeneity Chi2 = 466 df = 4 (P = 032) I2 =14
Test for overall effect Z = 069 (P = 049)
01 02 05 1 2 5 10
Favours bile acids Favours control
Analysis 12 Comparison 1 Bile acids for liver-transplanted patients Outcome 2 All-cause mortality worst-
best case and best-worst case scenarios
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 2 All-cause mortality worst-best case and best-worst case scenarios
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 Worst-best case scenario
Angelico 1999 516 217 65 266 [ 060 1180 ]
Barnes 1997 828 724 253 098 [ 042 230 ]
Fleckenstein 1998 314 416 125 086 [ 023 319 ]
Keiding 1997 1954 1048 355 169 [ 087 327 ]
Sama 1991 520 620 201 083 [ 030 229 ]
Subtotal (95 CI) 132 125 1000 130 [ 086 196 ]
Total events 40 (Bile acids) 29 (Control)
Heterogeneity Chi2 = 303 df = 4 (P = 055) I2 =00
Test for overall effect Z = 123 (P = 022)
2 Best-worst case scenario
005 02 1 5 20
Favours bile acids Favours control
(Continued )
34Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Angelico 1999 316 417 90 080 [ 021 302 ]
Barnes 1997 228 1124 274 016 [ 004 063 ]
Fleckenstein 1998 214 616 130 038 [ 009 159 ]
Keiding 1997 1454 1548 368 083 [ 045 154 ]
Sama 1991 520 620 139 083 [ 030 229 ]
Subtotal (95 CI) 132 125 1000 058 [ 038 090 ]
Total events 26 (Bile acids) 42 (Control)
Heterogeneity Chi2 = 567 df = 4 (P = 023) I2 =29
Test for overall effect Z = 247 (P = 0014)
005 02 1 5 20
Favours bile acids Favours control
Analysis 13 Comparison 1 Bile acids for liver-transplanted patients Outcome 3 Subgroup analyses all-
cause mortality at maximum follow-up according to time of start of bile acids
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 3 Subgroup analyses all-cause mortality at maximum follow-up according to time of start of bile acids
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 Less than three days after transplantation
Keiding 1997 1454 1048 355 124 [ 061 254 ]
Subtotal (95 CI) 54 48 355 124 [ 061 254 ]
Total events 14 (Bile acids) 10 (Control)
Heterogeneity not applicable
Test for overall effect Z = 060 (P = 055)
2 Three days or more after transplantation
Angelico 1999 316 217 65 159 [ 030 833 ]
Barnes 1997 228 724 253 024 [ 006 107 ]
Fleckenstein 1998 214 416 125 057 [ 012 266 ]
Sama 1991 520 620 201 083 [ 030 229 ]
005 02 1 5 20
Favours bile acids Favours control
(Continued )
35Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Subtotal (95 CI) 78 77 645 063 [ 033 120 ]
Total events 12 (Bile acids) 19 (Control)
Heterogeneity Chi2 = 310 df = 3 (P = 038) I2 =3
Test for overall effect Z = 141 (P = 016)
Total (95 CI) 132 125 1000 085 [ 053 136 ]
Total events 26 (Bile acids) 29 (Control)
Heterogeneity Chi2 = 466 df = 4 (P = 032) I2 =14
Test for overall effect Z = 069 (P = 049)
005 02 1 5 20
Favours bile acids Favours control
Analysis 14 Comparison 1 Bile acids for liver-transplanted patients Outcome 4 Subgroup analyses all
cause mortality at maximum follow-up according to treatment duration
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 4 Subgroup analyses all cause mortality at maximum follow-up according to treatment duration
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 Less than six months
Barnes 1997 228 724 253 024 [ 006 107 ]
Fleckenstein 1998 214 416 125 057 [ 012 266 ]
Keiding 1997 1454 1048 355 124 [ 061 254 ]
Subtotal (95 CI) 96 88 734 078 [ 045 138 ]
Total events 18 (Bile acids) 21 (Control)
Heterogeneity Chi2 = 417 df = 2 (P = 012) I2 =52
Test for overall effect Z = 084 (P = 040)
2 Six months or more
Angelico 1999 316 217 65 159 [ 030 833 ]
Sama 1991 520 620 201 083 [ 030 229 ]
Subtotal (95 CI) 36 37 266 102 [ 043 240 ]
Total events 8 (Bile acids) 8 (Control)
Heterogeneity Chi2 = 043 df = 1 (P = 051) I2 =00
005 02 1 5 20
Favours bile acids Favours control
(Continued )
36Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Test for overall effect Z = 004 (P = 097)
Total (95 CI) 132 125 1000 085 [ 053 136 ]
Total events 26 (Bile acids) 29 (Control)
Heterogeneity Chi2 = 466 df = 4 (P = 032) I2 =14
Test for overall effect Z = 069 (P = 049)
005 02 1 5 20
Favours bile acids Favours control
Analysis 15 Comparison 1 Bile acids for liver-transplanted patients Outcome 5 Number of deaths related
to rejection at maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 5 Number of deaths related to rejection at maximum follow-up
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 UDCA versus placebo
Keiding 1997 054 148 1000 030 [ 001 712 ]
Total (95 CI) 54 48 1000 030 [ 001 712 ]
Total events 0 (Bile acids) 1 (Control)
Heterogeneity not applicable
Test for overall effect Z = 075 (P = 045)
0001 001 01 1 10 100 1000
Favours bile acids Favours control
37Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 16 Comparison 1 Bile acids for liver-transplanted patients Outcome 6 Number of
retransplantations at maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 6 Number of retransplantations at maximum follow-up
Study or subgroup Bile acids Placebo Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Fleckenstein 1998 214 016 100 567 [ 029 10891 ]
Keiding 1997 154 448 900 022 [ 003 192 ]
Total (95 CI) 68 64 1000 076 [ 020 286 ]
Total events 3 (Bile acids) 4 (Placebo)
Heterogeneity Chi2 = 303 df = 1 (P = 008) I2 =67
Test for overall effect Z = 040 (P = 069)
0001 001 01 1 10 100 1000
Favours bile acids Favours placebo
Analysis 17 Comparison 1 Bile acids for liver-transplanted patients Outcome 7 Number of patients with
acute cellular rejection at maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 7 Number of patients with acute cellular rejection at maximum follow-up
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 UDCA versus placebo or no treatment
Barnes 1997 1728 1724 180 086 [ 058 127 ]
Fleckenstein 1998 814 916 83 102 [ 054 190 ]
Keiding 1997 3554 3248 333 097 [ 073 129 ]
Koneru 1993 316 916 89 033 [ 011 101 ]
Pageaux 1995 926 924 92 092 [ 044 193 ]
Sama 1991 1320 1320 128 100 [ 063 158 ]
Subtotal (95 CI) 158 148 905 089 [ 074 108 ]
01 02 05 1 2 5 10
Favours bile acids Favours control
(Continued )
38Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Total events 85 (Bile acids) 89 (Control)
Heterogeneity Chi2 = 387 df = 5 (P = 057) I2 =00
Test for overall effect Z = 120 (P = 023)
2 TUDCA versus no treatment
Angelico 1999 816 1017 95 085 [ 045 160 ]
Subtotal (95 CI) 16 17 95 085 [ 045 160 ]
Total events 8 (Bile acids) 10 (Control)
Heterogeneity not applicable
Test for overall effect Z = 050 (P = 061)
Total (95 CI) 174 165 1000 089 [ 074 106 ]
Total events 93 (Bile acids) 99 (Control)
Heterogeneity Chi2 = 392 df = 6 (P = 069) I2 =00
Test for overall effect Z = 130 (P = 019)
01 02 05 1 2 5 10
Favours bile acids Favours control
Analysis 18 Comparison 1 Bile acids for liver-transplanted patients Outcome 8 Subgroup analysis
number of patients with acute cellular rejection according to time of start of bile acid
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 8 Subgroup analysis number of patients with acute cellular rejection according to time of start of bile acid
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 Less than three days after transplantation
Keiding 1997 3554 3248 333 097 [ 073 129 ]
Koneru 1993 316 916 89 033 [ 011 101 ]
Subtotal (95 CI) 70 64 422 084 [ 063 111 ]
Total events 38 (Bile acids) 41 (Control)
Heterogeneity Chi2 = 374 df = 1 (P = 005) I2 =73
Test for overall effect Z = 124 (P = 022)
2 Three days or more after liver transplantation
Angelico 1999 816 1017 95 085 [ 045 160 ]
01 02 05 1 2 5 10
Favours bile acids Favours control
(Continued )
39Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Barnes 1997 1728 1724 180 086 [ 058 127 ]
Fleckenstein 1998 814 916 83 102 [ 054 190 ]
Pageaux 1995 926 924 92 092 [ 044 193 ]
Sama 1991 1320 1320 128 100 [ 063 158 ]
Subtotal (95 CI) 104 101 578 092 [ 072 117 ]
Total events 55 (Bile acids) 58 (Control)
Heterogeneity Chi2 = 041 df = 4 (P = 098) I2 =00
Test for overall effect Z = 067 (P = 050)
Total (95 CI) 174 165 1000 089 [ 074 106 ]
Total events 93 (Bile acids) 99 (Control)
Heterogeneity Chi2 = 392 df = 6 (P = 069) I2 =00
Test for overall effect Z = 130 (P = 019)
01 02 05 1 2 5 10
Favours bile acids Favours control
40Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 19 Comparison 1 Bile acids for liver-transplanted patients Outcome 9 Subgroup analysis
number of patients with acute cellular rejection according to treatment duration
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 9 Subgroup analysis number of patients with acute cellular rejection according to treatment duration
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 Less than six months
Barnes 1997 1728 1724 180 086 [ 058 127 ]
Fleckenstein 1998 814 916 83 102 [ 054 190 ]
Keiding 1997 3554 3248 333 097 [ 073 129 ]
Koneru 1993 316 916 89 033 [ 011 101 ]
Pageaux 1995 926 924 92 092 [ 044 193 ]
Subtotal (95 CI) 138 128 777 087 [ 071 107 ]
Total events 72 (Bile acids) 76 (Control)
Heterogeneity Chi2 = 374 df = 4 (P = 044) I2 =00
Test for overall effect Z = 129 (P = 020)
2 Six months or more
Angelico 1999 816 1017 95 085 [ 045 160 ]
Sama 1991 1320 1320 128 100 [ 063 158 ]
Subtotal (95 CI) 36 37 223 094 [ 065 136 ]
Total events 21 (Bile acids) 23 (Control)
Heterogeneity Chi2 = 017 df = 1 (P = 068) I2 =00
Test for overall effect Z = 035 (P = 073)
Total (95 CI) 174 165 1000 089 [ 074 106 ]
Total events 93 (Bile acids) 99 (Control)
Heterogeneity Chi2 = 392 df = 6 (P = 069) I2 =00
Test for overall effect Z = 130 (P = 019)
01 02 05 1 2 5 10
Favours bile acids Favours control
41Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 110 Comparison 1 Bile acids for liver-transplanted patients Outcome 10 Number of patients
with chronic rejection at maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 10 Number of patients with chronic rejection at maximum follow-up
Study or subgroup Bile acids Placebo Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Barnes 1997 128 624 611 014 [ 002 110 ]
Fleckenstein 1998 114 116 88 114 [ 008 1663 ]
Keiding 1997 154 348 300 030 [ 003 275 ]
Total (95 CI) 96 88 1000 028 [ 008 095 ]
Total events 3 (Bile acids) 10 (Placebo)
Heterogeneity Chi2 = 148 df = 2 (P = 048) I2 =00
Test for overall effect Z = 204 (P = 0041)
0001 001 01 1 10 100 1000
Favours bile acids Favours placebo
Analysis 111 Comparison 1 Bile acids for liver-transplanted patients Outcome 11 Number of patients
with steroid-resistant rejection at maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 11 Number of patients with steroid-resistant rejection at maximum follow-up
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Barnes 1997 328 724 277 037 [ 011 127 ]
Fleckenstein 1998 314 316 103 114 [ 027 478 ]
Keiding 1997 1454 1548 583 083 [ 045 154 ]
Pageaux 1995 226 124 38 185 [ 018 1908 ]
Total (95 CI) 122 112 1000 077 [ 047 127 ]
Total events 22 (Bile acids) 26 (Control)
Heterogeneity Chi2 = 226 df = 3 (P = 052) I2 =00
Test for overall effect Z = 102 (P = 031)
001 01 1 10 100
Favours bile acids Favours placebo
42Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 112 Comparison 1 Bile acids for liver-transplanted patients Outcome 12 Serum bilirubin (mgdl)
at the end of treatment
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 12 Serum bilirubin (mgdl) at the end of treatment
Study or subgroup Bile acids Placebo Mean Difference Weight Mean Difference
N Mean(SD) N Mean(SD) IVFixed95 CI IVFixed95 CI
Fleckenstein 1998 14 319 (68) 16 059 (022) 1000 260 [ -096 616 ]
Total (95 CI) 14 16 1000 260 [ -096 616 ]
Heterogeneity not applicable
Test for overall effect Z = 143 (P = 015)
-10 -5 0 5 10
Favours bile acids Favours placebo
Analysis 113 Comparison 1 Bile acids for liver-transplanted patients Outcome 13 Number of days of
hospitalisation after liver transplantation
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 13 Number of days of hospitalisation after liver transplantation
Study or subgroup Bile acids Placebo Mean Difference Weight Mean Difference
N Mean(SD) N Mean(SD) IVFixed95 CI IVFixed95 CI
Barnes 1997 28 25 (17) 24 335 (13) 1000 -850 [ -1667 -033 ]
Total (95 CI) 28 24 1000 -850 [ -1667 -033 ]
Heterogeneity not applicable
Test for overall effect Z = 204 (P = 0041)
-100 -50 0 50 100
Favours bile acids Favours placebo
43Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 114 Comparison 1 Bile acids for liver-transplanted patients Outcome 14 Adverse events
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 14 Adverse events
Study or subgroup Bile acids Placebo Risk Ratio Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Angelico 1999 016 017 00 [ 00 00 ]
Barnes 1997 128 124 086 [ 006 1298 ]
Keiding 1997 554 548 089 [ 027 288 ]
Total (95 CI) 98 89 088 [ 030 260 ]
Total events 6 (Bile acids) 6 (Placebo)
Heterogeneity Chi2 = 000 df = 1 (P = 098) I2 =00
Test for overall effect Z = 022 (P = 082)
001 01 1 10 100
Favours bile acids Favours placebo
A P P E N D I C E S
Appendix 1 Search strategies
Data Base Date of Search Search Strategy
The Cochrane Hepato-Biliary Group Con-
trolled Trials Register
September 2009 1 rsquoliver transplantationrsquo and rsquochenodeoxy-
cholicrsquo
2 rsquoliver transplantationrsquo and rsquocholicrsquo
3 rsquoliver transplantationrsquo and rsquodeoxycholicrsquo
4 rsquoliver transplantationrsquo and rsquoglycochen-
odeoxycholicrsquo
5 rsquoliver transplantationrsquo and rsquoglycocholicrsquo
6 rsquoliver transplantationrsquo and rsquoglycodeoxy-
cholicrsquo
7 rsquoliver transplantationrsquo and rsquoglycolitho-
cholicrsquo
8 rsquoliver transplantationrsquo and rsquohyodeoxy-
cholicrsquo
9 rsquoliver transplantationrsquo and rsquolithocholicrsquo
10 rsquoliver transplantationrsquo and rsquotaurochen-
odeoxycholicrsquo
44Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
11 rsquoliver transplantationrsquo and rsquotauro-
cholicrsquo
12 rsquoliver transplantationrsquo and rsquotaurodehy-
drocholicrsquo
13 rsquoliver transplantationrsquo and rsquotau-
rodeoxycholicrsquo
14 rsquoliver transplantationrsquo and rsquotauroglyco-
cholicrsquo
15 rsquoliver transplantationrsquo and rsquotaurolitho-
cholicrsquo
16 rsquoliver transplantationrsquo and rsquotaurosel-
cholicrsquo
17 rsquoliver transplantationrsquo and rsquotaurourso-
cholicrsquo
18 rsquoliver transplantationrsquo and rsquotaurour-
sodeoxycholicrsquo
19 rsquoliver transplantationrsquo and rsquoursocholicrsquo
20 rsquoliver transplantationrsquo and rsquoursodeoxy-
cholicrsquo
The Cochrane Central Register of Con-
trolled Trials in The Cochrane Library
Issue 3 2009 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
6 3 or 4
7 5 and 6
MEDLINE September 2009 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
45Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
6 3 or 4
7 5 and 6
8 RANDOMIZED-CONTROLLED-
TRIAL ME
9 RANDOM
10 8 or 9
11 7 and 10
EMBASE September 2009 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
6 3 or 4
7 5 and 6
8 RANDOMIZED-CONTROLLED-
TRIAL ME
9 RANDOM
10 8 or 9
11 7 and 10
46Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
Science Citation Index Expanded September 2009 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
6 3 or 4
7 5 and 6
8 RANDOMIZED-CONTROLLED-
TRIAL ME
9 RANDOM
10 8 or 9
11 7 and 10
The Chinese Biomedical Database Searched from January 1980 to April 2002 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
47Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
6 3 or 4
7 5 and 6
8 RANDOMIZED-CONTROLLED-
TRIAL ME
9 RANDOM
10 8 or 9
11 7 and 10
W H A T rsquo S N E W
Last assessed as up-to-date 8 February 2010
18 September 2009 New citation required but conclusions have not
changed
This review is an updated version of a review that was
published for the first time in Issue 3 2005 of TheCochrane Library by Chen 2003b
18 September 2009 New search has been performed No new studies fulfilled the inclusion criteria
H I S T O R Y
Protocol first published Issue 3 2003
Review first published Issue 3 2005
C O N T R I B U T I O N S O F A U T H O R S
GP and VG independently performed searches of relevant databases GP validated the search selected trials for inclusion contacted
the authors of the trials performed data extraction and data analysis and drafted the systematic review VG revised the review update
CG and DS revised the review update solved discrepancies of data extraction validated data analyses and provided consultation
D E C L A R A T I O N S O F I N T E R E S T
None known
48Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
S O U R C E S O F S U P P O R T
Internal sources
bull Copenhagen Trial Unit Denmark
External sources
bull Danish Medical Research Councilrsquos Grant on Getting Research into Practice (GRIP) Denmark
D I F F E R E N C E S B E T W E E N P R O T O C O L A N D R E V I E W
We assessed the risk of bias in the included studies for another four domains that were added to the review protocol (incomplete
outcome data selective outcome reporting baseline imbalance and early stopping of trial) In general the text of the risk of bias
domains were updated following Higgins 2008 Trials were considered at low risk of bias when judged as adequate in all domains
Quasi-randomised studies observational and case-control studies were included for the report of adverse events
We performed trial sequential analysis for outcomes demonstrating a statistically significant result
I N D E X T E R M S
Medical Subject Headings (MeSH)
lowastLiver Transplantation Cholagogues and Choleretics [lowasttherapeutic use] Graft Rejection [lowastprevention amp control] Randomized Con-
trolled Trials as Topic Taurochenodeoxycholic Acid [lowasttherapeutic use] Ursodeoxycholic Acid [lowasttherapeutic use]
MeSH check words
Humans
49Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Keiding 1997 (Continued)
Outcomes All cause mortality
Number of deaths related to rejection
Number of patients with acute cellular rejection
Number of patients with chronic rejection
Number of patients with steroid-resistant rejection
Adverse events
Notes Letter was sent to the authors in September 2009 No reply was received
Risk of bias
Item Authorsrsquo judgement Description
Adequate sequence generation Unclear Patients were randomised at a ratio of 11
Allocation concealment Yes Quote ldquo The allocation was performed in
blocks of 10 patients using the sealed serial
envelope methodrdquo
Blinding Yes Quote ldquoThe UDCA and the placebo cap-
sules had identical appearance and tasterdquo
Incomplete outcome data addressed
All outcomes
Yes Follow-up time 12 months Five UDCA
patients and five placebo patients withdrew
from study Reasons were reported
Free of selective reporting Unclear Insufficient information
Sample size calculation Yes Performed and allowed for a difference in
the incidence of at least one episode of
acute rejection of 50 between the treat-
ment and placebo groups with 90 statisti-
cal power and a significance level of P value
less than 005 The calculated sample size
was 80 patients
Intention-to-treat analysis Yes Stated and used
Baseline imbalance Yes The study seems to be free of baseline im-
balance
Early stopping of trial Yes Study attained the pre-specified sample
size
25Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Koneru 1993
Methods Study design randomised controlled trial
Participants Country United States
Publication language English
Inclusion criteria
- patients who underwent liver transplantation
Exclusion criteria
- not mentioned
Participants
- UDCA group (n = 16)
Mean age (years +- SD)
no information
Ratio of sex (malefemale) no information
Origins of liver diseases
no information
- Control group (n = 16)
Mean age (years +- SD)
no information
Ratio of sex (malefemale) no information
Origins of liver diseases
no information
Interventions UDCA group
- Dose 900 mgday
- Route orally
- Duration immediately after intestinal transit recovery usually between postoperative
days three and five and continue for three months
Control group
- no treatment
Co-interventions all patients received standard triple-drug regimens (steroids azathio-
prine and cyclosporine)
Outcomes Number of patients with retransplantation due to rejection
Number of patients with rejection episodes
Notes Abstract
Letter was sent to the authors in September 2009 No reply was received
Risk of bias
Item Authorsrsquo judgement Description
Adequate sequence generation Unclear No information provided
Allocation concealment Unclear No information provided
Blinding No Not performed
26Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Koneru 1993 (Continued)
Incomplete outcome data addressed
All outcomes
Unclear The study gives the impression that there
were no withdrawals but this was not ex-
plicitly stated
Free of selective reporting Unclear Insufficient information provided
Sample size calculation No Not performed
Intention-to-treat analysis Unclear No information provided
Baseline imbalance Unclear Not enough information provided
Early stopping of trial Unclear Not enough information provided
Pageaux 1995
Methods Study design double-blind randomised study
Participants Country France
Publication language English
Inclusion criteria
- patients who underwent liver transplantation
Exclusion criteria
- not mentioned
Participants
- UDCA group (n=26)
Mean age (years +- SD)
47 +- 10
Ratio of sex (malefemale) 179
Origins of liver diseases alcoholic cirrhosis 14
post-hepatic B cirrhosis 2
post-hepatitis C cirrhosis 4
PBC 2
liver cancer 2
fulminant hepatitis 1
miscellaneous 1
- Placebo group (n = 24)
Mean age (years +- SD)
51+- 9
Ratio of sex (malefemale) 159
Origins of liver diseases alcoholic cirrhosis 10
post-hepatic B cirrhosis 0
post-hepatic C cirrhosis 6
PBC 3
liver cancer 4
fulminant hepatitis 0
miscellaneous 1
27Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Pageaux 1995 (Continued)
Interventions UDCA group
- Dose 600 mgday in three divided doses
- Route orally
- Duration immediately after intestinal transit recovery usually between postoperative
days three and five and continue for two months
Placebo group
- identical-appearing capsules administered in the same quantity and manner
Co-interventions all patients received standard triple-drug regimens (steroids azathio-
prine and cyclosporine or tacrolimus)
Outcomes Number of patients with acute cellular rejection
Number of patients with steroid-resistant rejection
Notes Letter was sent to the authors in September 2009 No reply was received
Risk of bias
Item Authorsrsquo judgement Description
Adequate sequence generation Unclear No information provided
Allocation concealment Unclear No information provided
Blinding Unclear Method of blinding not described
Incomplete outcome data addressed
All outcomes
Yes Five patients died from non-immunologi-
cal causes before the end of the first month
and were excluded from the study Reasons
were reported
Free of selective reporting Unclear Not enough information provided
Sample size calculation No Not performed
Intention-to-treat analysis No Not stated and not used
Baseline imbalance Unclear Not enough information provided
Early stopping of trial Unclear Not enough information provided
Sama 1991
Methods Study design randomised controlled trial
Participants Country Italy
Publication language English
Inclusion criteria
28Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Sama 1991 (Continued)
- patients who underwent liver transplantation
Exclusion criteria
- not mentioned
Participants
- UDCA group (n = 20)
Mean age (years +- SD)
no information
Ratio of sex (malefemale) no information
Origins of liver diseases
no information
- Control group (n = 20)
Mean age (years +- SD)
no information
Ratio of sex (malefemale) no information
Origins of liver diseases
no information
Interventions UDCA group
- Dose 600 mgday in two divided doses
- Route orally
- Duration immediately after intestinal transit recovery usually between postoperative
day five and day seven and continue for six months
Control group
- no treatment
Co-interventions all patients received standard immunosuppressive treatment (steroids
and cyclosporine)
Outcomes All cause mortality
Number of patients with acute cellular rejection
Notes Abstract
Letter was sent to the authors in September 2009 No reply was received
Risk of bias
Item Authorsrsquo judgement Description
Adequate sequence generation Unclear A randomisation list was performed before
patients were admitted to the trial (infor-
mation from principal author)
Allocation concealment Unclear No information provided
Blinding Unclear The principle author provided information
that the study was made according to a
single-blind randomised protocol The pri-
mary outcome was the occurrence of biopsy
proven rejection episodes The pathologists
were blind but the patients were not
29Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Sama 1991 (Continued)
Incomplete outcome data addressed
All outcomes
Unclear Five patients from the UDCA group and
six patients from the placebo group were
excluded Reasons for exclusion were not
fully stated
Free of selective reporting No Data about survival of patients were not
adequately reported
Sample size calculation No Not performed
Intention-to-treat analysis No Not stated and not used
Baseline imbalance Unclear Basic characteristics of patients not re-
ported
Early stopping of trial Unclear Not enough information provided
UDCA = ursodeoxycholic acid
TUDCA = tauroursodeoxycholic acid
PBC = primary biliary cirrhosis
PSC = primary sclerosing cholangitis
OKT3 = anti-CD3 monoclonal antibody
Characteristics of excluded studies [ordered by study ID]
Assy 2007 A randomised controlled trial that included only recipients of liver transplantation with stable graft function and
no episodes of rejection for at least 2 years that were then offered total immunosuppression withdrawal Fourteen
patients received UDCA (15 mgkg body weightday) and 12 received placebo Rejection occurred in 43 and
75 of patients respectively (no significant difference) None developed chronic rejection After follow-up two
patients were free of immunosuppression 80 were steroid free and 50 were able to reduce their dose of
cyclosporine
Clavien 1996 Case series Fifty consecutive liver-transplanted patients were treated with a standard cyclosporine immunosup-
pressive regimen Twenty three of the 43 survivors developed an episode of rejection and UDCA (10 mgkg
weightday) was initiated Only one patient had a second episode of rejection
Friman 1992 Observational study Thirty-three liver-transplanted patients received 10 mg UDCAkg body weightday for
median of 10 months (range four to 21 months) Eight historical liver-transplanted patients served as control
group The rejection incidence was significantly lower in the patients who received the treatment with UDCA
Biochemistry one month after transplantation demonstrated significantly lower average values of aminotrans-
ferases and alkaline phosphatases in patients treated with UDCA than in the control group
30Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
Heathcote 1999 Observational study From 1987 to 1996 37 UDCA treated and 53 placebo treated patients with primary biliary
cirrhosis were referred for transplantation Posttransplantation survival rates at one month were 939 in the
UDCA group and 884 in the placebo group and one year survival rates were 903 and 784 respectively
(no significant differences) However rejection (type not defined - a secondary outcome measure) occurred
significantly less often in the UDCA group (429) than in placebo group (688)
Henriksson 1991 Observational study All patients in this study were given sequential quadruple immunosuppression with anti-
lymphocyte globulin azathioprine steroids and cyclosporine All patients with primary graft function (n = 11)
were treated with 10 mg UDCAkg body weightday starting during the first postoperative week Patients who
received liver transplantation in the first 6 months of 1989 (n = 8) served as controls In the control group one
patient died after 9 months with chronic graft dysfunction and six patients had rejection episodes during the
first postoperative month All patients in the UDCA group were alive without rejection episodes
Persson 1990 Observational study All 11 adult patients transplanted between August 1989 and January 1990 with primary
graft function were treated with 10 mg UDCA kg body weightday Eight patients transplanted during the first
half of 1989 served as control UDCA was started during the first postoperative week and the treatment was
continued for six months All patients in the UDCA treated group survived with satisfactory graft function In
the control group six patients had at least one rejection episode needing treatment during the first postoperative
month
Rafael 1995 Observational study Seventeen patients who underwent liver transplantation between February 1990 and April
1993 and developed biliary complications after transplantation were retrospectively analysed regarding treatment
with UDCA UDCA was given in a dose of 500 to 1000 mgday Ten patients were treated for at least one year while
seven patients were treated for 14 to 250 days UDCA significantly improved gammaglutamyl transpeptidase in
liver graft recipients with biliary complications There was also a trend towards improvement in serum bilirubin
and alanine transaminase values
Sama 1998 Observational study Thirty-four patients who underwent liver transplantation between January 1995 and June
1996 were included in the study Seventeen were treated with UDCA 10 mgkg body weightday during 6
months while 17 served as controls on the basis of having undergone liver transplantation closest to UDCA
patients A significant decrease in serum bilirubin levels was observed in UDCA patients There was a significantly
higher incidence of recurrent hepatitis in the control group
UDCA ursodeoxycholic acid
31Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
D A T A A N D A N A L Y S E S
Comparison 1 Bile acids for liver-transplanted patients
Outcome or subgroup titleNo of
studies
No of
participants Statistical method Effect size
1 All-cause mortality at maximum
follow-up
5 257 Risk Ratio (M-H Fixed 95 CI) 085 [053 136]
11 UDCA versus placebo or
no treatment
4 224 Risk Ratio (M-H Fixed 95 CI) 080 [049 130]
12 TUDCA versus no
treatment
1 33 Risk Ratio (M-H Fixed 95 CI) 159 [030 833]
2 All-cause mortality worst-best
case and best-worst case
scenarios
5 Risk Ratio (M-H Fixed 95 CI) Subtotals only
21 Worst-best case scenario 5 257 Risk Ratio (M-H Fixed 95 CI) 130 [086 196]
22 Best-worst case scenario 5 257 Risk Ratio (M-H Fixed 95 CI) 058 [038 090]
3 Subgroup analyses all-cause
mortality at maximum
follow-up according to time of
start of bile acids
5 257 Risk Ratio (M-H Fixed 95 CI) 085 [053 136]
31 Less than three days after
transplantation
1 102 Risk Ratio (M-H Fixed 95 CI) 124 [061 254]
32 Three days or more after
transplantation
4 155 Risk Ratio (M-H Fixed 95 CI) 063 [033 120]
4 Subgroup analyses all cause
mortality at maximum
follow-up according to
treatment duration
5 257 Risk Ratio (M-H Fixed 95 CI) 085 [053 136]
41 Less than six months 3 184 Risk Ratio (M-H Fixed 95 CI) 078 [045 138]
42 Six months or more 2 73 Risk Ratio (M-H Fixed 95 CI) 102 [043 240]
5 Number of deaths related
to rejection at maximum
follow-up
1 102 Risk Ratio (M-H Fixed 95 CI) 030 [001 712]
51 UDCA versus placebo 1 102 Risk Ratio (M-H Fixed 95 CI) 030 [001 712]
6 Number of retransplantations at
maximum follow-up
2 132 Risk Ratio (M-H Fixed 95 CI) 076 [020 286]
7 Number of patients with acute
cellular rejection at maximum
follow-up
7 339 Risk Ratio (M-H Fixed 95 CI) 089 [074 106]
71 UDCA versus placebo or
no treatment
6 306 Risk Ratio (M-H Fixed 95 CI) 089 [074 108]
72 TUDCA versus no
treatment
1 33 Risk Ratio (M-H Fixed 95 CI) 085 [045 160]
8 Subgroup analysis number of
patients with acute cellular
rejection according to time of
start of bile acid
7 339 Risk Ratio (M-H Fixed 95 CI) 089 [074 106]
32Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
81 Less than three days after
transplantation
2 134 Risk Ratio (M-H Fixed 95 CI) 084 [063 111]
82 Three days or more after
liver transplantation
5 205 Risk Ratio (M-H Fixed 95 CI) 092 [072 117]
9 Subgroup analysis number
of patients with acute
cellular rejection according to
treatment duration
7 339 Risk Ratio (M-H Fixed 95 CI) 089 [074 106]
91 Less than six months 5 266 Risk Ratio (M-H Fixed 95 CI) 087 [071 107]
92 Six months or more 2 73 Risk Ratio (M-H Fixed 95 CI) 094 [065 136]
10 Number of patients with
chronic rejection at maximum
follow-up
3 184 Risk Ratio (M-H Fixed 95 CI) 028 [008 095]
11 Number of patients with
steroid-resistant rejection at
maximum follow-up
4 234 Risk Ratio (M-H Fixed 95 CI) 077 [047 127]
12 Serum bilirubin (mgdl) at the
end of treatment
1 30 Mean Difference (IV Fixed 95 CI) 26 [-096 616]
13 Number of days of
hospitalisation after liver
transplantation
1 52 Mean Difference (IV Fixed 95 CI) -85 [-1667 -033]
14 Adverse events 3 187 Risk Ratio (M-H Fixed 95 CI) 088 [030 260]
Analysis 11 Comparison 1 Bile acids for liver-transplanted patients Outcome 1 All-cause mortality at
maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 1 All-cause mortality at maximum follow-up
Study or subgroup Favours bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 UDCA versus placebo or no treatment
Barnes 1997 228 724 253 024 [ 006 107 ]
Fleckenstein 1998 214 416 125 057 [ 012 266 ]
Keiding 1997 1454 1048 355 124 [ 061 254 ]
Sama 1991 520 620 201 083 [ 030 229 ]
Subtotal (95 CI) 116 108 935 080 [ 049 130 ]
Total events 23 (Favours bile acids) 27 (Control)
Heterogeneity Chi2 = 416 df = 3 (P = 025) I2 =28
Test for overall effect Z = 091 (P = 036)
01 02 05 1 2 5 10
Favours bile acids Favours control
(Continued )
33Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Favours bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
2 TUDCA versus no treatment
Angelico 1999 316 217 65 159 [ 030 833 ]
Subtotal (95 CI) 16 17 65 159 [ 030 833 ]
Total events 3 (Favours bile acids) 2 (Control)
Heterogeneity not applicable
Test for overall effect Z = 055 (P = 058)
Total (95 CI) 132 125 1000 085 [ 053 136 ]
Total events 26 (Favours bile acids) 29 (Control)
Heterogeneity Chi2 = 466 df = 4 (P = 032) I2 =14
Test for overall effect Z = 069 (P = 049)
01 02 05 1 2 5 10
Favours bile acids Favours control
Analysis 12 Comparison 1 Bile acids for liver-transplanted patients Outcome 2 All-cause mortality worst-
best case and best-worst case scenarios
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 2 All-cause mortality worst-best case and best-worst case scenarios
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 Worst-best case scenario
Angelico 1999 516 217 65 266 [ 060 1180 ]
Barnes 1997 828 724 253 098 [ 042 230 ]
Fleckenstein 1998 314 416 125 086 [ 023 319 ]
Keiding 1997 1954 1048 355 169 [ 087 327 ]
Sama 1991 520 620 201 083 [ 030 229 ]
Subtotal (95 CI) 132 125 1000 130 [ 086 196 ]
Total events 40 (Bile acids) 29 (Control)
Heterogeneity Chi2 = 303 df = 4 (P = 055) I2 =00
Test for overall effect Z = 123 (P = 022)
2 Best-worst case scenario
005 02 1 5 20
Favours bile acids Favours control
(Continued )
34Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Angelico 1999 316 417 90 080 [ 021 302 ]
Barnes 1997 228 1124 274 016 [ 004 063 ]
Fleckenstein 1998 214 616 130 038 [ 009 159 ]
Keiding 1997 1454 1548 368 083 [ 045 154 ]
Sama 1991 520 620 139 083 [ 030 229 ]
Subtotal (95 CI) 132 125 1000 058 [ 038 090 ]
Total events 26 (Bile acids) 42 (Control)
Heterogeneity Chi2 = 567 df = 4 (P = 023) I2 =29
Test for overall effect Z = 247 (P = 0014)
005 02 1 5 20
Favours bile acids Favours control
Analysis 13 Comparison 1 Bile acids for liver-transplanted patients Outcome 3 Subgroup analyses all-
cause mortality at maximum follow-up according to time of start of bile acids
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 3 Subgroup analyses all-cause mortality at maximum follow-up according to time of start of bile acids
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 Less than three days after transplantation
Keiding 1997 1454 1048 355 124 [ 061 254 ]
Subtotal (95 CI) 54 48 355 124 [ 061 254 ]
Total events 14 (Bile acids) 10 (Control)
Heterogeneity not applicable
Test for overall effect Z = 060 (P = 055)
2 Three days or more after transplantation
Angelico 1999 316 217 65 159 [ 030 833 ]
Barnes 1997 228 724 253 024 [ 006 107 ]
Fleckenstein 1998 214 416 125 057 [ 012 266 ]
Sama 1991 520 620 201 083 [ 030 229 ]
005 02 1 5 20
Favours bile acids Favours control
(Continued )
35Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Subtotal (95 CI) 78 77 645 063 [ 033 120 ]
Total events 12 (Bile acids) 19 (Control)
Heterogeneity Chi2 = 310 df = 3 (P = 038) I2 =3
Test for overall effect Z = 141 (P = 016)
Total (95 CI) 132 125 1000 085 [ 053 136 ]
Total events 26 (Bile acids) 29 (Control)
Heterogeneity Chi2 = 466 df = 4 (P = 032) I2 =14
Test for overall effect Z = 069 (P = 049)
005 02 1 5 20
Favours bile acids Favours control
Analysis 14 Comparison 1 Bile acids for liver-transplanted patients Outcome 4 Subgroup analyses all
cause mortality at maximum follow-up according to treatment duration
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 4 Subgroup analyses all cause mortality at maximum follow-up according to treatment duration
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 Less than six months
Barnes 1997 228 724 253 024 [ 006 107 ]
Fleckenstein 1998 214 416 125 057 [ 012 266 ]
Keiding 1997 1454 1048 355 124 [ 061 254 ]
Subtotal (95 CI) 96 88 734 078 [ 045 138 ]
Total events 18 (Bile acids) 21 (Control)
Heterogeneity Chi2 = 417 df = 2 (P = 012) I2 =52
Test for overall effect Z = 084 (P = 040)
2 Six months or more
Angelico 1999 316 217 65 159 [ 030 833 ]
Sama 1991 520 620 201 083 [ 030 229 ]
Subtotal (95 CI) 36 37 266 102 [ 043 240 ]
Total events 8 (Bile acids) 8 (Control)
Heterogeneity Chi2 = 043 df = 1 (P = 051) I2 =00
005 02 1 5 20
Favours bile acids Favours control
(Continued )
36Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Test for overall effect Z = 004 (P = 097)
Total (95 CI) 132 125 1000 085 [ 053 136 ]
Total events 26 (Bile acids) 29 (Control)
Heterogeneity Chi2 = 466 df = 4 (P = 032) I2 =14
Test for overall effect Z = 069 (P = 049)
005 02 1 5 20
Favours bile acids Favours control
Analysis 15 Comparison 1 Bile acids for liver-transplanted patients Outcome 5 Number of deaths related
to rejection at maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 5 Number of deaths related to rejection at maximum follow-up
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 UDCA versus placebo
Keiding 1997 054 148 1000 030 [ 001 712 ]
Total (95 CI) 54 48 1000 030 [ 001 712 ]
Total events 0 (Bile acids) 1 (Control)
Heterogeneity not applicable
Test for overall effect Z = 075 (P = 045)
0001 001 01 1 10 100 1000
Favours bile acids Favours control
37Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 16 Comparison 1 Bile acids for liver-transplanted patients Outcome 6 Number of
retransplantations at maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 6 Number of retransplantations at maximum follow-up
Study or subgroup Bile acids Placebo Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Fleckenstein 1998 214 016 100 567 [ 029 10891 ]
Keiding 1997 154 448 900 022 [ 003 192 ]
Total (95 CI) 68 64 1000 076 [ 020 286 ]
Total events 3 (Bile acids) 4 (Placebo)
Heterogeneity Chi2 = 303 df = 1 (P = 008) I2 =67
Test for overall effect Z = 040 (P = 069)
0001 001 01 1 10 100 1000
Favours bile acids Favours placebo
Analysis 17 Comparison 1 Bile acids for liver-transplanted patients Outcome 7 Number of patients with
acute cellular rejection at maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 7 Number of patients with acute cellular rejection at maximum follow-up
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 UDCA versus placebo or no treatment
Barnes 1997 1728 1724 180 086 [ 058 127 ]
Fleckenstein 1998 814 916 83 102 [ 054 190 ]
Keiding 1997 3554 3248 333 097 [ 073 129 ]
Koneru 1993 316 916 89 033 [ 011 101 ]
Pageaux 1995 926 924 92 092 [ 044 193 ]
Sama 1991 1320 1320 128 100 [ 063 158 ]
Subtotal (95 CI) 158 148 905 089 [ 074 108 ]
01 02 05 1 2 5 10
Favours bile acids Favours control
(Continued )
38Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Total events 85 (Bile acids) 89 (Control)
Heterogeneity Chi2 = 387 df = 5 (P = 057) I2 =00
Test for overall effect Z = 120 (P = 023)
2 TUDCA versus no treatment
Angelico 1999 816 1017 95 085 [ 045 160 ]
Subtotal (95 CI) 16 17 95 085 [ 045 160 ]
Total events 8 (Bile acids) 10 (Control)
Heterogeneity not applicable
Test for overall effect Z = 050 (P = 061)
Total (95 CI) 174 165 1000 089 [ 074 106 ]
Total events 93 (Bile acids) 99 (Control)
Heterogeneity Chi2 = 392 df = 6 (P = 069) I2 =00
Test for overall effect Z = 130 (P = 019)
01 02 05 1 2 5 10
Favours bile acids Favours control
Analysis 18 Comparison 1 Bile acids for liver-transplanted patients Outcome 8 Subgroup analysis
number of patients with acute cellular rejection according to time of start of bile acid
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 8 Subgroup analysis number of patients with acute cellular rejection according to time of start of bile acid
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 Less than three days after transplantation
Keiding 1997 3554 3248 333 097 [ 073 129 ]
Koneru 1993 316 916 89 033 [ 011 101 ]
Subtotal (95 CI) 70 64 422 084 [ 063 111 ]
Total events 38 (Bile acids) 41 (Control)
Heterogeneity Chi2 = 374 df = 1 (P = 005) I2 =73
Test for overall effect Z = 124 (P = 022)
2 Three days or more after liver transplantation
Angelico 1999 816 1017 95 085 [ 045 160 ]
01 02 05 1 2 5 10
Favours bile acids Favours control
(Continued )
39Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Barnes 1997 1728 1724 180 086 [ 058 127 ]
Fleckenstein 1998 814 916 83 102 [ 054 190 ]
Pageaux 1995 926 924 92 092 [ 044 193 ]
Sama 1991 1320 1320 128 100 [ 063 158 ]
Subtotal (95 CI) 104 101 578 092 [ 072 117 ]
Total events 55 (Bile acids) 58 (Control)
Heterogeneity Chi2 = 041 df = 4 (P = 098) I2 =00
Test for overall effect Z = 067 (P = 050)
Total (95 CI) 174 165 1000 089 [ 074 106 ]
Total events 93 (Bile acids) 99 (Control)
Heterogeneity Chi2 = 392 df = 6 (P = 069) I2 =00
Test for overall effect Z = 130 (P = 019)
01 02 05 1 2 5 10
Favours bile acids Favours control
40Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 19 Comparison 1 Bile acids for liver-transplanted patients Outcome 9 Subgroup analysis
number of patients with acute cellular rejection according to treatment duration
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 9 Subgroup analysis number of patients with acute cellular rejection according to treatment duration
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 Less than six months
Barnes 1997 1728 1724 180 086 [ 058 127 ]
Fleckenstein 1998 814 916 83 102 [ 054 190 ]
Keiding 1997 3554 3248 333 097 [ 073 129 ]
Koneru 1993 316 916 89 033 [ 011 101 ]
Pageaux 1995 926 924 92 092 [ 044 193 ]
Subtotal (95 CI) 138 128 777 087 [ 071 107 ]
Total events 72 (Bile acids) 76 (Control)
Heterogeneity Chi2 = 374 df = 4 (P = 044) I2 =00
Test for overall effect Z = 129 (P = 020)
2 Six months or more
Angelico 1999 816 1017 95 085 [ 045 160 ]
Sama 1991 1320 1320 128 100 [ 063 158 ]
Subtotal (95 CI) 36 37 223 094 [ 065 136 ]
Total events 21 (Bile acids) 23 (Control)
Heterogeneity Chi2 = 017 df = 1 (P = 068) I2 =00
Test for overall effect Z = 035 (P = 073)
Total (95 CI) 174 165 1000 089 [ 074 106 ]
Total events 93 (Bile acids) 99 (Control)
Heterogeneity Chi2 = 392 df = 6 (P = 069) I2 =00
Test for overall effect Z = 130 (P = 019)
01 02 05 1 2 5 10
Favours bile acids Favours control
41Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 110 Comparison 1 Bile acids for liver-transplanted patients Outcome 10 Number of patients
with chronic rejection at maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 10 Number of patients with chronic rejection at maximum follow-up
Study or subgroup Bile acids Placebo Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Barnes 1997 128 624 611 014 [ 002 110 ]
Fleckenstein 1998 114 116 88 114 [ 008 1663 ]
Keiding 1997 154 348 300 030 [ 003 275 ]
Total (95 CI) 96 88 1000 028 [ 008 095 ]
Total events 3 (Bile acids) 10 (Placebo)
Heterogeneity Chi2 = 148 df = 2 (P = 048) I2 =00
Test for overall effect Z = 204 (P = 0041)
0001 001 01 1 10 100 1000
Favours bile acids Favours placebo
Analysis 111 Comparison 1 Bile acids for liver-transplanted patients Outcome 11 Number of patients
with steroid-resistant rejection at maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 11 Number of patients with steroid-resistant rejection at maximum follow-up
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Barnes 1997 328 724 277 037 [ 011 127 ]
Fleckenstein 1998 314 316 103 114 [ 027 478 ]
Keiding 1997 1454 1548 583 083 [ 045 154 ]
Pageaux 1995 226 124 38 185 [ 018 1908 ]
Total (95 CI) 122 112 1000 077 [ 047 127 ]
Total events 22 (Bile acids) 26 (Control)
Heterogeneity Chi2 = 226 df = 3 (P = 052) I2 =00
Test for overall effect Z = 102 (P = 031)
001 01 1 10 100
Favours bile acids Favours placebo
42Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 112 Comparison 1 Bile acids for liver-transplanted patients Outcome 12 Serum bilirubin (mgdl)
at the end of treatment
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 12 Serum bilirubin (mgdl) at the end of treatment
Study or subgroup Bile acids Placebo Mean Difference Weight Mean Difference
N Mean(SD) N Mean(SD) IVFixed95 CI IVFixed95 CI
Fleckenstein 1998 14 319 (68) 16 059 (022) 1000 260 [ -096 616 ]
Total (95 CI) 14 16 1000 260 [ -096 616 ]
Heterogeneity not applicable
Test for overall effect Z = 143 (P = 015)
-10 -5 0 5 10
Favours bile acids Favours placebo
Analysis 113 Comparison 1 Bile acids for liver-transplanted patients Outcome 13 Number of days of
hospitalisation after liver transplantation
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 13 Number of days of hospitalisation after liver transplantation
Study or subgroup Bile acids Placebo Mean Difference Weight Mean Difference
N Mean(SD) N Mean(SD) IVFixed95 CI IVFixed95 CI
Barnes 1997 28 25 (17) 24 335 (13) 1000 -850 [ -1667 -033 ]
Total (95 CI) 28 24 1000 -850 [ -1667 -033 ]
Heterogeneity not applicable
Test for overall effect Z = 204 (P = 0041)
-100 -50 0 50 100
Favours bile acids Favours placebo
43Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 114 Comparison 1 Bile acids for liver-transplanted patients Outcome 14 Adverse events
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 14 Adverse events
Study or subgroup Bile acids Placebo Risk Ratio Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Angelico 1999 016 017 00 [ 00 00 ]
Barnes 1997 128 124 086 [ 006 1298 ]
Keiding 1997 554 548 089 [ 027 288 ]
Total (95 CI) 98 89 088 [ 030 260 ]
Total events 6 (Bile acids) 6 (Placebo)
Heterogeneity Chi2 = 000 df = 1 (P = 098) I2 =00
Test for overall effect Z = 022 (P = 082)
001 01 1 10 100
Favours bile acids Favours placebo
A P P E N D I C E S
Appendix 1 Search strategies
Data Base Date of Search Search Strategy
The Cochrane Hepato-Biliary Group Con-
trolled Trials Register
September 2009 1 rsquoliver transplantationrsquo and rsquochenodeoxy-
cholicrsquo
2 rsquoliver transplantationrsquo and rsquocholicrsquo
3 rsquoliver transplantationrsquo and rsquodeoxycholicrsquo
4 rsquoliver transplantationrsquo and rsquoglycochen-
odeoxycholicrsquo
5 rsquoliver transplantationrsquo and rsquoglycocholicrsquo
6 rsquoliver transplantationrsquo and rsquoglycodeoxy-
cholicrsquo
7 rsquoliver transplantationrsquo and rsquoglycolitho-
cholicrsquo
8 rsquoliver transplantationrsquo and rsquohyodeoxy-
cholicrsquo
9 rsquoliver transplantationrsquo and rsquolithocholicrsquo
10 rsquoliver transplantationrsquo and rsquotaurochen-
odeoxycholicrsquo
44Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
11 rsquoliver transplantationrsquo and rsquotauro-
cholicrsquo
12 rsquoliver transplantationrsquo and rsquotaurodehy-
drocholicrsquo
13 rsquoliver transplantationrsquo and rsquotau-
rodeoxycholicrsquo
14 rsquoliver transplantationrsquo and rsquotauroglyco-
cholicrsquo
15 rsquoliver transplantationrsquo and rsquotaurolitho-
cholicrsquo
16 rsquoliver transplantationrsquo and rsquotaurosel-
cholicrsquo
17 rsquoliver transplantationrsquo and rsquotaurourso-
cholicrsquo
18 rsquoliver transplantationrsquo and rsquotaurour-
sodeoxycholicrsquo
19 rsquoliver transplantationrsquo and rsquoursocholicrsquo
20 rsquoliver transplantationrsquo and rsquoursodeoxy-
cholicrsquo
The Cochrane Central Register of Con-
trolled Trials in The Cochrane Library
Issue 3 2009 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
6 3 or 4
7 5 and 6
MEDLINE September 2009 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
45Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
6 3 or 4
7 5 and 6
8 RANDOMIZED-CONTROLLED-
TRIAL ME
9 RANDOM
10 8 or 9
11 7 and 10
EMBASE September 2009 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
6 3 or 4
7 5 and 6
8 RANDOMIZED-CONTROLLED-
TRIAL ME
9 RANDOM
10 8 or 9
11 7 and 10
46Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
Science Citation Index Expanded September 2009 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
6 3 or 4
7 5 and 6
8 RANDOMIZED-CONTROLLED-
TRIAL ME
9 RANDOM
10 8 or 9
11 7 and 10
The Chinese Biomedical Database Searched from January 1980 to April 2002 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
47Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
6 3 or 4
7 5 and 6
8 RANDOMIZED-CONTROLLED-
TRIAL ME
9 RANDOM
10 8 or 9
11 7 and 10
W H A T rsquo S N E W
Last assessed as up-to-date 8 February 2010
18 September 2009 New citation required but conclusions have not
changed
This review is an updated version of a review that was
published for the first time in Issue 3 2005 of TheCochrane Library by Chen 2003b
18 September 2009 New search has been performed No new studies fulfilled the inclusion criteria
H I S T O R Y
Protocol first published Issue 3 2003
Review first published Issue 3 2005
C O N T R I B U T I O N S O F A U T H O R S
GP and VG independently performed searches of relevant databases GP validated the search selected trials for inclusion contacted
the authors of the trials performed data extraction and data analysis and drafted the systematic review VG revised the review update
CG and DS revised the review update solved discrepancies of data extraction validated data analyses and provided consultation
D E C L A R A T I O N S O F I N T E R E S T
None known
48Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
S O U R C E S O F S U P P O R T
Internal sources
bull Copenhagen Trial Unit Denmark
External sources
bull Danish Medical Research Councilrsquos Grant on Getting Research into Practice (GRIP) Denmark
D I F F E R E N C E S B E T W E E N P R O T O C O L A N D R E V I E W
We assessed the risk of bias in the included studies for another four domains that were added to the review protocol (incomplete
outcome data selective outcome reporting baseline imbalance and early stopping of trial) In general the text of the risk of bias
domains were updated following Higgins 2008 Trials were considered at low risk of bias when judged as adequate in all domains
Quasi-randomised studies observational and case-control studies were included for the report of adverse events
We performed trial sequential analysis for outcomes demonstrating a statistically significant result
I N D E X T E R M S
Medical Subject Headings (MeSH)
lowastLiver Transplantation Cholagogues and Choleretics [lowasttherapeutic use] Graft Rejection [lowastprevention amp control] Randomized Con-
trolled Trials as Topic Taurochenodeoxycholic Acid [lowasttherapeutic use] Ursodeoxycholic Acid [lowasttherapeutic use]
MeSH check words
Humans
49Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Koneru 1993
Methods Study design randomised controlled trial
Participants Country United States
Publication language English
Inclusion criteria
- patients who underwent liver transplantation
Exclusion criteria
- not mentioned
Participants
- UDCA group (n = 16)
Mean age (years +- SD)
no information
Ratio of sex (malefemale) no information
Origins of liver diseases
no information
- Control group (n = 16)
Mean age (years +- SD)
no information
Ratio of sex (malefemale) no information
Origins of liver diseases
no information
Interventions UDCA group
- Dose 900 mgday
- Route orally
- Duration immediately after intestinal transit recovery usually between postoperative
days three and five and continue for three months
Control group
- no treatment
Co-interventions all patients received standard triple-drug regimens (steroids azathio-
prine and cyclosporine)
Outcomes Number of patients with retransplantation due to rejection
Number of patients with rejection episodes
Notes Abstract
Letter was sent to the authors in September 2009 No reply was received
Risk of bias
Item Authorsrsquo judgement Description
Adequate sequence generation Unclear No information provided
Allocation concealment Unclear No information provided
Blinding No Not performed
26Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Koneru 1993 (Continued)
Incomplete outcome data addressed
All outcomes
Unclear The study gives the impression that there
were no withdrawals but this was not ex-
plicitly stated
Free of selective reporting Unclear Insufficient information provided
Sample size calculation No Not performed
Intention-to-treat analysis Unclear No information provided
Baseline imbalance Unclear Not enough information provided
Early stopping of trial Unclear Not enough information provided
Pageaux 1995
Methods Study design double-blind randomised study
Participants Country France
Publication language English
Inclusion criteria
- patients who underwent liver transplantation
Exclusion criteria
- not mentioned
Participants
- UDCA group (n=26)
Mean age (years +- SD)
47 +- 10
Ratio of sex (malefemale) 179
Origins of liver diseases alcoholic cirrhosis 14
post-hepatic B cirrhosis 2
post-hepatitis C cirrhosis 4
PBC 2
liver cancer 2
fulminant hepatitis 1
miscellaneous 1
- Placebo group (n = 24)
Mean age (years +- SD)
51+- 9
Ratio of sex (malefemale) 159
Origins of liver diseases alcoholic cirrhosis 10
post-hepatic B cirrhosis 0
post-hepatic C cirrhosis 6
PBC 3
liver cancer 4
fulminant hepatitis 0
miscellaneous 1
27Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Pageaux 1995 (Continued)
Interventions UDCA group
- Dose 600 mgday in three divided doses
- Route orally
- Duration immediately after intestinal transit recovery usually between postoperative
days three and five and continue for two months
Placebo group
- identical-appearing capsules administered in the same quantity and manner
Co-interventions all patients received standard triple-drug regimens (steroids azathio-
prine and cyclosporine or tacrolimus)
Outcomes Number of patients with acute cellular rejection
Number of patients with steroid-resistant rejection
Notes Letter was sent to the authors in September 2009 No reply was received
Risk of bias
Item Authorsrsquo judgement Description
Adequate sequence generation Unclear No information provided
Allocation concealment Unclear No information provided
Blinding Unclear Method of blinding not described
Incomplete outcome data addressed
All outcomes
Yes Five patients died from non-immunologi-
cal causes before the end of the first month
and were excluded from the study Reasons
were reported
Free of selective reporting Unclear Not enough information provided
Sample size calculation No Not performed
Intention-to-treat analysis No Not stated and not used
Baseline imbalance Unclear Not enough information provided
Early stopping of trial Unclear Not enough information provided
Sama 1991
Methods Study design randomised controlled trial
Participants Country Italy
Publication language English
Inclusion criteria
28Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Sama 1991 (Continued)
- patients who underwent liver transplantation
Exclusion criteria
- not mentioned
Participants
- UDCA group (n = 20)
Mean age (years +- SD)
no information
Ratio of sex (malefemale) no information
Origins of liver diseases
no information
- Control group (n = 20)
Mean age (years +- SD)
no information
Ratio of sex (malefemale) no information
Origins of liver diseases
no information
Interventions UDCA group
- Dose 600 mgday in two divided doses
- Route orally
- Duration immediately after intestinal transit recovery usually between postoperative
day five and day seven and continue for six months
Control group
- no treatment
Co-interventions all patients received standard immunosuppressive treatment (steroids
and cyclosporine)
Outcomes All cause mortality
Number of patients with acute cellular rejection
Notes Abstract
Letter was sent to the authors in September 2009 No reply was received
Risk of bias
Item Authorsrsquo judgement Description
Adequate sequence generation Unclear A randomisation list was performed before
patients were admitted to the trial (infor-
mation from principal author)
Allocation concealment Unclear No information provided
Blinding Unclear The principle author provided information
that the study was made according to a
single-blind randomised protocol The pri-
mary outcome was the occurrence of biopsy
proven rejection episodes The pathologists
were blind but the patients were not
29Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Sama 1991 (Continued)
Incomplete outcome data addressed
All outcomes
Unclear Five patients from the UDCA group and
six patients from the placebo group were
excluded Reasons for exclusion were not
fully stated
Free of selective reporting No Data about survival of patients were not
adequately reported
Sample size calculation No Not performed
Intention-to-treat analysis No Not stated and not used
Baseline imbalance Unclear Basic characteristics of patients not re-
ported
Early stopping of trial Unclear Not enough information provided
UDCA = ursodeoxycholic acid
TUDCA = tauroursodeoxycholic acid
PBC = primary biliary cirrhosis
PSC = primary sclerosing cholangitis
OKT3 = anti-CD3 monoclonal antibody
Characteristics of excluded studies [ordered by study ID]
Assy 2007 A randomised controlled trial that included only recipients of liver transplantation with stable graft function and
no episodes of rejection for at least 2 years that were then offered total immunosuppression withdrawal Fourteen
patients received UDCA (15 mgkg body weightday) and 12 received placebo Rejection occurred in 43 and
75 of patients respectively (no significant difference) None developed chronic rejection After follow-up two
patients were free of immunosuppression 80 were steroid free and 50 were able to reduce their dose of
cyclosporine
Clavien 1996 Case series Fifty consecutive liver-transplanted patients were treated with a standard cyclosporine immunosup-
pressive regimen Twenty three of the 43 survivors developed an episode of rejection and UDCA (10 mgkg
weightday) was initiated Only one patient had a second episode of rejection
Friman 1992 Observational study Thirty-three liver-transplanted patients received 10 mg UDCAkg body weightday for
median of 10 months (range four to 21 months) Eight historical liver-transplanted patients served as control
group The rejection incidence was significantly lower in the patients who received the treatment with UDCA
Biochemistry one month after transplantation demonstrated significantly lower average values of aminotrans-
ferases and alkaline phosphatases in patients treated with UDCA than in the control group
30Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
Heathcote 1999 Observational study From 1987 to 1996 37 UDCA treated and 53 placebo treated patients with primary biliary
cirrhosis were referred for transplantation Posttransplantation survival rates at one month were 939 in the
UDCA group and 884 in the placebo group and one year survival rates were 903 and 784 respectively
(no significant differences) However rejection (type not defined - a secondary outcome measure) occurred
significantly less often in the UDCA group (429) than in placebo group (688)
Henriksson 1991 Observational study All patients in this study were given sequential quadruple immunosuppression with anti-
lymphocyte globulin azathioprine steroids and cyclosporine All patients with primary graft function (n = 11)
were treated with 10 mg UDCAkg body weightday starting during the first postoperative week Patients who
received liver transplantation in the first 6 months of 1989 (n = 8) served as controls In the control group one
patient died after 9 months with chronic graft dysfunction and six patients had rejection episodes during the
first postoperative month All patients in the UDCA group were alive without rejection episodes
Persson 1990 Observational study All 11 adult patients transplanted between August 1989 and January 1990 with primary
graft function were treated with 10 mg UDCA kg body weightday Eight patients transplanted during the first
half of 1989 served as control UDCA was started during the first postoperative week and the treatment was
continued for six months All patients in the UDCA treated group survived with satisfactory graft function In
the control group six patients had at least one rejection episode needing treatment during the first postoperative
month
Rafael 1995 Observational study Seventeen patients who underwent liver transplantation between February 1990 and April
1993 and developed biliary complications after transplantation were retrospectively analysed regarding treatment
with UDCA UDCA was given in a dose of 500 to 1000 mgday Ten patients were treated for at least one year while
seven patients were treated for 14 to 250 days UDCA significantly improved gammaglutamyl transpeptidase in
liver graft recipients with biliary complications There was also a trend towards improvement in serum bilirubin
and alanine transaminase values
Sama 1998 Observational study Thirty-four patients who underwent liver transplantation between January 1995 and June
1996 were included in the study Seventeen were treated with UDCA 10 mgkg body weightday during 6
months while 17 served as controls on the basis of having undergone liver transplantation closest to UDCA
patients A significant decrease in serum bilirubin levels was observed in UDCA patients There was a significantly
higher incidence of recurrent hepatitis in the control group
UDCA ursodeoxycholic acid
31Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
D A T A A N D A N A L Y S E S
Comparison 1 Bile acids for liver-transplanted patients
Outcome or subgroup titleNo of
studies
No of
participants Statistical method Effect size
1 All-cause mortality at maximum
follow-up
5 257 Risk Ratio (M-H Fixed 95 CI) 085 [053 136]
11 UDCA versus placebo or
no treatment
4 224 Risk Ratio (M-H Fixed 95 CI) 080 [049 130]
12 TUDCA versus no
treatment
1 33 Risk Ratio (M-H Fixed 95 CI) 159 [030 833]
2 All-cause mortality worst-best
case and best-worst case
scenarios
5 Risk Ratio (M-H Fixed 95 CI) Subtotals only
21 Worst-best case scenario 5 257 Risk Ratio (M-H Fixed 95 CI) 130 [086 196]
22 Best-worst case scenario 5 257 Risk Ratio (M-H Fixed 95 CI) 058 [038 090]
3 Subgroup analyses all-cause
mortality at maximum
follow-up according to time of
start of bile acids
5 257 Risk Ratio (M-H Fixed 95 CI) 085 [053 136]
31 Less than three days after
transplantation
1 102 Risk Ratio (M-H Fixed 95 CI) 124 [061 254]
32 Three days or more after
transplantation
4 155 Risk Ratio (M-H Fixed 95 CI) 063 [033 120]
4 Subgroup analyses all cause
mortality at maximum
follow-up according to
treatment duration
5 257 Risk Ratio (M-H Fixed 95 CI) 085 [053 136]
41 Less than six months 3 184 Risk Ratio (M-H Fixed 95 CI) 078 [045 138]
42 Six months or more 2 73 Risk Ratio (M-H Fixed 95 CI) 102 [043 240]
5 Number of deaths related
to rejection at maximum
follow-up
1 102 Risk Ratio (M-H Fixed 95 CI) 030 [001 712]
51 UDCA versus placebo 1 102 Risk Ratio (M-H Fixed 95 CI) 030 [001 712]
6 Number of retransplantations at
maximum follow-up
2 132 Risk Ratio (M-H Fixed 95 CI) 076 [020 286]
7 Number of patients with acute
cellular rejection at maximum
follow-up
7 339 Risk Ratio (M-H Fixed 95 CI) 089 [074 106]
71 UDCA versus placebo or
no treatment
6 306 Risk Ratio (M-H Fixed 95 CI) 089 [074 108]
72 TUDCA versus no
treatment
1 33 Risk Ratio (M-H Fixed 95 CI) 085 [045 160]
8 Subgroup analysis number of
patients with acute cellular
rejection according to time of
start of bile acid
7 339 Risk Ratio (M-H Fixed 95 CI) 089 [074 106]
32Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
81 Less than three days after
transplantation
2 134 Risk Ratio (M-H Fixed 95 CI) 084 [063 111]
82 Three days or more after
liver transplantation
5 205 Risk Ratio (M-H Fixed 95 CI) 092 [072 117]
9 Subgroup analysis number
of patients with acute
cellular rejection according to
treatment duration
7 339 Risk Ratio (M-H Fixed 95 CI) 089 [074 106]
91 Less than six months 5 266 Risk Ratio (M-H Fixed 95 CI) 087 [071 107]
92 Six months or more 2 73 Risk Ratio (M-H Fixed 95 CI) 094 [065 136]
10 Number of patients with
chronic rejection at maximum
follow-up
3 184 Risk Ratio (M-H Fixed 95 CI) 028 [008 095]
11 Number of patients with
steroid-resistant rejection at
maximum follow-up
4 234 Risk Ratio (M-H Fixed 95 CI) 077 [047 127]
12 Serum bilirubin (mgdl) at the
end of treatment
1 30 Mean Difference (IV Fixed 95 CI) 26 [-096 616]
13 Number of days of
hospitalisation after liver
transplantation
1 52 Mean Difference (IV Fixed 95 CI) -85 [-1667 -033]
14 Adverse events 3 187 Risk Ratio (M-H Fixed 95 CI) 088 [030 260]
Analysis 11 Comparison 1 Bile acids for liver-transplanted patients Outcome 1 All-cause mortality at
maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 1 All-cause mortality at maximum follow-up
Study or subgroup Favours bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 UDCA versus placebo or no treatment
Barnes 1997 228 724 253 024 [ 006 107 ]
Fleckenstein 1998 214 416 125 057 [ 012 266 ]
Keiding 1997 1454 1048 355 124 [ 061 254 ]
Sama 1991 520 620 201 083 [ 030 229 ]
Subtotal (95 CI) 116 108 935 080 [ 049 130 ]
Total events 23 (Favours bile acids) 27 (Control)
Heterogeneity Chi2 = 416 df = 3 (P = 025) I2 =28
Test for overall effect Z = 091 (P = 036)
01 02 05 1 2 5 10
Favours bile acids Favours control
(Continued )
33Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Favours bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
2 TUDCA versus no treatment
Angelico 1999 316 217 65 159 [ 030 833 ]
Subtotal (95 CI) 16 17 65 159 [ 030 833 ]
Total events 3 (Favours bile acids) 2 (Control)
Heterogeneity not applicable
Test for overall effect Z = 055 (P = 058)
Total (95 CI) 132 125 1000 085 [ 053 136 ]
Total events 26 (Favours bile acids) 29 (Control)
Heterogeneity Chi2 = 466 df = 4 (P = 032) I2 =14
Test for overall effect Z = 069 (P = 049)
01 02 05 1 2 5 10
Favours bile acids Favours control
Analysis 12 Comparison 1 Bile acids for liver-transplanted patients Outcome 2 All-cause mortality worst-
best case and best-worst case scenarios
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 2 All-cause mortality worst-best case and best-worst case scenarios
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 Worst-best case scenario
Angelico 1999 516 217 65 266 [ 060 1180 ]
Barnes 1997 828 724 253 098 [ 042 230 ]
Fleckenstein 1998 314 416 125 086 [ 023 319 ]
Keiding 1997 1954 1048 355 169 [ 087 327 ]
Sama 1991 520 620 201 083 [ 030 229 ]
Subtotal (95 CI) 132 125 1000 130 [ 086 196 ]
Total events 40 (Bile acids) 29 (Control)
Heterogeneity Chi2 = 303 df = 4 (P = 055) I2 =00
Test for overall effect Z = 123 (P = 022)
2 Best-worst case scenario
005 02 1 5 20
Favours bile acids Favours control
(Continued )
34Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Angelico 1999 316 417 90 080 [ 021 302 ]
Barnes 1997 228 1124 274 016 [ 004 063 ]
Fleckenstein 1998 214 616 130 038 [ 009 159 ]
Keiding 1997 1454 1548 368 083 [ 045 154 ]
Sama 1991 520 620 139 083 [ 030 229 ]
Subtotal (95 CI) 132 125 1000 058 [ 038 090 ]
Total events 26 (Bile acids) 42 (Control)
Heterogeneity Chi2 = 567 df = 4 (P = 023) I2 =29
Test for overall effect Z = 247 (P = 0014)
005 02 1 5 20
Favours bile acids Favours control
Analysis 13 Comparison 1 Bile acids for liver-transplanted patients Outcome 3 Subgroup analyses all-
cause mortality at maximum follow-up according to time of start of bile acids
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 3 Subgroup analyses all-cause mortality at maximum follow-up according to time of start of bile acids
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 Less than three days after transplantation
Keiding 1997 1454 1048 355 124 [ 061 254 ]
Subtotal (95 CI) 54 48 355 124 [ 061 254 ]
Total events 14 (Bile acids) 10 (Control)
Heterogeneity not applicable
Test for overall effect Z = 060 (P = 055)
2 Three days or more after transplantation
Angelico 1999 316 217 65 159 [ 030 833 ]
Barnes 1997 228 724 253 024 [ 006 107 ]
Fleckenstein 1998 214 416 125 057 [ 012 266 ]
Sama 1991 520 620 201 083 [ 030 229 ]
005 02 1 5 20
Favours bile acids Favours control
(Continued )
35Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Subtotal (95 CI) 78 77 645 063 [ 033 120 ]
Total events 12 (Bile acids) 19 (Control)
Heterogeneity Chi2 = 310 df = 3 (P = 038) I2 =3
Test for overall effect Z = 141 (P = 016)
Total (95 CI) 132 125 1000 085 [ 053 136 ]
Total events 26 (Bile acids) 29 (Control)
Heterogeneity Chi2 = 466 df = 4 (P = 032) I2 =14
Test for overall effect Z = 069 (P = 049)
005 02 1 5 20
Favours bile acids Favours control
Analysis 14 Comparison 1 Bile acids for liver-transplanted patients Outcome 4 Subgroup analyses all
cause mortality at maximum follow-up according to treatment duration
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 4 Subgroup analyses all cause mortality at maximum follow-up according to treatment duration
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 Less than six months
Barnes 1997 228 724 253 024 [ 006 107 ]
Fleckenstein 1998 214 416 125 057 [ 012 266 ]
Keiding 1997 1454 1048 355 124 [ 061 254 ]
Subtotal (95 CI) 96 88 734 078 [ 045 138 ]
Total events 18 (Bile acids) 21 (Control)
Heterogeneity Chi2 = 417 df = 2 (P = 012) I2 =52
Test for overall effect Z = 084 (P = 040)
2 Six months or more
Angelico 1999 316 217 65 159 [ 030 833 ]
Sama 1991 520 620 201 083 [ 030 229 ]
Subtotal (95 CI) 36 37 266 102 [ 043 240 ]
Total events 8 (Bile acids) 8 (Control)
Heterogeneity Chi2 = 043 df = 1 (P = 051) I2 =00
005 02 1 5 20
Favours bile acids Favours control
(Continued )
36Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Test for overall effect Z = 004 (P = 097)
Total (95 CI) 132 125 1000 085 [ 053 136 ]
Total events 26 (Bile acids) 29 (Control)
Heterogeneity Chi2 = 466 df = 4 (P = 032) I2 =14
Test for overall effect Z = 069 (P = 049)
005 02 1 5 20
Favours bile acids Favours control
Analysis 15 Comparison 1 Bile acids for liver-transplanted patients Outcome 5 Number of deaths related
to rejection at maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 5 Number of deaths related to rejection at maximum follow-up
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 UDCA versus placebo
Keiding 1997 054 148 1000 030 [ 001 712 ]
Total (95 CI) 54 48 1000 030 [ 001 712 ]
Total events 0 (Bile acids) 1 (Control)
Heterogeneity not applicable
Test for overall effect Z = 075 (P = 045)
0001 001 01 1 10 100 1000
Favours bile acids Favours control
37Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 16 Comparison 1 Bile acids for liver-transplanted patients Outcome 6 Number of
retransplantations at maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 6 Number of retransplantations at maximum follow-up
Study or subgroup Bile acids Placebo Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Fleckenstein 1998 214 016 100 567 [ 029 10891 ]
Keiding 1997 154 448 900 022 [ 003 192 ]
Total (95 CI) 68 64 1000 076 [ 020 286 ]
Total events 3 (Bile acids) 4 (Placebo)
Heterogeneity Chi2 = 303 df = 1 (P = 008) I2 =67
Test for overall effect Z = 040 (P = 069)
0001 001 01 1 10 100 1000
Favours bile acids Favours placebo
Analysis 17 Comparison 1 Bile acids for liver-transplanted patients Outcome 7 Number of patients with
acute cellular rejection at maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 7 Number of patients with acute cellular rejection at maximum follow-up
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 UDCA versus placebo or no treatment
Barnes 1997 1728 1724 180 086 [ 058 127 ]
Fleckenstein 1998 814 916 83 102 [ 054 190 ]
Keiding 1997 3554 3248 333 097 [ 073 129 ]
Koneru 1993 316 916 89 033 [ 011 101 ]
Pageaux 1995 926 924 92 092 [ 044 193 ]
Sama 1991 1320 1320 128 100 [ 063 158 ]
Subtotal (95 CI) 158 148 905 089 [ 074 108 ]
01 02 05 1 2 5 10
Favours bile acids Favours control
(Continued )
38Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Total events 85 (Bile acids) 89 (Control)
Heterogeneity Chi2 = 387 df = 5 (P = 057) I2 =00
Test for overall effect Z = 120 (P = 023)
2 TUDCA versus no treatment
Angelico 1999 816 1017 95 085 [ 045 160 ]
Subtotal (95 CI) 16 17 95 085 [ 045 160 ]
Total events 8 (Bile acids) 10 (Control)
Heterogeneity not applicable
Test for overall effect Z = 050 (P = 061)
Total (95 CI) 174 165 1000 089 [ 074 106 ]
Total events 93 (Bile acids) 99 (Control)
Heterogeneity Chi2 = 392 df = 6 (P = 069) I2 =00
Test for overall effect Z = 130 (P = 019)
01 02 05 1 2 5 10
Favours bile acids Favours control
Analysis 18 Comparison 1 Bile acids for liver-transplanted patients Outcome 8 Subgroup analysis
number of patients with acute cellular rejection according to time of start of bile acid
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 8 Subgroup analysis number of patients with acute cellular rejection according to time of start of bile acid
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 Less than three days after transplantation
Keiding 1997 3554 3248 333 097 [ 073 129 ]
Koneru 1993 316 916 89 033 [ 011 101 ]
Subtotal (95 CI) 70 64 422 084 [ 063 111 ]
Total events 38 (Bile acids) 41 (Control)
Heterogeneity Chi2 = 374 df = 1 (P = 005) I2 =73
Test for overall effect Z = 124 (P = 022)
2 Three days or more after liver transplantation
Angelico 1999 816 1017 95 085 [ 045 160 ]
01 02 05 1 2 5 10
Favours bile acids Favours control
(Continued )
39Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Barnes 1997 1728 1724 180 086 [ 058 127 ]
Fleckenstein 1998 814 916 83 102 [ 054 190 ]
Pageaux 1995 926 924 92 092 [ 044 193 ]
Sama 1991 1320 1320 128 100 [ 063 158 ]
Subtotal (95 CI) 104 101 578 092 [ 072 117 ]
Total events 55 (Bile acids) 58 (Control)
Heterogeneity Chi2 = 041 df = 4 (P = 098) I2 =00
Test for overall effect Z = 067 (P = 050)
Total (95 CI) 174 165 1000 089 [ 074 106 ]
Total events 93 (Bile acids) 99 (Control)
Heterogeneity Chi2 = 392 df = 6 (P = 069) I2 =00
Test for overall effect Z = 130 (P = 019)
01 02 05 1 2 5 10
Favours bile acids Favours control
40Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 19 Comparison 1 Bile acids for liver-transplanted patients Outcome 9 Subgroup analysis
number of patients with acute cellular rejection according to treatment duration
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 9 Subgroup analysis number of patients with acute cellular rejection according to treatment duration
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 Less than six months
Barnes 1997 1728 1724 180 086 [ 058 127 ]
Fleckenstein 1998 814 916 83 102 [ 054 190 ]
Keiding 1997 3554 3248 333 097 [ 073 129 ]
Koneru 1993 316 916 89 033 [ 011 101 ]
Pageaux 1995 926 924 92 092 [ 044 193 ]
Subtotal (95 CI) 138 128 777 087 [ 071 107 ]
Total events 72 (Bile acids) 76 (Control)
Heterogeneity Chi2 = 374 df = 4 (P = 044) I2 =00
Test for overall effect Z = 129 (P = 020)
2 Six months or more
Angelico 1999 816 1017 95 085 [ 045 160 ]
Sama 1991 1320 1320 128 100 [ 063 158 ]
Subtotal (95 CI) 36 37 223 094 [ 065 136 ]
Total events 21 (Bile acids) 23 (Control)
Heterogeneity Chi2 = 017 df = 1 (P = 068) I2 =00
Test for overall effect Z = 035 (P = 073)
Total (95 CI) 174 165 1000 089 [ 074 106 ]
Total events 93 (Bile acids) 99 (Control)
Heterogeneity Chi2 = 392 df = 6 (P = 069) I2 =00
Test for overall effect Z = 130 (P = 019)
01 02 05 1 2 5 10
Favours bile acids Favours control
41Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 110 Comparison 1 Bile acids for liver-transplanted patients Outcome 10 Number of patients
with chronic rejection at maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 10 Number of patients with chronic rejection at maximum follow-up
Study or subgroup Bile acids Placebo Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Barnes 1997 128 624 611 014 [ 002 110 ]
Fleckenstein 1998 114 116 88 114 [ 008 1663 ]
Keiding 1997 154 348 300 030 [ 003 275 ]
Total (95 CI) 96 88 1000 028 [ 008 095 ]
Total events 3 (Bile acids) 10 (Placebo)
Heterogeneity Chi2 = 148 df = 2 (P = 048) I2 =00
Test for overall effect Z = 204 (P = 0041)
0001 001 01 1 10 100 1000
Favours bile acids Favours placebo
Analysis 111 Comparison 1 Bile acids for liver-transplanted patients Outcome 11 Number of patients
with steroid-resistant rejection at maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 11 Number of patients with steroid-resistant rejection at maximum follow-up
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Barnes 1997 328 724 277 037 [ 011 127 ]
Fleckenstein 1998 314 316 103 114 [ 027 478 ]
Keiding 1997 1454 1548 583 083 [ 045 154 ]
Pageaux 1995 226 124 38 185 [ 018 1908 ]
Total (95 CI) 122 112 1000 077 [ 047 127 ]
Total events 22 (Bile acids) 26 (Control)
Heterogeneity Chi2 = 226 df = 3 (P = 052) I2 =00
Test for overall effect Z = 102 (P = 031)
001 01 1 10 100
Favours bile acids Favours placebo
42Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 112 Comparison 1 Bile acids for liver-transplanted patients Outcome 12 Serum bilirubin (mgdl)
at the end of treatment
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 12 Serum bilirubin (mgdl) at the end of treatment
Study or subgroup Bile acids Placebo Mean Difference Weight Mean Difference
N Mean(SD) N Mean(SD) IVFixed95 CI IVFixed95 CI
Fleckenstein 1998 14 319 (68) 16 059 (022) 1000 260 [ -096 616 ]
Total (95 CI) 14 16 1000 260 [ -096 616 ]
Heterogeneity not applicable
Test for overall effect Z = 143 (P = 015)
-10 -5 0 5 10
Favours bile acids Favours placebo
Analysis 113 Comparison 1 Bile acids for liver-transplanted patients Outcome 13 Number of days of
hospitalisation after liver transplantation
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 13 Number of days of hospitalisation after liver transplantation
Study or subgroup Bile acids Placebo Mean Difference Weight Mean Difference
N Mean(SD) N Mean(SD) IVFixed95 CI IVFixed95 CI
Barnes 1997 28 25 (17) 24 335 (13) 1000 -850 [ -1667 -033 ]
Total (95 CI) 28 24 1000 -850 [ -1667 -033 ]
Heterogeneity not applicable
Test for overall effect Z = 204 (P = 0041)
-100 -50 0 50 100
Favours bile acids Favours placebo
43Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 114 Comparison 1 Bile acids for liver-transplanted patients Outcome 14 Adverse events
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 14 Adverse events
Study or subgroup Bile acids Placebo Risk Ratio Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Angelico 1999 016 017 00 [ 00 00 ]
Barnes 1997 128 124 086 [ 006 1298 ]
Keiding 1997 554 548 089 [ 027 288 ]
Total (95 CI) 98 89 088 [ 030 260 ]
Total events 6 (Bile acids) 6 (Placebo)
Heterogeneity Chi2 = 000 df = 1 (P = 098) I2 =00
Test for overall effect Z = 022 (P = 082)
001 01 1 10 100
Favours bile acids Favours placebo
A P P E N D I C E S
Appendix 1 Search strategies
Data Base Date of Search Search Strategy
The Cochrane Hepato-Biliary Group Con-
trolled Trials Register
September 2009 1 rsquoliver transplantationrsquo and rsquochenodeoxy-
cholicrsquo
2 rsquoliver transplantationrsquo and rsquocholicrsquo
3 rsquoliver transplantationrsquo and rsquodeoxycholicrsquo
4 rsquoliver transplantationrsquo and rsquoglycochen-
odeoxycholicrsquo
5 rsquoliver transplantationrsquo and rsquoglycocholicrsquo
6 rsquoliver transplantationrsquo and rsquoglycodeoxy-
cholicrsquo
7 rsquoliver transplantationrsquo and rsquoglycolitho-
cholicrsquo
8 rsquoliver transplantationrsquo and rsquohyodeoxy-
cholicrsquo
9 rsquoliver transplantationrsquo and rsquolithocholicrsquo
10 rsquoliver transplantationrsquo and rsquotaurochen-
odeoxycholicrsquo
44Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
11 rsquoliver transplantationrsquo and rsquotauro-
cholicrsquo
12 rsquoliver transplantationrsquo and rsquotaurodehy-
drocholicrsquo
13 rsquoliver transplantationrsquo and rsquotau-
rodeoxycholicrsquo
14 rsquoliver transplantationrsquo and rsquotauroglyco-
cholicrsquo
15 rsquoliver transplantationrsquo and rsquotaurolitho-
cholicrsquo
16 rsquoliver transplantationrsquo and rsquotaurosel-
cholicrsquo
17 rsquoliver transplantationrsquo and rsquotaurourso-
cholicrsquo
18 rsquoliver transplantationrsquo and rsquotaurour-
sodeoxycholicrsquo
19 rsquoliver transplantationrsquo and rsquoursocholicrsquo
20 rsquoliver transplantationrsquo and rsquoursodeoxy-
cholicrsquo
The Cochrane Central Register of Con-
trolled Trials in The Cochrane Library
Issue 3 2009 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
6 3 or 4
7 5 and 6
MEDLINE September 2009 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
45Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
6 3 or 4
7 5 and 6
8 RANDOMIZED-CONTROLLED-
TRIAL ME
9 RANDOM
10 8 or 9
11 7 and 10
EMBASE September 2009 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
6 3 or 4
7 5 and 6
8 RANDOMIZED-CONTROLLED-
TRIAL ME
9 RANDOM
10 8 or 9
11 7 and 10
46Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
Science Citation Index Expanded September 2009 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
6 3 or 4
7 5 and 6
8 RANDOMIZED-CONTROLLED-
TRIAL ME
9 RANDOM
10 8 or 9
11 7 and 10
The Chinese Biomedical Database Searched from January 1980 to April 2002 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
47Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
6 3 or 4
7 5 and 6
8 RANDOMIZED-CONTROLLED-
TRIAL ME
9 RANDOM
10 8 or 9
11 7 and 10
W H A T rsquo S N E W
Last assessed as up-to-date 8 February 2010
18 September 2009 New citation required but conclusions have not
changed
This review is an updated version of a review that was
published for the first time in Issue 3 2005 of TheCochrane Library by Chen 2003b
18 September 2009 New search has been performed No new studies fulfilled the inclusion criteria
H I S T O R Y
Protocol first published Issue 3 2003
Review first published Issue 3 2005
C O N T R I B U T I O N S O F A U T H O R S
GP and VG independently performed searches of relevant databases GP validated the search selected trials for inclusion contacted
the authors of the trials performed data extraction and data analysis and drafted the systematic review VG revised the review update
CG and DS revised the review update solved discrepancies of data extraction validated data analyses and provided consultation
D E C L A R A T I O N S O F I N T E R E S T
None known
48Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
S O U R C E S O F S U P P O R T
Internal sources
bull Copenhagen Trial Unit Denmark
External sources
bull Danish Medical Research Councilrsquos Grant on Getting Research into Practice (GRIP) Denmark
D I F F E R E N C E S B E T W E E N P R O T O C O L A N D R E V I E W
We assessed the risk of bias in the included studies for another four domains that were added to the review protocol (incomplete
outcome data selective outcome reporting baseline imbalance and early stopping of trial) In general the text of the risk of bias
domains were updated following Higgins 2008 Trials were considered at low risk of bias when judged as adequate in all domains
Quasi-randomised studies observational and case-control studies were included for the report of adverse events
We performed trial sequential analysis for outcomes demonstrating a statistically significant result
I N D E X T E R M S
Medical Subject Headings (MeSH)
lowastLiver Transplantation Cholagogues and Choleretics [lowasttherapeutic use] Graft Rejection [lowastprevention amp control] Randomized Con-
trolled Trials as Topic Taurochenodeoxycholic Acid [lowasttherapeutic use] Ursodeoxycholic Acid [lowasttherapeutic use]
MeSH check words
Humans
49Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Koneru 1993 (Continued)
Incomplete outcome data addressed
All outcomes
Unclear The study gives the impression that there
were no withdrawals but this was not ex-
plicitly stated
Free of selective reporting Unclear Insufficient information provided
Sample size calculation No Not performed
Intention-to-treat analysis Unclear No information provided
Baseline imbalance Unclear Not enough information provided
Early stopping of trial Unclear Not enough information provided
Pageaux 1995
Methods Study design double-blind randomised study
Participants Country France
Publication language English
Inclusion criteria
- patients who underwent liver transplantation
Exclusion criteria
- not mentioned
Participants
- UDCA group (n=26)
Mean age (years +- SD)
47 +- 10
Ratio of sex (malefemale) 179
Origins of liver diseases alcoholic cirrhosis 14
post-hepatic B cirrhosis 2
post-hepatitis C cirrhosis 4
PBC 2
liver cancer 2
fulminant hepatitis 1
miscellaneous 1
- Placebo group (n = 24)
Mean age (years +- SD)
51+- 9
Ratio of sex (malefemale) 159
Origins of liver diseases alcoholic cirrhosis 10
post-hepatic B cirrhosis 0
post-hepatic C cirrhosis 6
PBC 3
liver cancer 4
fulminant hepatitis 0
miscellaneous 1
27Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Pageaux 1995 (Continued)
Interventions UDCA group
- Dose 600 mgday in three divided doses
- Route orally
- Duration immediately after intestinal transit recovery usually between postoperative
days three and five and continue for two months
Placebo group
- identical-appearing capsules administered in the same quantity and manner
Co-interventions all patients received standard triple-drug regimens (steroids azathio-
prine and cyclosporine or tacrolimus)
Outcomes Number of patients with acute cellular rejection
Number of patients with steroid-resistant rejection
Notes Letter was sent to the authors in September 2009 No reply was received
Risk of bias
Item Authorsrsquo judgement Description
Adequate sequence generation Unclear No information provided
Allocation concealment Unclear No information provided
Blinding Unclear Method of blinding not described
Incomplete outcome data addressed
All outcomes
Yes Five patients died from non-immunologi-
cal causes before the end of the first month
and were excluded from the study Reasons
were reported
Free of selective reporting Unclear Not enough information provided
Sample size calculation No Not performed
Intention-to-treat analysis No Not stated and not used
Baseline imbalance Unclear Not enough information provided
Early stopping of trial Unclear Not enough information provided
Sama 1991
Methods Study design randomised controlled trial
Participants Country Italy
Publication language English
Inclusion criteria
28Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Sama 1991 (Continued)
- patients who underwent liver transplantation
Exclusion criteria
- not mentioned
Participants
- UDCA group (n = 20)
Mean age (years +- SD)
no information
Ratio of sex (malefemale) no information
Origins of liver diseases
no information
- Control group (n = 20)
Mean age (years +- SD)
no information
Ratio of sex (malefemale) no information
Origins of liver diseases
no information
Interventions UDCA group
- Dose 600 mgday in two divided doses
- Route orally
- Duration immediately after intestinal transit recovery usually between postoperative
day five and day seven and continue for six months
Control group
- no treatment
Co-interventions all patients received standard immunosuppressive treatment (steroids
and cyclosporine)
Outcomes All cause mortality
Number of patients with acute cellular rejection
Notes Abstract
Letter was sent to the authors in September 2009 No reply was received
Risk of bias
Item Authorsrsquo judgement Description
Adequate sequence generation Unclear A randomisation list was performed before
patients were admitted to the trial (infor-
mation from principal author)
Allocation concealment Unclear No information provided
Blinding Unclear The principle author provided information
that the study was made according to a
single-blind randomised protocol The pri-
mary outcome was the occurrence of biopsy
proven rejection episodes The pathologists
were blind but the patients were not
29Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Sama 1991 (Continued)
Incomplete outcome data addressed
All outcomes
Unclear Five patients from the UDCA group and
six patients from the placebo group were
excluded Reasons for exclusion were not
fully stated
Free of selective reporting No Data about survival of patients were not
adequately reported
Sample size calculation No Not performed
Intention-to-treat analysis No Not stated and not used
Baseline imbalance Unclear Basic characteristics of patients not re-
ported
Early stopping of trial Unclear Not enough information provided
UDCA = ursodeoxycholic acid
TUDCA = tauroursodeoxycholic acid
PBC = primary biliary cirrhosis
PSC = primary sclerosing cholangitis
OKT3 = anti-CD3 monoclonal antibody
Characteristics of excluded studies [ordered by study ID]
Assy 2007 A randomised controlled trial that included only recipients of liver transplantation with stable graft function and
no episodes of rejection for at least 2 years that were then offered total immunosuppression withdrawal Fourteen
patients received UDCA (15 mgkg body weightday) and 12 received placebo Rejection occurred in 43 and
75 of patients respectively (no significant difference) None developed chronic rejection After follow-up two
patients were free of immunosuppression 80 were steroid free and 50 were able to reduce their dose of
cyclosporine
Clavien 1996 Case series Fifty consecutive liver-transplanted patients were treated with a standard cyclosporine immunosup-
pressive regimen Twenty three of the 43 survivors developed an episode of rejection and UDCA (10 mgkg
weightday) was initiated Only one patient had a second episode of rejection
Friman 1992 Observational study Thirty-three liver-transplanted patients received 10 mg UDCAkg body weightday for
median of 10 months (range four to 21 months) Eight historical liver-transplanted patients served as control
group The rejection incidence was significantly lower in the patients who received the treatment with UDCA
Biochemistry one month after transplantation demonstrated significantly lower average values of aminotrans-
ferases and alkaline phosphatases in patients treated with UDCA than in the control group
30Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
Heathcote 1999 Observational study From 1987 to 1996 37 UDCA treated and 53 placebo treated patients with primary biliary
cirrhosis were referred for transplantation Posttransplantation survival rates at one month were 939 in the
UDCA group and 884 in the placebo group and one year survival rates were 903 and 784 respectively
(no significant differences) However rejection (type not defined - a secondary outcome measure) occurred
significantly less often in the UDCA group (429) than in placebo group (688)
Henriksson 1991 Observational study All patients in this study were given sequential quadruple immunosuppression with anti-
lymphocyte globulin azathioprine steroids and cyclosporine All patients with primary graft function (n = 11)
were treated with 10 mg UDCAkg body weightday starting during the first postoperative week Patients who
received liver transplantation in the first 6 months of 1989 (n = 8) served as controls In the control group one
patient died after 9 months with chronic graft dysfunction and six patients had rejection episodes during the
first postoperative month All patients in the UDCA group were alive without rejection episodes
Persson 1990 Observational study All 11 adult patients transplanted between August 1989 and January 1990 with primary
graft function were treated with 10 mg UDCA kg body weightday Eight patients transplanted during the first
half of 1989 served as control UDCA was started during the first postoperative week and the treatment was
continued for six months All patients in the UDCA treated group survived with satisfactory graft function In
the control group six patients had at least one rejection episode needing treatment during the first postoperative
month
Rafael 1995 Observational study Seventeen patients who underwent liver transplantation between February 1990 and April
1993 and developed biliary complications after transplantation were retrospectively analysed regarding treatment
with UDCA UDCA was given in a dose of 500 to 1000 mgday Ten patients were treated for at least one year while
seven patients were treated for 14 to 250 days UDCA significantly improved gammaglutamyl transpeptidase in
liver graft recipients with biliary complications There was also a trend towards improvement in serum bilirubin
and alanine transaminase values
Sama 1998 Observational study Thirty-four patients who underwent liver transplantation between January 1995 and June
1996 were included in the study Seventeen were treated with UDCA 10 mgkg body weightday during 6
months while 17 served as controls on the basis of having undergone liver transplantation closest to UDCA
patients A significant decrease in serum bilirubin levels was observed in UDCA patients There was a significantly
higher incidence of recurrent hepatitis in the control group
UDCA ursodeoxycholic acid
31Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
D A T A A N D A N A L Y S E S
Comparison 1 Bile acids for liver-transplanted patients
Outcome or subgroup titleNo of
studies
No of
participants Statistical method Effect size
1 All-cause mortality at maximum
follow-up
5 257 Risk Ratio (M-H Fixed 95 CI) 085 [053 136]
11 UDCA versus placebo or
no treatment
4 224 Risk Ratio (M-H Fixed 95 CI) 080 [049 130]
12 TUDCA versus no
treatment
1 33 Risk Ratio (M-H Fixed 95 CI) 159 [030 833]
2 All-cause mortality worst-best
case and best-worst case
scenarios
5 Risk Ratio (M-H Fixed 95 CI) Subtotals only
21 Worst-best case scenario 5 257 Risk Ratio (M-H Fixed 95 CI) 130 [086 196]
22 Best-worst case scenario 5 257 Risk Ratio (M-H Fixed 95 CI) 058 [038 090]
3 Subgroup analyses all-cause
mortality at maximum
follow-up according to time of
start of bile acids
5 257 Risk Ratio (M-H Fixed 95 CI) 085 [053 136]
31 Less than three days after
transplantation
1 102 Risk Ratio (M-H Fixed 95 CI) 124 [061 254]
32 Three days or more after
transplantation
4 155 Risk Ratio (M-H Fixed 95 CI) 063 [033 120]
4 Subgroup analyses all cause
mortality at maximum
follow-up according to
treatment duration
5 257 Risk Ratio (M-H Fixed 95 CI) 085 [053 136]
41 Less than six months 3 184 Risk Ratio (M-H Fixed 95 CI) 078 [045 138]
42 Six months or more 2 73 Risk Ratio (M-H Fixed 95 CI) 102 [043 240]
5 Number of deaths related
to rejection at maximum
follow-up
1 102 Risk Ratio (M-H Fixed 95 CI) 030 [001 712]
51 UDCA versus placebo 1 102 Risk Ratio (M-H Fixed 95 CI) 030 [001 712]
6 Number of retransplantations at
maximum follow-up
2 132 Risk Ratio (M-H Fixed 95 CI) 076 [020 286]
7 Number of patients with acute
cellular rejection at maximum
follow-up
7 339 Risk Ratio (M-H Fixed 95 CI) 089 [074 106]
71 UDCA versus placebo or
no treatment
6 306 Risk Ratio (M-H Fixed 95 CI) 089 [074 108]
72 TUDCA versus no
treatment
1 33 Risk Ratio (M-H Fixed 95 CI) 085 [045 160]
8 Subgroup analysis number of
patients with acute cellular
rejection according to time of
start of bile acid
7 339 Risk Ratio (M-H Fixed 95 CI) 089 [074 106]
32Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
81 Less than three days after
transplantation
2 134 Risk Ratio (M-H Fixed 95 CI) 084 [063 111]
82 Three days or more after
liver transplantation
5 205 Risk Ratio (M-H Fixed 95 CI) 092 [072 117]
9 Subgroup analysis number
of patients with acute
cellular rejection according to
treatment duration
7 339 Risk Ratio (M-H Fixed 95 CI) 089 [074 106]
91 Less than six months 5 266 Risk Ratio (M-H Fixed 95 CI) 087 [071 107]
92 Six months or more 2 73 Risk Ratio (M-H Fixed 95 CI) 094 [065 136]
10 Number of patients with
chronic rejection at maximum
follow-up
3 184 Risk Ratio (M-H Fixed 95 CI) 028 [008 095]
11 Number of patients with
steroid-resistant rejection at
maximum follow-up
4 234 Risk Ratio (M-H Fixed 95 CI) 077 [047 127]
12 Serum bilirubin (mgdl) at the
end of treatment
1 30 Mean Difference (IV Fixed 95 CI) 26 [-096 616]
13 Number of days of
hospitalisation after liver
transplantation
1 52 Mean Difference (IV Fixed 95 CI) -85 [-1667 -033]
14 Adverse events 3 187 Risk Ratio (M-H Fixed 95 CI) 088 [030 260]
Analysis 11 Comparison 1 Bile acids for liver-transplanted patients Outcome 1 All-cause mortality at
maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 1 All-cause mortality at maximum follow-up
Study or subgroup Favours bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 UDCA versus placebo or no treatment
Barnes 1997 228 724 253 024 [ 006 107 ]
Fleckenstein 1998 214 416 125 057 [ 012 266 ]
Keiding 1997 1454 1048 355 124 [ 061 254 ]
Sama 1991 520 620 201 083 [ 030 229 ]
Subtotal (95 CI) 116 108 935 080 [ 049 130 ]
Total events 23 (Favours bile acids) 27 (Control)
Heterogeneity Chi2 = 416 df = 3 (P = 025) I2 =28
Test for overall effect Z = 091 (P = 036)
01 02 05 1 2 5 10
Favours bile acids Favours control
(Continued )
33Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Favours bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
2 TUDCA versus no treatment
Angelico 1999 316 217 65 159 [ 030 833 ]
Subtotal (95 CI) 16 17 65 159 [ 030 833 ]
Total events 3 (Favours bile acids) 2 (Control)
Heterogeneity not applicable
Test for overall effect Z = 055 (P = 058)
Total (95 CI) 132 125 1000 085 [ 053 136 ]
Total events 26 (Favours bile acids) 29 (Control)
Heterogeneity Chi2 = 466 df = 4 (P = 032) I2 =14
Test for overall effect Z = 069 (P = 049)
01 02 05 1 2 5 10
Favours bile acids Favours control
Analysis 12 Comparison 1 Bile acids for liver-transplanted patients Outcome 2 All-cause mortality worst-
best case and best-worst case scenarios
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 2 All-cause mortality worst-best case and best-worst case scenarios
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 Worst-best case scenario
Angelico 1999 516 217 65 266 [ 060 1180 ]
Barnes 1997 828 724 253 098 [ 042 230 ]
Fleckenstein 1998 314 416 125 086 [ 023 319 ]
Keiding 1997 1954 1048 355 169 [ 087 327 ]
Sama 1991 520 620 201 083 [ 030 229 ]
Subtotal (95 CI) 132 125 1000 130 [ 086 196 ]
Total events 40 (Bile acids) 29 (Control)
Heterogeneity Chi2 = 303 df = 4 (P = 055) I2 =00
Test for overall effect Z = 123 (P = 022)
2 Best-worst case scenario
005 02 1 5 20
Favours bile acids Favours control
(Continued )
34Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Angelico 1999 316 417 90 080 [ 021 302 ]
Barnes 1997 228 1124 274 016 [ 004 063 ]
Fleckenstein 1998 214 616 130 038 [ 009 159 ]
Keiding 1997 1454 1548 368 083 [ 045 154 ]
Sama 1991 520 620 139 083 [ 030 229 ]
Subtotal (95 CI) 132 125 1000 058 [ 038 090 ]
Total events 26 (Bile acids) 42 (Control)
Heterogeneity Chi2 = 567 df = 4 (P = 023) I2 =29
Test for overall effect Z = 247 (P = 0014)
005 02 1 5 20
Favours bile acids Favours control
Analysis 13 Comparison 1 Bile acids for liver-transplanted patients Outcome 3 Subgroup analyses all-
cause mortality at maximum follow-up according to time of start of bile acids
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 3 Subgroup analyses all-cause mortality at maximum follow-up according to time of start of bile acids
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 Less than three days after transplantation
Keiding 1997 1454 1048 355 124 [ 061 254 ]
Subtotal (95 CI) 54 48 355 124 [ 061 254 ]
Total events 14 (Bile acids) 10 (Control)
Heterogeneity not applicable
Test for overall effect Z = 060 (P = 055)
2 Three days or more after transplantation
Angelico 1999 316 217 65 159 [ 030 833 ]
Barnes 1997 228 724 253 024 [ 006 107 ]
Fleckenstein 1998 214 416 125 057 [ 012 266 ]
Sama 1991 520 620 201 083 [ 030 229 ]
005 02 1 5 20
Favours bile acids Favours control
(Continued )
35Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Subtotal (95 CI) 78 77 645 063 [ 033 120 ]
Total events 12 (Bile acids) 19 (Control)
Heterogeneity Chi2 = 310 df = 3 (P = 038) I2 =3
Test for overall effect Z = 141 (P = 016)
Total (95 CI) 132 125 1000 085 [ 053 136 ]
Total events 26 (Bile acids) 29 (Control)
Heterogeneity Chi2 = 466 df = 4 (P = 032) I2 =14
Test for overall effect Z = 069 (P = 049)
005 02 1 5 20
Favours bile acids Favours control
Analysis 14 Comparison 1 Bile acids for liver-transplanted patients Outcome 4 Subgroup analyses all
cause mortality at maximum follow-up according to treatment duration
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 4 Subgroup analyses all cause mortality at maximum follow-up according to treatment duration
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 Less than six months
Barnes 1997 228 724 253 024 [ 006 107 ]
Fleckenstein 1998 214 416 125 057 [ 012 266 ]
Keiding 1997 1454 1048 355 124 [ 061 254 ]
Subtotal (95 CI) 96 88 734 078 [ 045 138 ]
Total events 18 (Bile acids) 21 (Control)
Heterogeneity Chi2 = 417 df = 2 (P = 012) I2 =52
Test for overall effect Z = 084 (P = 040)
2 Six months or more
Angelico 1999 316 217 65 159 [ 030 833 ]
Sama 1991 520 620 201 083 [ 030 229 ]
Subtotal (95 CI) 36 37 266 102 [ 043 240 ]
Total events 8 (Bile acids) 8 (Control)
Heterogeneity Chi2 = 043 df = 1 (P = 051) I2 =00
005 02 1 5 20
Favours bile acids Favours control
(Continued )
36Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Test for overall effect Z = 004 (P = 097)
Total (95 CI) 132 125 1000 085 [ 053 136 ]
Total events 26 (Bile acids) 29 (Control)
Heterogeneity Chi2 = 466 df = 4 (P = 032) I2 =14
Test for overall effect Z = 069 (P = 049)
005 02 1 5 20
Favours bile acids Favours control
Analysis 15 Comparison 1 Bile acids for liver-transplanted patients Outcome 5 Number of deaths related
to rejection at maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 5 Number of deaths related to rejection at maximum follow-up
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 UDCA versus placebo
Keiding 1997 054 148 1000 030 [ 001 712 ]
Total (95 CI) 54 48 1000 030 [ 001 712 ]
Total events 0 (Bile acids) 1 (Control)
Heterogeneity not applicable
Test for overall effect Z = 075 (P = 045)
0001 001 01 1 10 100 1000
Favours bile acids Favours control
37Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 16 Comparison 1 Bile acids for liver-transplanted patients Outcome 6 Number of
retransplantations at maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 6 Number of retransplantations at maximum follow-up
Study or subgroup Bile acids Placebo Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Fleckenstein 1998 214 016 100 567 [ 029 10891 ]
Keiding 1997 154 448 900 022 [ 003 192 ]
Total (95 CI) 68 64 1000 076 [ 020 286 ]
Total events 3 (Bile acids) 4 (Placebo)
Heterogeneity Chi2 = 303 df = 1 (P = 008) I2 =67
Test for overall effect Z = 040 (P = 069)
0001 001 01 1 10 100 1000
Favours bile acids Favours placebo
Analysis 17 Comparison 1 Bile acids for liver-transplanted patients Outcome 7 Number of patients with
acute cellular rejection at maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 7 Number of patients with acute cellular rejection at maximum follow-up
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 UDCA versus placebo or no treatment
Barnes 1997 1728 1724 180 086 [ 058 127 ]
Fleckenstein 1998 814 916 83 102 [ 054 190 ]
Keiding 1997 3554 3248 333 097 [ 073 129 ]
Koneru 1993 316 916 89 033 [ 011 101 ]
Pageaux 1995 926 924 92 092 [ 044 193 ]
Sama 1991 1320 1320 128 100 [ 063 158 ]
Subtotal (95 CI) 158 148 905 089 [ 074 108 ]
01 02 05 1 2 5 10
Favours bile acids Favours control
(Continued )
38Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Total events 85 (Bile acids) 89 (Control)
Heterogeneity Chi2 = 387 df = 5 (P = 057) I2 =00
Test for overall effect Z = 120 (P = 023)
2 TUDCA versus no treatment
Angelico 1999 816 1017 95 085 [ 045 160 ]
Subtotal (95 CI) 16 17 95 085 [ 045 160 ]
Total events 8 (Bile acids) 10 (Control)
Heterogeneity not applicable
Test for overall effect Z = 050 (P = 061)
Total (95 CI) 174 165 1000 089 [ 074 106 ]
Total events 93 (Bile acids) 99 (Control)
Heterogeneity Chi2 = 392 df = 6 (P = 069) I2 =00
Test for overall effect Z = 130 (P = 019)
01 02 05 1 2 5 10
Favours bile acids Favours control
Analysis 18 Comparison 1 Bile acids for liver-transplanted patients Outcome 8 Subgroup analysis
number of patients with acute cellular rejection according to time of start of bile acid
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 8 Subgroup analysis number of patients with acute cellular rejection according to time of start of bile acid
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 Less than three days after transplantation
Keiding 1997 3554 3248 333 097 [ 073 129 ]
Koneru 1993 316 916 89 033 [ 011 101 ]
Subtotal (95 CI) 70 64 422 084 [ 063 111 ]
Total events 38 (Bile acids) 41 (Control)
Heterogeneity Chi2 = 374 df = 1 (P = 005) I2 =73
Test for overall effect Z = 124 (P = 022)
2 Three days or more after liver transplantation
Angelico 1999 816 1017 95 085 [ 045 160 ]
01 02 05 1 2 5 10
Favours bile acids Favours control
(Continued )
39Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Barnes 1997 1728 1724 180 086 [ 058 127 ]
Fleckenstein 1998 814 916 83 102 [ 054 190 ]
Pageaux 1995 926 924 92 092 [ 044 193 ]
Sama 1991 1320 1320 128 100 [ 063 158 ]
Subtotal (95 CI) 104 101 578 092 [ 072 117 ]
Total events 55 (Bile acids) 58 (Control)
Heterogeneity Chi2 = 041 df = 4 (P = 098) I2 =00
Test for overall effect Z = 067 (P = 050)
Total (95 CI) 174 165 1000 089 [ 074 106 ]
Total events 93 (Bile acids) 99 (Control)
Heterogeneity Chi2 = 392 df = 6 (P = 069) I2 =00
Test for overall effect Z = 130 (P = 019)
01 02 05 1 2 5 10
Favours bile acids Favours control
40Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 19 Comparison 1 Bile acids for liver-transplanted patients Outcome 9 Subgroup analysis
number of patients with acute cellular rejection according to treatment duration
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 9 Subgroup analysis number of patients with acute cellular rejection according to treatment duration
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 Less than six months
Barnes 1997 1728 1724 180 086 [ 058 127 ]
Fleckenstein 1998 814 916 83 102 [ 054 190 ]
Keiding 1997 3554 3248 333 097 [ 073 129 ]
Koneru 1993 316 916 89 033 [ 011 101 ]
Pageaux 1995 926 924 92 092 [ 044 193 ]
Subtotal (95 CI) 138 128 777 087 [ 071 107 ]
Total events 72 (Bile acids) 76 (Control)
Heterogeneity Chi2 = 374 df = 4 (P = 044) I2 =00
Test for overall effect Z = 129 (P = 020)
2 Six months or more
Angelico 1999 816 1017 95 085 [ 045 160 ]
Sama 1991 1320 1320 128 100 [ 063 158 ]
Subtotal (95 CI) 36 37 223 094 [ 065 136 ]
Total events 21 (Bile acids) 23 (Control)
Heterogeneity Chi2 = 017 df = 1 (P = 068) I2 =00
Test for overall effect Z = 035 (P = 073)
Total (95 CI) 174 165 1000 089 [ 074 106 ]
Total events 93 (Bile acids) 99 (Control)
Heterogeneity Chi2 = 392 df = 6 (P = 069) I2 =00
Test for overall effect Z = 130 (P = 019)
01 02 05 1 2 5 10
Favours bile acids Favours control
41Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 110 Comparison 1 Bile acids for liver-transplanted patients Outcome 10 Number of patients
with chronic rejection at maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 10 Number of patients with chronic rejection at maximum follow-up
Study or subgroup Bile acids Placebo Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Barnes 1997 128 624 611 014 [ 002 110 ]
Fleckenstein 1998 114 116 88 114 [ 008 1663 ]
Keiding 1997 154 348 300 030 [ 003 275 ]
Total (95 CI) 96 88 1000 028 [ 008 095 ]
Total events 3 (Bile acids) 10 (Placebo)
Heterogeneity Chi2 = 148 df = 2 (P = 048) I2 =00
Test for overall effect Z = 204 (P = 0041)
0001 001 01 1 10 100 1000
Favours bile acids Favours placebo
Analysis 111 Comparison 1 Bile acids for liver-transplanted patients Outcome 11 Number of patients
with steroid-resistant rejection at maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 11 Number of patients with steroid-resistant rejection at maximum follow-up
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Barnes 1997 328 724 277 037 [ 011 127 ]
Fleckenstein 1998 314 316 103 114 [ 027 478 ]
Keiding 1997 1454 1548 583 083 [ 045 154 ]
Pageaux 1995 226 124 38 185 [ 018 1908 ]
Total (95 CI) 122 112 1000 077 [ 047 127 ]
Total events 22 (Bile acids) 26 (Control)
Heterogeneity Chi2 = 226 df = 3 (P = 052) I2 =00
Test for overall effect Z = 102 (P = 031)
001 01 1 10 100
Favours bile acids Favours placebo
42Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 112 Comparison 1 Bile acids for liver-transplanted patients Outcome 12 Serum bilirubin (mgdl)
at the end of treatment
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 12 Serum bilirubin (mgdl) at the end of treatment
Study or subgroup Bile acids Placebo Mean Difference Weight Mean Difference
N Mean(SD) N Mean(SD) IVFixed95 CI IVFixed95 CI
Fleckenstein 1998 14 319 (68) 16 059 (022) 1000 260 [ -096 616 ]
Total (95 CI) 14 16 1000 260 [ -096 616 ]
Heterogeneity not applicable
Test for overall effect Z = 143 (P = 015)
-10 -5 0 5 10
Favours bile acids Favours placebo
Analysis 113 Comparison 1 Bile acids for liver-transplanted patients Outcome 13 Number of days of
hospitalisation after liver transplantation
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 13 Number of days of hospitalisation after liver transplantation
Study or subgroup Bile acids Placebo Mean Difference Weight Mean Difference
N Mean(SD) N Mean(SD) IVFixed95 CI IVFixed95 CI
Barnes 1997 28 25 (17) 24 335 (13) 1000 -850 [ -1667 -033 ]
Total (95 CI) 28 24 1000 -850 [ -1667 -033 ]
Heterogeneity not applicable
Test for overall effect Z = 204 (P = 0041)
-100 -50 0 50 100
Favours bile acids Favours placebo
43Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 114 Comparison 1 Bile acids for liver-transplanted patients Outcome 14 Adverse events
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 14 Adverse events
Study or subgroup Bile acids Placebo Risk Ratio Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Angelico 1999 016 017 00 [ 00 00 ]
Barnes 1997 128 124 086 [ 006 1298 ]
Keiding 1997 554 548 089 [ 027 288 ]
Total (95 CI) 98 89 088 [ 030 260 ]
Total events 6 (Bile acids) 6 (Placebo)
Heterogeneity Chi2 = 000 df = 1 (P = 098) I2 =00
Test for overall effect Z = 022 (P = 082)
001 01 1 10 100
Favours bile acids Favours placebo
A P P E N D I C E S
Appendix 1 Search strategies
Data Base Date of Search Search Strategy
The Cochrane Hepato-Biliary Group Con-
trolled Trials Register
September 2009 1 rsquoliver transplantationrsquo and rsquochenodeoxy-
cholicrsquo
2 rsquoliver transplantationrsquo and rsquocholicrsquo
3 rsquoliver transplantationrsquo and rsquodeoxycholicrsquo
4 rsquoliver transplantationrsquo and rsquoglycochen-
odeoxycholicrsquo
5 rsquoliver transplantationrsquo and rsquoglycocholicrsquo
6 rsquoliver transplantationrsquo and rsquoglycodeoxy-
cholicrsquo
7 rsquoliver transplantationrsquo and rsquoglycolitho-
cholicrsquo
8 rsquoliver transplantationrsquo and rsquohyodeoxy-
cholicrsquo
9 rsquoliver transplantationrsquo and rsquolithocholicrsquo
10 rsquoliver transplantationrsquo and rsquotaurochen-
odeoxycholicrsquo
44Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
11 rsquoliver transplantationrsquo and rsquotauro-
cholicrsquo
12 rsquoliver transplantationrsquo and rsquotaurodehy-
drocholicrsquo
13 rsquoliver transplantationrsquo and rsquotau-
rodeoxycholicrsquo
14 rsquoliver transplantationrsquo and rsquotauroglyco-
cholicrsquo
15 rsquoliver transplantationrsquo and rsquotaurolitho-
cholicrsquo
16 rsquoliver transplantationrsquo and rsquotaurosel-
cholicrsquo
17 rsquoliver transplantationrsquo and rsquotaurourso-
cholicrsquo
18 rsquoliver transplantationrsquo and rsquotaurour-
sodeoxycholicrsquo
19 rsquoliver transplantationrsquo and rsquoursocholicrsquo
20 rsquoliver transplantationrsquo and rsquoursodeoxy-
cholicrsquo
The Cochrane Central Register of Con-
trolled Trials in The Cochrane Library
Issue 3 2009 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
6 3 or 4
7 5 and 6
MEDLINE September 2009 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
45Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
6 3 or 4
7 5 and 6
8 RANDOMIZED-CONTROLLED-
TRIAL ME
9 RANDOM
10 8 or 9
11 7 and 10
EMBASE September 2009 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
6 3 or 4
7 5 and 6
8 RANDOMIZED-CONTROLLED-
TRIAL ME
9 RANDOM
10 8 or 9
11 7 and 10
46Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
Science Citation Index Expanded September 2009 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
6 3 or 4
7 5 and 6
8 RANDOMIZED-CONTROLLED-
TRIAL ME
9 RANDOM
10 8 or 9
11 7 and 10
The Chinese Biomedical Database Searched from January 1980 to April 2002 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
47Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
6 3 or 4
7 5 and 6
8 RANDOMIZED-CONTROLLED-
TRIAL ME
9 RANDOM
10 8 or 9
11 7 and 10
W H A T rsquo S N E W
Last assessed as up-to-date 8 February 2010
18 September 2009 New citation required but conclusions have not
changed
This review is an updated version of a review that was
published for the first time in Issue 3 2005 of TheCochrane Library by Chen 2003b
18 September 2009 New search has been performed No new studies fulfilled the inclusion criteria
H I S T O R Y
Protocol first published Issue 3 2003
Review first published Issue 3 2005
C O N T R I B U T I O N S O F A U T H O R S
GP and VG independently performed searches of relevant databases GP validated the search selected trials for inclusion contacted
the authors of the trials performed data extraction and data analysis and drafted the systematic review VG revised the review update
CG and DS revised the review update solved discrepancies of data extraction validated data analyses and provided consultation
D E C L A R A T I O N S O F I N T E R E S T
None known
48Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
S O U R C E S O F S U P P O R T
Internal sources
bull Copenhagen Trial Unit Denmark
External sources
bull Danish Medical Research Councilrsquos Grant on Getting Research into Practice (GRIP) Denmark
D I F F E R E N C E S B E T W E E N P R O T O C O L A N D R E V I E W
We assessed the risk of bias in the included studies for another four domains that were added to the review protocol (incomplete
outcome data selective outcome reporting baseline imbalance and early stopping of trial) In general the text of the risk of bias
domains were updated following Higgins 2008 Trials were considered at low risk of bias when judged as adequate in all domains
Quasi-randomised studies observational and case-control studies were included for the report of adverse events
We performed trial sequential analysis for outcomes demonstrating a statistically significant result
I N D E X T E R M S
Medical Subject Headings (MeSH)
lowastLiver Transplantation Cholagogues and Choleretics [lowasttherapeutic use] Graft Rejection [lowastprevention amp control] Randomized Con-
trolled Trials as Topic Taurochenodeoxycholic Acid [lowasttherapeutic use] Ursodeoxycholic Acid [lowasttherapeutic use]
MeSH check words
Humans
49Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Pageaux 1995 (Continued)
Interventions UDCA group
- Dose 600 mgday in three divided doses
- Route orally
- Duration immediately after intestinal transit recovery usually between postoperative
days three and five and continue for two months
Placebo group
- identical-appearing capsules administered in the same quantity and manner
Co-interventions all patients received standard triple-drug regimens (steroids azathio-
prine and cyclosporine or tacrolimus)
Outcomes Number of patients with acute cellular rejection
Number of patients with steroid-resistant rejection
Notes Letter was sent to the authors in September 2009 No reply was received
Risk of bias
Item Authorsrsquo judgement Description
Adequate sequence generation Unclear No information provided
Allocation concealment Unclear No information provided
Blinding Unclear Method of blinding not described
Incomplete outcome data addressed
All outcomes
Yes Five patients died from non-immunologi-
cal causes before the end of the first month
and were excluded from the study Reasons
were reported
Free of selective reporting Unclear Not enough information provided
Sample size calculation No Not performed
Intention-to-treat analysis No Not stated and not used
Baseline imbalance Unclear Not enough information provided
Early stopping of trial Unclear Not enough information provided
Sama 1991
Methods Study design randomised controlled trial
Participants Country Italy
Publication language English
Inclusion criteria
28Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Sama 1991 (Continued)
- patients who underwent liver transplantation
Exclusion criteria
- not mentioned
Participants
- UDCA group (n = 20)
Mean age (years +- SD)
no information
Ratio of sex (malefemale) no information
Origins of liver diseases
no information
- Control group (n = 20)
Mean age (years +- SD)
no information
Ratio of sex (malefemale) no information
Origins of liver diseases
no information
Interventions UDCA group
- Dose 600 mgday in two divided doses
- Route orally
- Duration immediately after intestinal transit recovery usually between postoperative
day five and day seven and continue for six months
Control group
- no treatment
Co-interventions all patients received standard immunosuppressive treatment (steroids
and cyclosporine)
Outcomes All cause mortality
Number of patients with acute cellular rejection
Notes Abstract
Letter was sent to the authors in September 2009 No reply was received
Risk of bias
Item Authorsrsquo judgement Description
Adequate sequence generation Unclear A randomisation list was performed before
patients were admitted to the trial (infor-
mation from principal author)
Allocation concealment Unclear No information provided
Blinding Unclear The principle author provided information
that the study was made according to a
single-blind randomised protocol The pri-
mary outcome was the occurrence of biopsy
proven rejection episodes The pathologists
were blind but the patients were not
29Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Sama 1991 (Continued)
Incomplete outcome data addressed
All outcomes
Unclear Five patients from the UDCA group and
six patients from the placebo group were
excluded Reasons for exclusion were not
fully stated
Free of selective reporting No Data about survival of patients were not
adequately reported
Sample size calculation No Not performed
Intention-to-treat analysis No Not stated and not used
Baseline imbalance Unclear Basic characteristics of patients not re-
ported
Early stopping of trial Unclear Not enough information provided
UDCA = ursodeoxycholic acid
TUDCA = tauroursodeoxycholic acid
PBC = primary biliary cirrhosis
PSC = primary sclerosing cholangitis
OKT3 = anti-CD3 monoclonal antibody
Characteristics of excluded studies [ordered by study ID]
Assy 2007 A randomised controlled trial that included only recipients of liver transplantation with stable graft function and
no episodes of rejection for at least 2 years that were then offered total immunosuppression withdrawal Fourteen
patients received UDCA (15 mgkg body weightday) and 12 received placebo Rejection occurred in 43 and
75 of patients respectively (no significant difference) None developed chronic rejection After follow-up two
patients were free of immunosuppression 80 were steroid free and 50 were able to reduce their dose of
cyclosporine
Clavien 1996 Case series Fifty consecutive liver-transplanted patients were treated with a standard cyclosporine immunosup-
pressive regimen Twenty three of the 43 survivors developed an episode of rejection and UDCA (10 mgkg
weightday) was initiated Only one patient had a second episode of rejection
Friman 1992 Observational study Thirty-three liver-transplanted patients received 10 mg UDCAkg body weightday for
median of 10 months (range four to 21 months) Eight historical liver-transplanted patients served as control
group The rejection incidence was significantly lower in the patients who received the treatment with UDCA
Biochemistry one month after transplantation demonstrated significantly lower average values of aminotrans-
ferases and alkaline phosphatases in patients treated with UDCA than in the control group
30Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
Heathcote 1999 Observational study From 1987 to 1996 37 UDCA treated and 53 placebo treated patients with primary biliary
cirrhosis were referred for transplantation Posttransplantation survival rates at one month were 939 in the
UDCA group and 884 in the placebo group and one year survival rates were 903 and 784 respectively
(no significant differences) However rejection (type not defined - a secondary outcome measure) occurred
significantly less often in the UDCA group (429) than in placebo group (688)
Henriksson 1991 Observational study All patients in this study were given sequential quadruple immunosuppression with anti-
lymphocyte globulin azathioprine steroids and cyclosporine All patients with primary graft function (n = 11)
were treated with 10 mg UDCAkg body weightday starting during the first postoperative week Patients who
received liver transplantation in the first 6 months of 1989 (n = 8) served as controls In the control group one
patient died after 9 months with chronic graft dysfunction and six patients had rejection episodes during the
first postoperative month All patients in the UDCA group were alive without rejection episodes
Persson 1990 Observational study All 11 adult patients transplanted between August 1989 and January 1990 with primary
graft function were treated with 10 mg UDCA kg body weightday Eight patients transplanted during the first
half of 1989 served as control UDCA was started during the first postoperative week and the treatment was
continued for six months All patients in the UDCA treated group survived with satisfactory graft function In
the control group six patients had at least one rejection episode needing treatment during the first postoperative
month
Rafael 1995 Observational study Seventeen patients who underwent liver transplantation between February 1990 and April
1993 and developed biliary complications after transplantation were retrospectively analysed regarding treatment
with UDCA UDCA was given in a dose of 500 to 1000 mgday Ten patients were treated for at least one year while
seven patients were treated for 14 to 250 days UDCA significantly improved gammaglutamyl transpeptidase in
liver graft recipients with biliary complications There was also a trend towards improvement in serum bilirubin
and alanine transaminase values
Sama 1998 Observational study Thirty-four patients who underwent liver transplantation between January 1995 and June
1996 were included in the study Seventeen were treated with UDCA 10 mgkg body weightday during 6
months while 17 served as controls on the basis of having undergone liver transplantation closest to UDCA
patients A significant decrease in serum bilirubin levels was observed in UDCA patients There was a significantly
higher incidence of recurrent hepatitis in the control group
UDCA ursodeoxycholic acid
31Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
D A T A A N D A N A L Y S E S
Comparison 1 Bile acids for liver-transplanted patients
Outcome or subgroup titleNo of
studies
No of
participants Statistical method Effect size
1 All-cause mortality at maximum
follow-up
5 257 Risk Ratio (M-H Fixed 95 CI) 085 [053 136]
11 UDCA versus placebo or
no treatment
4 224 Risk Ratio (M-H Fixed 95 CI) 080 [049 130]
12 TUDCA versus no
treatment
1 33 Risk Ratio (M-H Fixed 95 CI) 159 [030 833]
2 All-cause mortality worst-best
case and best-worst case
scenarios
5 Risk Ratio (M-H Fixed 95 CI) Subtotals only
21 Worst-best case scenario 5 257 Risk Ratio (M-H Fixed 95 CI) 130 [086 196]
22 Best-worst case scenario 5 257 Risk Ratio (M-H Fixed 95 CI) 058 [038 090]
3 Subgroup analyses all-cause
mortality at maximum
follow-up according to time of
start of bile acids
5 257 Risk Ratio (M-H Fixed 95 CI) 085 [053 136]
31 Less than three days after
transplantation
1 102 Risk Ratio (M-H Fixed 95 CI) 124 [061 254]
32 Three days or more after
transplantation
4 155 Risk Ratio (M-H Fixed 95 CI) 063 [033 120]
4 Subgroup analyses all cause
mortality at maximum
follow-up according to
treatment duration
5 257 Risk Ratio (M-H Fixed 95 CI) 085 [053 136]
41 Less than six months 3 184 Risk Ratio (M-H Fixed 95 CI) 078 [045 138]
42 Six months or more 2 73 Risk Ratio (M-H Fixed 95 CI) 102 [043 240]
5 Number of deaths related
to rejection at maximum
follow-up
1 102 Risk Ratio (M-H Fixed 95 CI) 030 [001 712]
51 UDCA versus placebo 1 102 Risk Ratio (M-H Fixed 95 CI) 030 [001 712]
6 Number of retransplantations at
maximum follow-up
2 132 Risk Ratio (M-H Fixed 95 CI) 076 [020 286]
7 Number of patients with acute
cellular rejection at maximum
follow-up
7 339 Risk Ratio (M-H Fixed 95 CI) 089 [074 106]
71 UDCA versus placebo or
no treatment
6 306 Risk Ratio (M-H Fixed 95 CI) 089 [074 108]
72 TUDCA versus no
treatment
1 33 Risk Ratio (M-H Fixed 95 CI) 085 [045 160]
8 Subgroup analysis number of
patients with acute cellular
rejection according to time of
start of bile acid
7 339 Risk Ratio (M-H Fixed 95 CI) 089 [074 106]
32Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
81 Less than three days after
transplantation
2 134 Risk Ratio (M-H Fixed 95 CI) 084 [063 111]
82 Three days or more after
liver transplantation
5 205 Risk Ratio (M-H Fixed 95 CI) 092 [072 117]
9 Subgroup analysis number
of patients with acute
cellular rejection according to
treatment duration
7 339 Risk Ratio (M-H Fixed 95 CI) 089 [074 106]
91 Less than six months 5 266 Risk Ratio (M-H Fixed 95 CI) 087 [071 107]
92 Six months or more 2 73 Risk Ratio (M-H Fixed 95 CI) 094 [065 136]
10 Number of patients with
chronic rejection at maximum
follow-up
3 184 Risk Ratio (M-H Fixed 95 CI) 028 [008 095]
11 Number of patients with
steroid-resistant rejection at
maximum follow-up
4 234 Risk Ratio (M-H Fixed 95 CI) 077 [047 127]
12 Serum bilirubin (mgdl) at the
end of treatment
1 30 Mean Difference (IV Fixed 95 CI) 26 [-096 616]
13 Number of days of
hospitalisation after liver
transplantation
1 52 Mean Difference (IV Fixed 95 CI) -85 [-1667 -033]
14 Adverse events 3 187 Risk Ratio (M-H Fixed 95 CI) 088 [030 260]
Analysis 11 Comparison 1 Bile acids for liver-transplanted patients Outcome 1 All-cause mortality at
maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 1 All-cause mortality at maximum follow-up
Study or subgroup Favours bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 UDCA versus placebo or no treatment
Barnes 1997 228 724 253 024 [ 006 107 ]
Fleckenstein 1998 214 416 125 057 [ 012 266 ]
Keiding 1997 1454 1048 355 124 [ 061 254 ]
Sama 1991 520 620 201 083 [ 030 229 ]
Subtotal (95 CI) 116 108 935 080 [ 049 130 ]
Total events 23 (Favours bile acids) 27 (Control)
Heterogeneity Chi2 = 416 df = 3 (P = 025) I2 =28
Test for overall effect Z = 091 (P = 036)
01 02 05 1 2 5 10
Favours bile acids Favours control
(Continued )
33Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Favours bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
2 TUDCA versus no treatment
Angelico 1999 316 217 65 159 [ 030 833 ]
Subtotal (95 CI) 16 17 65 159 [ 030 833 ]
Total events 3 (Favours bile acids) 2 (Control)
Heterogeneity not applicable
Test for overall effect Z = 055 (P = 058)
Total (95 CI) 132 125 1000 085 [ 053 136 ]
Total events 26 (Favours bile acids) 29 (Control)
Heterogeneity Chi2 = 466 df = 4 (P = 032) I2 =14
Test for overall effect Z = 069 (P = 049)
01 02 05 1 2 5 10
Favours bile acids Favours control
Analysis 12 Comparison 1 Bile acids for liver-transplanted patients Outcome 2 All-cause mortality worst-
best case and best-worst case scenarios
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 2 All-cause mortality worst-best case and best-worst case scenarios
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 Worst-best case scenario
Angelico 1999 516 217 65 266 [ 060 1180 ]
Barnes 1997 828 724 253 098 [ 042 230 ]
Fleckenstein 1998 314 416 125 086 [ 023 319 ]
Keiding 1997 1954 1048 355 169 [ 087 327 ]
Sama 1991 520 620 201 083 [ 030 229 ]
Subtotal (95 CI) 132 125 1000 130 [ 086 196 ]
Total events 40 (Bile acids) 29 (Control)
Heterogeneity Chi2 = 303 df = 4 (P = 055) I2 =00
Test for overall effect Z = 123 (P = 022)
2 Best-worst case scenario
005 02 1 5 20
Favours bile acids Favours control
(Continued )
34Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Angelico 1999 316 417 90 080 [ 021 302 ]
Barnes 1997 228 1124 274 016 [ 004 063 ]
Fleckenstein 1998 214 616 130 038 [ 009 159 ]
Keiding 1997 1454 1548 368 083 [ 045 154 ]
Sama 1991 520 620 139 083 [ 030 229 ]
Subtotal (95 CI) 132 125 1000 058 [ 038 090 ]
Total events 26 (Bile acids) 42 (Control)
Heterogeneity Chi2 = 567 df = 4 (P = 023) I2 =29
Test for overall effect Z = 247 (P = 0014)
005 02 1 5 20
Favours bile acids Favours control
Analysis 13 Comparison 1 Bile acids for liver-transplanted patients Outcome 3 Subgroup analyses all-
cause mortality at maximum follow-up according to time of start of bile acids
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 3 Subgroup analyses all-cause mortality at maximum follow-up according to time of start of bile acids
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 Less than three days after transplantation
Keiding 1997 1454 1048 355 124 [ 061 254 ]
Subtotal (95 CI) 54 48 355 124 [ 061 254 ]
Total events 14 (Bile acids) 10 (Control)
Heterogeneity not applicable
Test for overall effect Z = 060 (P = 055)
2 Three days or more after transplantation
Angelico 1999 316 217 65 159 [ 030 833 ]
Barnes 1997 228 724 253 024 [ 006 107 ]
Fleckenstein 1998 214 416 125 057 [ 012 266 ]
Sama 1991 520 620 201 083 [ 030 229 ]
005 02 1 5 20
Favours bile acids Favours control
(Continued )
35Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Subtotal (95 CI) 78 77 645 063 [ 033 120 ]
Total events 12 (Bile acids) 19 (Control)
Heterogeneity Chi2 = 310 df = 3 (P = 038) I2 =3
Test for overall effect Z = 141 (P = 016)
Total (95 CI) 132 125 1000 085 [ 053 136 ]
Total events 26 (Bile acids) 29 (Control)
Heterogeneity Chi2 = 466 df = 4 (P = 032) I2 =14
Test for overall effect Z = 069 (P = 049)
005 02 1 5 20
Favours bile acids Favours control
Analysis 14 Comparison 1 Bile acids for liver-transplanted patients Outcome 4 Subgroup analyses all
cause mortality at maximum follow-up according to treatment duration
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 4 Subgroup analyses all cause mortality at maximum follow-up according to treatment duration
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 Less than six months
Barnes 1997 228 724 253 024 [ 006 107 ]
Fleckenstein 1998 214 416 125 057 [ 012 266 ]
Keiding 1997 1454 1048 355 124 [ 061 254 ]
Subtotal (95 CI) 96 88 734 078 [ 045 138 ]
Total events 18 (Bile acids) 21 (Control)
Heterogeneity Chi2 = 417 df = 2 (P = 012) I2 =52
Test for overall effect Z = 084 (P = 040)
2 Six months or more
Angelico 1999 316 217 65 159 [ 030 833 ]
Sama 1991 520 620 201 083 [ 030 229 ]
Subtotal (95 CI) 36 37 266 102 [ 043 240 ]
Total events 8 (Bile acids) 8 (Control)
Heterogeneity Chi2 = 043 df = 1 (P = 051) I2 =00
005 02 1 5 20
Favours bile acids Favours control
(Continued )
36Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Test for overall effect Z = 004 (P = 097)
Total (95 CI) 132 125 1000 085 [ 053 136 ]
Total events 26 (Bile acids) 29 (Control)
Heterogeneity Chi2 = 466 df = 4 (P = 032) I2 =14
Test for overall effect Z = 069 (P = 049)
005 02 1 5 20
Favours bile acids Favours control
Analysis 15 Comparison 1 Bile acids for liver-transplanted patients Outcome 5 Number of deaths related
to rejection at maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 5 Number of deaths related to rejection at maximum follow-up
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 UDCA versus placebo
Keiding 1997 054 148 1000 030 [ 001 712 ]
Total (95 CI) 54 48 1000 030 [ 001 712 ]
Total events 0 (Bile acids) 1 (Control)
Heterogeneity not applicable
Test for overall effect Z = 075 (P = 045)
0001 001 01 1 10 100 1000
Favours bile acids Favours control
37Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 16 Comparison 1 Bile acids for liver-transplanted patients Outcome 6 Number of
retransplantations at maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 6 Number of retransplantations at maximum follow-up
Study or subgroup Bile acids Placebo Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Fleckenstein 1998 214 016 100 567 [ 029 10891 ]
Keiding 1997 154 448 900 022 [ 003 192 ]
Total (95 CI) 68 64 1000 076 [ 020 286 ]
Total events 3 (Bile acids) 4 (Placebo)
Heterogeneity Chi2 = 303 df = 1 (P = 008) I2 =67
Test for overall effect Z = 040 (P = 069)
0001 001 01 1 10 100 1000
Favours bile acids Favours placebo
Analysis 17 Comparison 1 Bile acids for liver-transplanted patients Outcome 7 Number of patients with
acute cellular rejection at maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 7 Number of patients with acute cellular rejection at maximum follow-up
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 UDCA versus placebo or no treatment
Barnes 1997 1728 1724 180 086 [ 058 127 ]
Fleckenstein 1998 814 916 83 102 [ 054 190 ]
Keiding 1997 3554 3248 333 097 [ 073 129 ]
Koneru 1993 316 916 89 033 [ 011 101 ]
Pageaux 1995 926 924 92 092 [ 044 193 ]
Sama 1991 1320 1320 128 100 [ 063 158 ]
Subtotal (95 CI) 158 148 905 089 [ 074 108 ]
01 02 05 1 2 5 10
Favours bile acids Favours control
(Continued )
38Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Total events 85 (Bile acids) 89 (Control)
Heterogeneity Chi2 = 387 df = 5 (P = 057) I2 =00
Test for overall effect Z = 120 (P = 023)
2 TUDCA versus no treatment
Angelico 1999 816 1017 95 085 [ 045 160 ]
Subtotal (95 CI) 16 17 95 085 [ 045 160 ]
Total events 8 (Bile acids) 10 (Control)
Heterogeneity not applicable
Test for overall effect Z = 050 (P = 061)
Total (95 CI) 174 165 1000 089 [ 074 106 ]
Total events 93 (Bile acids) 99 (Control)
Heterogeneity Chi2 = 392 df = 6 (P = 069) I2 =00
Test for overall effect Z = 130 (P = 019)
01 02 05 1 2 5 10
Favours bile acids Favours control
Analysis 18 Comparison 1 Bile acids for liver-transplanted patients Outcome 8 Subgroup analysis
number of patients with acute cellular rejection according to time of start of bile acid
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 8 Subgroup analysis number of patients with acute cellular rejection according to time of start of bile acid
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 Less than three days after transplantation
Keiding 1997 3554 3248 333 097 [ 073 129 ]
Koneru 1993 316 916 89 033 [ 011 101 ]
Subtotal (95 CI) 70 64 422 084 [ 063 111 ]
Total events 38 (Bile acids) 41 (Control)
Heterogeneity Chi2 = 374 df = 1 (P = 005) I2 =73
Test for overall effect Z = 124 (P = 022)
2 Three days or more after liver transplantation
Angelico 1999 816 1017 95 085 [ 045 160 ]
01 02 05 1 2 5 10
Favours bile acids Favours control
(Continued )
39Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Barnes 1997 1728 1724 180 086 [ 058 127 ]
Fleckenstein 1998 814 916 83 102 [ 054 190 ]
Pageaux 1995 926 924 92 092 [ 044 193 ]
Sama 1991 1320 1320 128 100 [ 063 158 ]
Subtotal (95 CI) 104 101 578 092 [ 072 117 ]
Total events 55 (Bile acids) 58 (Control)
Heterogeneity Chi2 = 041 df = 4 (P = 098) I2 =00
Test for overall effect Z = 067 (P = 050)
Total (95 CI) 174 165 1000 089 [ 074 106 ]
Total events 93 (Bile acids) 99 (Control)
Heterogeneity Chi2 = 392 df = 6 (P = 069) I2 =00
Test for overall effect Z = 130 (P = 019)
01 02 05 1 2 5 10
Favours bile acids Favours control
40Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 19 Comparison 1 Bile acids for liver-transplanted patients Outcome 9 Subgroup analysis
number of patients with acute cellular rejection according to treatment duration
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 9 Subgroup analysis number of patients with acute cellular rejection according to treatment duration
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 Less than six months
Barnes 1997 1728 1724 180 086 [ 058 127 ]
Fleckenstein 1998 814 916 83 102 [ 054 190 ]
Keiding 1997 3554 3248 333 097 [ 073 129 ]
Koneru 1993 316 916 89 033 [ 011 101 ]
Pageaux 1995 926 924 92 092 [ 044 193 ]
Subtotal (95 CI) 138 128 777 087 [ 071 107 ]
Total events 72 (Bile acids) 76 (Control)
Heterogeneity Chi2 = 374 df = 4 (P = 044) I2 =00
Test for overall effect Z = 129 (P = 020)
2 Six months or more
Angelico 1999 816 1017 95 085 [ 045 160 ]
Sama 1991 1320 1320 128 100 [ 063 158 ]
Subtotal (95 CI) 36 37 223 094 [ 065 136 ]
Total events 21 (Bile acids) 23 (Control)
Heterogeneity Chi2 = 017 df = 1 (P = 068) I2 =00
Test for overall effect Z = 035 (P = 073)
Total (95 CI) 174 165 1000 089 [ 074 106 ]
Total events 93 (Bile acids) 99 (Control)
Heterogeneity Chi2 = 392 df = 6 (P = 069) I2 =00
Test for overall effect Z = 130 (P = 019)
01 02 05 1 2 5 10
Favours bile acids Favours control
41Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 110 Comparison 1 Bile acids for liver-transplanted patients Outcome 10 Number of patients
with chronic rejection at maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 10 Number of patients with chronic rejection at maximum follow-up
Study or subgroup Bile acids Placebo Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Barnes 1997 128 624 611 014 [ 002 110 ]
Fleckenstein 1998 114 116 88 114 [ 008 1663 ]
Keiding 1997 154 348 300 030 [ 003 275 ]
Total (95 CI) 96 88 1000 028 [ 008 095 ]
Total events 3 (Bile acids) 10 (Placebo)
Heterogeneity Chi2 = 148 df = 2 (P = 048) I2 =00
Test for overall effect Z = 204 (P = 0041)
0001 001 01 1 10 100 1000
Favours bile acids Favours placebo
Analysis 111 Comparison 1 Bile acids for liver-transplanted patients Outcome 11 Number of patients
with steroid-resistant rejection at maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 11 Number of patients with steroid-resistant rejection at maximum follow-up
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Barnes 1997 328 724 277 037 [ 011 127 ]
Fleckenstein 1998 314 316 103 114 [ 027 478 ]
Keiding 1997 1454 1548 583 083 [ 045 154 ]
Pageaux 1995 226 124 38 185 [ 018 1908 ]
Total (95 CI) 122 112 1000 077 [ 047 127 ]
Total events 22 (Bile acids) 26 (Control)
Heterogeneity Chi2 = 226 df = 3 (P = 052) I2 =00
Test for overall effect Z = 102 (P = 031)
001 01 1 10 100
Favours bile acids Favours placebo
42Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 112 Comparison 1 Bile acids for liver-transplanted patients Outcome 12 Serum bilirubin (mgdl)
at the end of treatment
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 12 Serum bilirubin (mgdl) at the end of treatment
Study or subgroup Bile acids Placebo Mean Difference Weight Mean Difference
N Mean(SD) N Mean(SD) IVFixed95 CI IVFixed95 CI
Fleckenstein 1998 14 319 (68) 16 059 (022) 1000 260 [ -096 616 ]
Total (95 CI) 14 16 1000 260 [ -096 616 ]
Heterogeneity not applicable
Test for overall effect Z = 143 (P = 015)
-10 -5 0 5 10
Favours bile acids Favours placebo
Analysis 113 Comparison 1 Bile acids for liver-transplanted patients Outcome 13 Number of days of
hospitalisation after liver transplantation
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 13 Number of days of hospitalisation after liver transplantation
Study or subgroup Bile acids Placebo Mean Difference Weight Mean Difference
N Mean(SD) N Mean(SD) IVFixed95 CI IVFixed95 CI
Barnes 1997 28 25 (17) 24 335 (13) 1000 -850 [ -1667 -033 ]
Total (95 CI) 28 24 1000 -850 [ -1667 -033 ]
Heterogeneity not applicable
Test for overall effect Z = 204 (P = 0041)
-100 -50 0 50 100
Favours bile acids Favours placebo
43Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 114 Comparison 1 Bile acids for liver-transplanted patients Outcome 14 Adverse events
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 14 Adverse events
Study or subgroup Bile acids Placebo Risk Ratio Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Angelico 1999 016 017 00 [ 00 00 ]
Barnes 1997 128 124 086 [ 006 1298 ]
Keiding 1997 554 548 089 [ 027 288 ]
Total (95 CI) 98 89 088 [ 030 260 ]
Total events 6 (Bile acids) 6 (Placebo)
Heterogeneity Chi2 = 000 df = 1 (P = 098) I2 =00
Test for overall effect Z = 022 (P = 082)
001 01 1 10 100
Favours bile acids Favours placebo
A P P E N D I C E S
Appendix 1 Search strategies
Data Base Date of Search Search Strategy
The Cochrane Hepato-Biliary Group Con-
trolled Trials Register
September 2009 1 rsquoliver transplantationrsquo and rsquochenodeoxy-
cholicrsquo
2 rsquoliver transplantationrsquo and rsquocholicrsquo
3 rsquoliver transplantationrsquo and rsquodeoxycholicrsquo
4 rsquoliver transplantationrsquo and rsquoglycochen-
odeoxycholicrsquo
5 rsquoliver transplantationrsquo and rsquoglycocholicrsquo
6 rsquoliver transplantationrsquo and rsquoglycodeoxy-
cholicrsquo
7 rsquoliver transplantationrsquo and rsquoglycolitho-
cholicrsquo
8 rsquoliver transplantationrsquo and rsquohyodeoxy-
cholicrsquo
9 rsquoliver transplantationrsquo and rsquolithocholicrsquo
10 rsquoliver transplantationrsquo and rsquotaurochen-
odeoxycholicrsquo
44Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
11 rsquoliver transplantationrsquo and rsquotauro-
cholicrsquo
12 rsquoliver transplantationrsquo and rsquotaurodehy-
drocholicrsquo
13 rsquoliver transplantationrsquo and rsquotau-
rodeoxycholicrsquo
14 rsquoliver transplantationrsquo and rsquotauroglyco-
cholicrsquo
15 rsquoliver transplantationrsquo and rsquotaurolitho-
cholicrsquo
16 rsquoliver transplantationrsquo and rsquotaurosel-
cholicrsquo
17 rsquoliver transplantationrsquo and rsquotaurourso-
cholicrsquo
18 rsquoliver transplantationrsquo and rsquotaurour-
sodeoxycholicrsquo
19 rsquoliver transplantationrsquo and rsquoursocholicrsquo
20 rsquoliver transplantationrsquo and rsquoursodeoxy-
cholicrsquo
The Cochrane Central Register of Con-
trolled Trials in The Cochrane Library
Issue 3 2009 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
6 3 or 4
7 5 and 6
MEDLINE September 2009 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
45Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
6 3 or 4
7 5 and 6
8 RANDOMIZED-CONTROLLED-
TRIAL ME
9 RANDOM
10 8 or 9
11 7 and 10
EMBASE September 2009 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
6 3 or 4
7 5 and 6
8 RANDOMIZED-CONTROLLED-
TRIAL ME
9 RANDOM
10 8 or 9
11 7 and 10
46Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
Science Citation Index Expanded September 2009 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
6 3 or 4
7 5 and 6
8 RANDOMIZED-CONTROLLED-
TRIAL ME
9 RANDOM
10 8 or 9
11 7 and 10
The Chinese Biomedical Database Searched from January 1980 to April 2002 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
47Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
6 3 or 4
7 5 and 6
8 RANDOMIZED-CONTROLLED-
TRIAL ME
9 RANDOM
10 8 or 9
11 7 and 10
W H A T rsquo S N E W
Last assessed as up-to-date 8 February 2010
18 September 2009 New citation required but conclusions have not
changed
This review is an updated version of a review that was
published for the first time in Issue 3 2005 of TheCochrane Library by Chen 2003b
18 September 2009 New search has been performed No new studies fulfilled the inclusion criteria
H I S T O R Y
Protocol first published Issue 3 2003
Review first published Issue 3 2005
C O N T R I B U T I O N S O F A U T H O R S
GP and VG independently performed searches of relevant databases GP validated the search selected trials for inclusion contacted
the authors of the trials performed data extraction and data analysis and drafted the systematic review VG revised the review update
CG and DS revised the review update solved discrepancies of data extraction validated data analyses and provided consultation
D E C L A R A T I O N S O F I N T E R E S T
None known
48Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
S O U R C E S O F S U P P O R T
Internal sources
bull Copenhagen Trial Unit Denmark
External sources
bull Danish Medical Research Councilrsquos Grant on Getting Research into Practice (GRIP) Denmark
D I F F E R E N C E S B E T W E E N P R O T O C O L A N D R E V I E W
We assessed the risk of bias in the included studies for another four domains that were added to the review protocol (incomplete
outcome data selective outcome reporting baseline imbalance and early stopping of trial) In general the text of the risk of bias
domains were updated following Higgins 2008 Trials were considered at low risk of bias when judged as adequate in all domains
Quasi-randomised studies observational and case-control studies were included for the report of adverse events
We performed trial sequential analysis for outcomes demonstrating a statistically significant result
I N D E X T E R M S
Medical Subject Headings (MeSH)
lowastLiver Transplantation Cholagogues and Choleretics [lowasttherapeutic use] Graft Rejection [lowastprevention amp control] Randomized Con-
trolled Trials as Topic Taurochenodeoxycholic Acid [lowasttherapeutic use] Ursodeoxycholic Acid [lowasttherapeutic use]
MeSH check words
Humans
49Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Sama 1991 (Continued)
- patients who underwent liver transplantation
Exclusion criteria
- not mentioned
Participants
- UDCA group (n = 20)
Mean age (years +- SD)
no information
Ratio of sex (malefemale) no information
Origins of liver diseases
no information
- Control group (n = 20)
Mean age (years +- SD)
no information
Ratio of sex (malefemale) no information
Origins of liver diseases
no information
Interventions UDCA group
- Dose 600 mgday in two divided doses
- Route orally
- Duration immediately after intestinal transit recovery usually between postoperative
day five and day seven and continue for six months
Control group
- no treatment
Co-interventions all patients received standard immunosuppressive treatment (steroids
and cyclosporine)
Outcomes All cause mortality
Number of patients with acute cellular rejection
Notes Abstract
Letter was sent to the authors in September 2009 No reply was received
Risk of bias
Item Authorsrsquo judgement Description
Adequate sequence generation Unclear A randomisation list was performed before
patients were admitted to the trial (infor-
mation from principal author)
Allocation concealment Unclear No information provided
Blinding Unclear The principle author provided information
that the study was made according to a
single-blind randomised protocol The pri-
mary outcome was the occurrence of biopsy
proven rejection episodes The pathologists
were blind but the patients were not
29Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Sama 1991 (Continued)
Incomplete outcome data addressed
All outcomes
Unclear Five patients from the UDCA group and
six patients from the placebo group were
excluded Reasons for exclusion were not
fully stated
Free of selective reporting No Data about survival of patients were not
adequately reported
Sample size calculation No Not performed
Intention-to-treat analysis No Not stated and not used
Baseline imbalance Unclear Basic characteristics of patients not re-
ported
Early stopping of trial Unclear Not enough information provided
UDCA = ursodeoxycholic acid
TUDCA = tauroursodeoxycholic acid
PBC = primary biliary cirrhosis
PSC = primary sclerosing cholangitis
OKT3 = anti-CD3 monoclonal antibody
Characteristics of excluded studies [ordered by study ID]
Assy 2007 A randomised controlled trial that included only recipients of liver transplantation with stable graft function and
no episodes of rejection for at least 2 years that were then offered total immunosuppression withdrawal Fourteen
patients received UDCA (15 mgkg body weightday) and 12 received placebo Rejection occurred in 43 and
75 of patients respectively (no significant difference) None developed chronic rejection After follow-up two
patients were free of immunosuppression 80 were steroid free and 50 were able to reduce their dose of
cyclosporine
Clavien 1996 Case series Fifty consecutive liver-transplanted patients were treated with a standard cyclosporine immunosup-
pressive regimen Twenty three of the 43 survivors developed an episode of rejection and UDCA (10 mgkg
weightday) was initiated Only one patient had a second episode of rejection
Friman 1992 Observational study Thirty-three liver-transplanted patients received 10 mg UDCAkg body weightday for
median of 10 months (range four to 21 months) Eight historical liver-transplanted patients served as control
group The rejection incidence was significantly lower in the patients who received the treatment with UDCA
Biochemistry one month after transplantation demonstrated significantly lower average values of aminotrans-
ferases and alkaline phosphatases in patients treated with UDCA than in the control group
30Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
Heathcote 1999 Observational study From 1987 to 1996 37 UDCA treated and 53 placebo treated patients with primary biliary
cirrhosis were referred for transplantation Posttransplantation survival rates at one month were 939 in the
UDCA group and 884 in the placebo group and one year survival rates were 903 and 784 respectively
(no significant differences) However rejection (type not defined - a secondary outcome measure) occurred
significantly less often in the UDCA group (429) than in placebo group (688)
Henriksson 1991 Observational study All patients in this study were given sequential quadruple immunosuppression with anti-
lymphocyte globulin azathioprine steroids and cyclosporine All patients with primary graft function (n = 11)
were treated with 10 mg UDCAkg body weightday starting during the first postoperative week Patients who
received liver transplantation in the first 6 months of 1989 (n = 8) served as controls In the control group one
patient died after 9 months with chronic graft dysfunction and six patients had rejection episodes during the
first postoperative month All patients in the UDCA group were alive without rejection episodes
Persson 1990 Observational study All 11 adult patients transplanted between August 1989 and January 1990 with primary
graft function were treated with 10 mg UDCA kg body weightday Eight patients transplanted during the first
half of 1989 served as control UDCA was started during the first postoperative week and the treatment was
continued for six months All patients in the UDCA treated group survived with satisfactory graft function In
the control group six patients had at least one rejection episode needing treatment during the first postoperative
month
Rafael 1995 Observational study Seventeen patients who underwent liver transplantation between February 1990 and April
1993 and developed biliary complications after transplantation were retrospectively analysed regarding treatment
with UDCA UDCA was given in a dose of 500 to 1000 mgday Ten patients were treated for at least one year while
seven patients were treated for 14 to 250 days UDCA significantly improved gammaglutamyl transpeptidase in
liver graft recipients with biliary complications There was also a trend towards improvement in serum bilirubin
and alanine transaminase values
Sama 1998 Observational study Thirty-four patients who underwent liver transplantation between January 1995 and June
1996 were included in the study Seventeen were treated with UDCA 10 mgkg body weightday during 6
months while 17 served as controls on the basis of having undergone liver transplantation closest to UDCA
patients A significant decrease in serum bilirubin levels was observed in UDCA patients There was a significantly
higher incidence of recurrent hepatitis in the control group
UDCA ursodeoxycholic acid
31Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
D A T A A N D A N A L Y S E S
Comparison 1 Bile acids for liver-transplanted patients
Outcome or subgroup titleNo of
studies
No of
participants Statistical method Effect size
1 All-cause mortality at maximum
follow-up
5 257 Risk Ratio (M-H Fixed 95 CI) 085 [053 136]
11 UDCA versus placebo or
no treatment
4 224 Risk Ratio (M-H Fixed 95 CI) 080 [049 130]
12 TUDCA versus no
treatment
1 33 Risk Ratio (M-H Fixed 95 CI) 159 [030 833]
2 All-cause mortality worst-best
case and best-worst case
scenarios
5 Risk Ratio (M-H Fixed 95 CI) Subtotals only
21 Worst-best case scenario 5 257 Risk Ratio (M-H Fixed 95 CI) 130 [086 196]
22 Best-worst case scenario 5 257 Risk Ratio (M-H Fixed 95 CI) 058 [038 090]
3 Subgroup analyses all-cause
mortality at maximum
follow-up according to time of
start of bile acids
5 257 Risk Ratio (M-H Fixed 95 CI) 085 [053 136]
31 Less than three days after
transplantation
1 102 Risk Ratio (M-H Fixed 95 CI) 124 [061 254]
32 Three days or more after
transplantation
4 155 Risk Ratio (M-H Fixed 95 CI) 063 [033 120]
4 Subgroup analyses all cause
mortality at maximum
follow-up according to
treatment duration
5 257 Risk Ratio (M-H Fixed 95 CI) 085 [053 136]
41 Less than six months 3 184 Risk Ratio (M-H Fixed 95 CI) 078 [045 138]
42 Six months or more 2 73 Risk Ratio (M-H Fixed 95 CI) 102 [043 240]
5 Number of deaths related
to rejection at maximum
follow-up
1 102 Risk Ratio (M-H Fixed 95 CI) 030 [001 712]
51 UDCA versus placebo 1 102 Risk Ratio (M-H Fixed 95 CI) 030 [001 712]
6 Number of retransplantations at
maximum follow-up
2 132 Risk Ratio (M-H Fixed 95 CI) 076 [020 286]
7 Number of patients with acute
cellular rejection at maximum
follow-up
7 339 Risk Ratio (M-H Fixed 95 CI) 089 [074 106]
71 UDCA versus placebo or
no treatment
6 306 Risk Ratio (M-H Fixed 95 CI) 089 [074 108]
72 TUDCA versus no
treatment
1 33 Risk Ratio (M-H Fixed 95 CI) 085 [045 160]
8 Subgroup analysis number of
patients with acute cellular
rejection according to time of
start of bile acid
7 339 Risk Ratio (M-H Fixed 95 CI) 089 [074 106]
32Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
81 Less than three days after
transplantation
2 134 Risk Ratio (M-H Fixed 95 CI) 084 [063 111]
82 Three days or more after
liver transplantation
5 205 Risk Ratio (M-H Fixed 95 CI) 092 [072 117]
9 Subgroup analysis number
of patients with acute
cellular rejection according to
treatment duration
7 339 Risk Ratio (M-H Fixed 95 CI) 089 [074 106]
91 Less than six months 5 266 Risk Ratio (M-H Fixed 95 CI) 087 [071 107]
92 Six months or more 2 73 Risk Ratio (M-H Fixed 95 CI) 094 [065 136]
10 Number of patients with
chronic rejection at maximum
follow-up
3 184 Risk Ratio (M-H Fixed 95 CI) 028 [008 095]
11 Number of patients with
steroid-resistant rejection at
maximum follow-up
4 234 Risk Ratio (M-H Fixed 95 CI) 077 [047 127]
12 Serum bilirubin (mgdl) at the
end of treatment
1 30 Mean Difference (IV Fixed 95 CI) 26 [-096 616]
13 Number of days of
hospitalisation after liver
transplantation
1 52 Mean Difference (IV Fixed 95 CI) -85 [-1667 -033]
14 Adverse events 3 187 Risk Ratio (M-H Fixed 95 CI) 088 [030 260]
Analysis 11 Comparison 1 Bile acids for liver-transplanted patients Outcome 1 All-cause mortality at
maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 1 All-cause mortality at maximum follow-up
Study or subgroup Favours bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 UDCA versus placebo or no treatment
Barnes 1997 228 724 253 024 [ 006 107 ]
Fleckenstein 1998 214 416 125 057 [ 012 266 ]
Keiding 1997 1454 1048 355 124 [ 061 254 ]
Sama 1991 520 620 201 083 [ 030 229 ]
Subtotal (95 CI) 116 108 935 080 [ 049 130 ]
Total events 23 (Favours bile acids) 27 (Control)
Heterogeneity Chi2 = 416 df = 3 (P = 025) I2 =28
Test for overall effect Z = 091 (P = 036)
01 02 05 1 2 5 10
Favours bile acids Favours control
(Continued )
33Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Favours bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
2 TUDCA versus no treatment
Angelico 1999 316 217 65 159 [ 030 833 ]
Subtotal (95 CI) 16 17 65 159 [ 030 833 ]
Total events 3 (Favours bile acids) 2 (Control)
Heterogeneity not applicable
Test for overall effect Z = 055 (P = 058)
Total (95 CI) 132 125 1000 085 [ 053 136 ]
Total events 26 (Favours bile acids) 29 (Control)
Heterogeneity Chi2 = 466 df = 4 (P = 032) I2 =14
Test for overall effect Z = 069 (P = 049)
01 02 05 1 2 5 10
Favours bile acids Favours control
Analysis 12 Comparison 1 Bile acids for liver-transplanted patients Outcome 2 All-cause mortality worst-
best case and best-worst case scenarios
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 2 All-cause mortality worst-best case and best-worst case scenarios
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 Worst-best case scenario
Angelico 1999 516 217 65 266 [ 060 1180 ]
Barnes 1997 828 724 253 098 [ 042 230 ]
Fleckenstein 1998 314 416 125 086 [ 023 319 ]
Keiding 1997 1954 1048 355 169 [ 087 327 ]
Sama 1991 520 620 201 083 [ 030 229 ]
Subtotal (95 CI) 132 125 1000 130 [ 086 196 ]
Total events 40 (Bile acids) 29 (Control)
Heterogeneity Chi2 = 303 df = 4 (P = 055) I2 =00
Test for overall effect Z = 123 (P = 022)
2 Best-worst case scenario
005 02 1 5 20
Favours bile acids Favours control
(Continued )
34Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Angelico 1999 316 417 90 080 [ 021 302 ]
Barnes 1997 228 1124 274 016 [ 004 063 ]
Fleckenstein 1998 214 616 130 038 [ 009 159 ]
Keiding 1997 1454 1548 368 083 [ 045 154 ]
Sama 1991 520 620 139 083 [ 030 229 ]
Subtotal (95 CI) 132 125 1000 058 [ 038 090 ]
Total events 26 (Bile acids) 42 (Control)
Heterogeneity Chi2 = 567 df = 4 (P = 023) I2 =29
Test for overall effect Z = 247 (P = 0014)
005 02 1 5 20
Favours bile acids Favours control
Analysis 13 Comparison 1 Bile acids for liver-transplanted patients Outcome 3 Subgroup analyses all-
cause mortality at maximum follow-up according to time of start of bile acids
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 3 Subgroup analyses all-cause mortality at maximum follow-up according to time of start of bile acids
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 Less than three days after transplantation
Keiding 1997 1454 1048 355 124 [ 061 254 ]
Subtotal (95 CI) 54 48 355 124 [ 061 254 ]
Total events 14 (Bile acids) 10 (Control)
Heterogeneity not applicable
Test for overall effect Z = 060 (P = 055)
2 Three days or more after transplantation
Angelico 1999 316 217 65 159 [ 030 833 ]
Barnes 1997 228 724 253 024 [ 006 107 ]
Fleckenstein 1998 214 416 125 057 [ 012 266 ]
Sama 1991 520 620 201 083 [ 030 229 ]
005 02 1 5 20
Favours bile acids Favours control
(Continued )
35Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Subtotal (95 CI) 78 77 645 063 [ 033 120 ]
Total events 12 (Bile acids) 19 (Control)
Heterogeneity Chi2 = 310 df = 3 (P = 038) I2 =3
Test for overall effect Z = 141 (P = 016)
Total (95 CI) 132 125 1000 085 [ 053 136 ]
Total events 26 (Bile acids) 29 (Control)
Heterogeneity Chi2 = 466 df = 4 (P = 032) I2 =14
Test for overall effect Z = 069 (P = 049)
005 02 1 5 20
Favours bile acids Favours control
Analysis 14 Comparison 1 Bile acids for liver-transplanted patients Outcome 4 Subgroup analyses all
cause mortality at maximum follow-up according to treatment duration
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 4 Subgroup analyses all cause mortality at maximum follow-up according to treatment duration
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 Less than six months
Barnes 1997 228 724 253 024 [ 006 107 ]
Fleckenstein 1998 214 416 125 057 [ 012 266 ]
Keiding 1997 1454 1048 355 124 [ 061 254 ]
Subtotal (95 CI) 96 88 734 078 [ 045 138 ]
Total events 18 (Bile acids) 21 (Control)
Heterogeneity Chi2 = 417 df = 2 (P = 012) I2 =52
Test for overall effect Z = 084 (P = 040)
2 Six months or more
Angelico 1999 316 217 65 159 [ 030 833 ]
Sama 1991 520 620 201 083 [ 030 229 ]
Subtotal (95 CI) 36 37 266 102 [ 043 240 ]
Total events 8 (Bile acids) 8 (Control)
Heterogeneity Chi2 = 043 df = 1 (P = 051) I2 =00
005 02 1 5 20
Favours bile acids Favours control
(Continued )
36Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Test for overall effect Z = 004 (P = 097)
Total (95 CI) 132 125 1000 085 [ 053 136 ]
Total events 26 (Bile acids) 29 (Control)
Heterogeneity Chi2 = 466 df = 4 (P = 032) I2 =14
Test for overall effect Z = 069 (P = 049)
005 02 1 5 20
Favours bile acids Favours control
Analysis 15 Comparison 1 Bile acids for liver-transplanted patients Outcome 5 Number of deaths related
to rejection at maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 5 Number of deaths related to rejection at maximum follow-up
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 UDCA versus placebo
Keiding 1997 054 148 1000 030 [ 001 712 ]
Total (95 CI) 54 48 1000 030 [ 001 712 ]
Total events 0 (Bile acids) 1 (Control)
Heterogeneity not applicable
Test for overall effect Z = 075 (P = 045)
0001 001 01 1 10 100 1000
Favours bile acids Favours control
37Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 16 Comparison 1 Bile acids for liver-transplanted patients Outcome 6 Number of
retransplantations at maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 6 Number of retransplantations at maximum follow-up
Study or subgroup Bile acids Placebo Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Fleckenstein 1998 214 016 100 567 [ 029 10891 ]
Keiding 1997 154 448 900 022 [ 003 192 ]
Total (95 CI) 68 64 1000 076 [ 020 286 ]
Total events 3 (Bile acids) 4 (Placebo)
Heterogeneity Chi2 = 303 df = 1 (P = 008) I2 =67
Test for overall effect Z = 040 (P = 069)
0001 001 01 1 10 100 1000
Favours bile acids Favours placebo
Analysis 17 Comparison 1 Bile acids for liver-transplanted patients Outcome 7 Number of patients with
acute cellular rejection at maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 7 Number of patients with acute cellular rejection at maximum follow-up
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 UDCA versus placebo or no treatment
Barnes 1997 1728 1724 180 086 [ 058 127 ]
Fleckenstein 1998 814 916 83 102 [ 054 190 ]
Keiding 1997 3554 3248 333 097 [ 073 129 ]
Koneru 1993 316 916 89 033 [ 011 101 ]
Pageaux 1995 926 924 92 092 [ 044 193 ]
Sama 1991 1320 1320 128 100 [ 063 158 ]
Subtotal (95 CI) 158 148 905 089 [ 074 108 ]
01 02 05 1 2 5 10
Favours bile acids Favours control
(Continued )
38Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Total events 85 (Bile acids) 89 (Control)
Heterogeneity Chi2 = 387 df = 5 (P = 057) I2 =00
Test for overall effect Z = 120 (P = 023)
2 TUDCA versus no treatment
Angelico 1999 816 1017 95 085 [ 045 160 ]
Subtotal (95 CI) 16 17 95 085 [ 045 160 ]
Total events 8 (Bile acids) 10 (Control)
Heterogeneity not applicable
Test for overall effect Z = 050 (P = 061)
Total (95 CI) 174 165 1000 089 [ 074 106 ]
Total events 93 (Bile acids) 99 (Control)
Heterogeneity Chi2 = 392 df = 6 (P = 069) I2 =00
Test for overall effect Z = 130 (P = 019)
01 02 05 1 2 5 10
Favours bile acids Favours control
Analysis 18 Comparison 1 Bile acids for liver-transplanted patients Outcome 8 Subgroup analysis
number of patients with acute cellular rejection according to time of start of bile acid
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 8 Subgroup analysis number of patients with acute cellular rejection according to time of start of bile acid
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 Less than three days after transplantation
Keiding 1997 3554 3248 333 097 [ 073 129 ]
Koneru 1993 316 916 89 033 [ 011 101 ]
Subtotal (95 CI) 70 64 422 084 [ 063 111 ]
Total events 38 (Bile acids) 41 (Control)
Heterogeneity Chi2 = 374 df = 1 (P = 005) I2 =73
Test for overall effect Z = 124 (P = 022)
2 Three days or more after liver transplantation
Angelico 1999 816 1017 95 085 [ 045 160 ]
01 02 05 1 2 5 10
Favours bile acids Favours control
(Continued )
39Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Barnes 1997 1728 1724 180 086 [ 058 127 ]
Fleckenstein 1998 814 916 83 102 [ 054 190 ]
Pageaux 1995 926 924 92 092 [ 044 193 ]
Sama 1991 1320 1320 128 100 [ 063 158 ]
Subtotal (95 CI) 104 101 578 092 [ 072 117 ]
Total events 55 (Bile acids) 58 (Control)
Heterogeneity Chi2 = 041 df = 4 (P = 098) I2 =00
Test for overall effect Z = 067 (P = 050)
Total (95 CI) 174 165 1000 089 [ 074 106 ]
Total events 93 (Bile acids) 99 (Control)
Heterogeneity Chi2 = 392 df = 6 (P = 069) I2 =00
Test for overall effect Z = 130 (P = 019)
01 02 05 1 2 5 10
Favours bile acids Favours control
40Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 19 Comparison 1 Bile acids for liver-transplanted patients Outcome 9 Subgroup analysis
number of patients with acute cellular rejection according to treatment duration
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 9 Subgroup analysis number of patients with acute cellular rejection according to treatment duration
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 Less than six months
Barnes 1997 1728 1724 180 086 [ 058 127 ]
Fleckenstein 1998 814 916 83 102 [ 054 190 ]
Keiding 1997 3554 3248 333 097 [ 073 129 ]
Koneru 1993 316 916 89 033 [ 011 101 ]
Pageaux 1995 926 924 92 092 [ 044 193 ]
Subtotal (95 CI) 138 128 777 087 [ 071 107 ]
Total events 72 (Bile acids) 76 (Control)
Heterogeneity Chi2 = 374 df = 4 (P = 044) I2 =00
Test for overall effect Z = 129 (P = 020)
2 Six months or more
Angelico 1999 816 1017 95 085 [ 045 160 ]
Sama 1991 1320 1320 128 100 [ 063 158 ]
Subtotal (95 CI) 36 37 223 094 [ 065 136 ]
Total events 21 (Bile acids) 23 (Control)
Heterogeneity Chi2 = 017 df = 1 (P = 068) I2 =00
Test for overall effect Z = 035 (P = 073)
Total (95 CI) 174 165 1000 089 [ 074 106 ]
Total events 93 (Bile acids) 99 (Control)
Heterogeneity Chi2 = 392 df = 6 (P = 069) I2 =00
Test for overall effect Z = 130 (P = 019)
01 02 05 1 2 5 10
Favours bile acids Favours control
41Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 110 Comparison 1 Bile acids for liver-transplanted patients Outcome 10 Number of patients
with chronic rejection at maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 10 Number of patients with chronic rejection at maximum follow-up
Study or subgroup Bile acids Placebo Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Barnes 1997 128 624 611 014 [ 002 110 ]
Fleckenstein 1998 114 116 88 114 [ 008 1663 ]
Keiding 1997 154 348 300 030 [ 003 275 ]
Total (95 CI) 96 88 1000 028 [ 008 095 ]
Total events 3 (Bile acids) 10 (Placebo)
Heterogeneity Chi2 = 148 df = 2 (P = 048) I2 =00
Test for overall effect Z = 204 (P = 0041)
0001 001 01 1 10 100 1000
Favours bile acids Favours placebo
Analysis 111 Comparison 1 Bile acids for liver-transplanted patients Outcome 11 Number of patients
with steroid-resistant rejection at maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 11 Number of patients with steroid-resistant rejection at maximum follow-up
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Barnes 1997 328 724 277 037 [ 011 127 ]
Fleckenstein 1998 314 316 103 114 [ 027 478 ]
Keiding 1997 1454 1548 583 083 [ 045 154 ]
Pageaux 1995 226 124 38 185 [ 018 1908 ]
Total (95 CI) 122 112 1000 077 [ 047 127 ]
Total events 22 (Bile acids) 26 (Control)
Heterogeneity Chi2 = 226 df = 3 (P = 052) I2 =00
Test for overall effect Z = 102 (P = 031)
001 01 1 10 100
Favours bile acids Favours placebo
42Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 112 Comparison 1 Bile acids for liver-transplanted patients Outcome 12 Serum bilirubin (mgdl)
at the end of treatment
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 12 Serum bilirubin (mgdl) at the end of treatment
Study or subgroup Bile acids Placebo Mean Difference Weight Mean Difference
N Mean(SD) N Mean(SD) IVFixed95 CI IVFixed95 CI
Fleckenstein 1998 14 319 (68) 16 059 (022) 1000 260 [ -096 616 ]
Total (95 CI) 14 16 1000 260 [ -096 616 ]
Heterogeneity not applicable
Test for overall effect Z = 143 (P = 015)
-10 -5 0 5 10
Favours bile acids Favours placebo
Analysis 113 Comparison 1 Bile acids for liver-transplanted patients Outcome 13 Number of days of
hospitalisation after liver transplantation
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 13 Number of days of hospitalisation after liver transplantation
Study or subgroup Bile acids Placebo Mean Difference Weight Mean Difference
N Mean(SD) N Mean(SD) IVFixed95 CI IVFixed95 CI
Barnes 1997 28 25 (17) 24 335 (13) 1000 -850 [ -1667 -033 ]
Total (95 CI) 28 24 1000 -850 [ -1667 -033 ]
Heterogeneity not applicable
Test for overall effect Z = 204 (P = 0041)
-100 -50 0 50 100
Favours bile acids Favours placebo
43Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 114 Comparison 1 Bile acids for liver-transplanted patients Outcome 14 Adverse events
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 14 Adverse events
Study or subgroup Bile acids Placebo Risk Ratio Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Angelico 1999 016 017 00 [ 00 00 ]
Barnes 1997 128 124 086 [ 006 1298 ]
Keiding 1997 554 548 089 [ 027 288 ]
Total (95 CI) 98 89 088 [ 030 260 ]
Total events 6 (Bile acids) 6 (Placebo)
Heterogeneity Chi2 = 000 df = 1 (P = 098) I2 =00
Test for overall effect Z = 022 (P = 082)
001 01 1 10 100
Favours bile acids Favours placebo
A P P E N D I C E S
Appendix 1 Search strategies
Data Base Date of Search Search Strategy
The Cochrane Hepato-Biliary Group Con-
trolled Trials Register
September 2009 1 rsquoliver transplantationrsquo and rsquochenodeoxy-
cholicrsquo
2 rsquoliver transplantationrsquo and rsquocholicrsquo
3 rsquoliver transplantationrsquo and rsquodeoxycholicrsquo
4 rsquoliver transplantationrsquo and rsquoglycochen-
odeoxycholicrsquo
5 rsquoliver transplantationrsquo and rsquoglycocholicrsquo
6 rsquoliver transplantationrsquo and rsquoglycodeoxy-
cholicrsquo
7 rsquoliver transplantationrsquo and rsquoglycolitho-
cholicrsquo
8 rsquoliver transplantationrsquo and rsquohyodeoxy-
cholicrsquo
9 rsquoliver transplantationrsquo and rsquolithocholicrsquo
10 rsquoliver transplantationrsquo and rsquotaurochen-
odeoxycholicrsquo
44Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
11 rsquoliver transplantationrsquo and rsquotauro-
cholicrsquo
12 rsquoliver transplantationrsquo and rsquotaurodehy-
drocholicrsquo
13 rsquoliver transplantationrsquo and rsquotau-
rodeoxycholicrsquo
14 rsquoliver transplantationrsquo and rsquotauroglyco-
cholicrsquo
15 rsquoliver transplantationrsquo and rsquotaurolitho-
cholicrsquo
16 rsquoliver transplantationrsquo and rsquotaurosel-
cholicrsquo
17 rsquoliver transplantationrsquo and rsquotaurourso-
cholicrsquo
18 rsquoliver transplantationrsquo and rsquotaurour-
sodeoxycholicrsquo
19 rsquoliver transplantationrsquo and rsquoursocholicrsquo
20 rsquoliver transplantationrsquo and rsquoursodeoxy-
cholicrsquo
The Cochrane Central Register of Con-
trolled Trials in The Cochrane Library
Issue 3 2009 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
6 3 or 4
7 5 and 6
MEDLINE September 2009 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
45Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
6 3 or 4
7 5 and 6
8 RANDOMIZED-CONTROLLED-
TRIAL ME
9 RANDOM
10 8 or 9
11 7 and 10
EMBASE September 2009 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
6 3 or 4
7 5 and 6
8 RANDOMIZED-CONTROLLED-
TRIAL ME
9 RANDOM
10 8 or 9
11 7 and 10
46Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
Science Citation Index Expanded September 2009 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
6 3 or 4
7 5 and 6
8 RANDOMIZED-CONTROLLED-
TRIAL ME
9 RANDOM
10 8 or 9
11 7 and 10
The Chinese Biomedical Database Searched from January 1980 to April 2002 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
47Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
6 3 or 4
7 5 and 6
8 RANDOMIZED-CONTROLLED-
TRIAL ME
9 RANDOM
10 8 or 9
11 7 and 10
W H A T rsquo S N E W
Last assessed as up-to-date 8 February 2010
18 September 2009 New citation required but conclusions have not
changed
This review is an updated version of a review that was
published for the first time in Issue 3 2005 of TheCochrane Library by Chen 2003b
18 September 2009 New search has been performed No new studies fulfilled the inclusion criteria
H I S T O R Y
Protocol first published Issue 3 2003
Review first published Issue 3 2005
C O N T R I B U T I O N S O F A U T H O R S
GP and VG independently performed searches of relevant databases GP validated the search selected trials for inclusion contacted
the authors of the trials performed data extraction and data analysis and drafted the systematic review VG revised the review update
CG and DS revised the review update solved discrepancies of data extraction validated data analyses and provided consultation
D E C L A R A T I O N S O F I N T E R E S T
None known
48Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
S O U R C E S O F S U P P O R T
Internal sources
bull Copenhagen Trial Unit Denmark
External sources
bull Danish Medical Research Councilrsquos Grant on Getting Research into Practice (GRIP) Denmark
D I F F E R E N C E S B E T W E E N P R O T O C O L A N D R E V I E W
We assessed the risk of bias in the included studies for another four domains that were added to the review protocol (incomplete
outcome data selective outcome reporting baseline imbalance and early stopping of trial) In general the text of the risk of bias
domains were updated following Higgins 2008 Trials were considered at low risk of bias when judged as adequate in all domains
Quasi-randomised studies observational and case-control studies were included for the report of adverse events
We performed trial sequential analysis for outcomes demonstrating a statistically significant result
I N D E X T E R M S
Medical Subject Headings (MeSH)
lowastLiver Transplantation Cholagogues and Choleretics [lowasttherapeutic use] Graft Rejection [lowastprevention amp control] Randomized Con-
trolled Trials as Topic Taurochenodeoxycholic Acid [lowasttherapeutic use] Ursodeoxycholic Acid [lowasttherapeutic use]
MeSH check words
Humans
49Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Sama 1991 (Continued)
Incomplete outcome data addressed
All outcomes
Unclear Five patients from the UDCA group and
six patients from the placebo group were
excluded Reasons for exclusion were not
fully stated
Free of selective reporting No Data about survival of patients were not
adequately reported
Sample size calculation No Not performed
Intention-to-treat analysis No Not stated and not used
Baseline imbalance Unclear Basic characteristics of patients not re-
ported
Early stopping of trial Unclear Not enough information provided
UDCA = ursodeoxycholic acid
TUDCA = tauroursodeoxycholic acid
PBC = primary biliary cirrhosis
PSC = primary sclerosing cholangitis
OKT3 = anti-CD3 monoclonal antibody
Characteristics of excluded studies [ordered by study ID]
Assy 2007 A randomised controlled trial that included only recipients of liver transplantation with stable graft function and
no episodes of rejection for at least 2 years that were then offered total immunosuppression withdrawal Fourteen
patients received UDCA (15 mgkg body weightday) and 12 received placebo Rejection occurred in 43 and
75 of patients respectively (no significant difference) None developed chronic rejection After follow-up two
patients were free of immunosuppression 80 were steroid free and 50 were able to reduce their dose of
cyclosporine
Clavien 1996 Case series Fifty consecutive liver-transplanted patients were treated with a standard cyclosporine immunosup-
pressive regimen Twenty three of the 43 survivors developed an episode of rejection and UDCA (10 mgkg
weightday) was initiated Only one patient had a second episode of rejection
Friman 1992 Observational study Thirty-three liver-transplanted patients received 10 mg UDCAkg body weightday for
median of 10 months (range four to 21 months) Eight historical liver-transplanted patients served as control
group The rejection incidence was significantly lower in the patients who received the treatment with UDCA
Biochemistry one month after transplantation demonstrated significantly lower average values of aminotrans-
ferases and alkaline phosphatases in patients treated with UDCA than in the control group
30Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
Heathcote 1999 Observational study From 1987 to 1996 37 UDCA treated and 53 placebo treated patients with primary biliary
cirrhosis were referred for transplantation Posttransplantation survival rates at one month were 939 in the
UDCA group and 884 in the placebo group and one year survival rates were 903 and 784 respectively
(no significant differences) However rejection (type not defined - a secondary outcome measure) occurred
significantly less often in the UDCA group (429) than in placebo group (688)
Henriksson 1991 Observational study All patients in this study were given sequential quadruple immunosuppression with anti-
lymphocyte globulin azathioprine steroids and cyclosporine All patients with primary graft function (n = 11)
were treated with 10 mg UDCAkg body weightday starting during the first postoperative week Patients who
received liver transplantation in the first 6 months of 1989 (n = 8) served as controls In the control group one
patient died after 9 months with chronic graft dysfunction and six patients had rejection episodes during the
first postoperative month All patients in the UDCA group were alive without rejection episodes
Persson 1990 Observational study All 11 adult patients transplanted between August 1989 and January 1990 with primary
graft function were treated with 10 mg UDCA kg body weightday Eight patients transplanted during the first
half of 1989 served as control UDCA was started during the first postoperative week and the treatment was
continued for six months All patients in the UDCA treated group survived with satisfactory graft function In
the control group six patients had at least one rejection episode needing treatment during the first postoperative
month
Rafael 1995 Observational study Seventeen patients who underwent liver transplantation between February 1990 and April
1993 and developed biliary complications after transplantation were retrospectively analysed regarding treatment
with UDCA UDCA was given in a dose of 500 to 1000 mgday Ten patients were treated for at least one year while
seven patients were treated for 14 to 250 days UDCA significantly improved gammaglutamyl transpeptidase in
liver graft recipients with biliary complications There was also a trend towards improvement in serum bilirubin
and alanine transaminase values
Sama 1998 Observational study Thirty-four patients who underwent liver transplantation between January 1995 and June
1996 were included in the study Seventeen were treated with UDCA 10 mgkg body weightday during 6
months while 17 served as controls on the basis of having undergone liver transplantation closest to UDCA
patients A significant decrease in serum bilirubin levels was observed in UDCA patients There was a significantly
higher incidence of recurrent hepatitis in the control group
UDCA ursodeoxycholic acid
31Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
D A T A A N D A N A L Y S E S
Comparison 1 Bile acids for liver-transplanted patients
Outcome or subgroup titleNo of
studies
No of
participants Statistical method Effect size
1 All-cause mortality at maximum
follow-up
5 257 Risk Ratio (M-H Fixed 95 CI) 085 [053 136]
11 UDCA versus placebo or
no treatment
4 224 Risk Ratio (M-H Fixed 95 CI) 080 [049 130]
12 TUDCA versus no
treatment
1 33 Risk Ratio (M-H Fixed 95 CI) 159 [030 833]
2 All-cause mortality worst-best
case and best-worst case
scenarios
5 Risk Ratio (M-H Fixed 95 CI) Subtotals only
21 Worst-best case scenario 5 257 Risk Ratio (M-H Fixed 95 CI) 130 [086 196]
22 Best-worst case scenario 5 257 Risk Ratio (M-H Fixed 95 CI) 058 [038 090]
3 Subgroup analyses all-cause
mortality at maximum
follow-up according to time of
start of bile acids
5 257 Risk Ratio (M-H Fixed 95 CI) 085 [053 136]
31 Less than three days after
transplantation
1 102 Risk Ratio (M-H Fixed 95 CI) 124 [061 254]
32 Three days or more after
transplantation
4 155 Risk Ratio (M-H Fixed 95 CI) 063 [033 120]
4 Subgroup analyses all cause
mortality at maximum
follow-up according to
treatment duration
5 257 Risk Ratio (M-H Fixed 95 CI) 085 [053 136]
41 Less than six months 3 184 Risk Ratio (M-H Fixed 95 CI) 078 [045 138]
42 Six months or more 2 73 Risk Ratio (M-H Fixed 95 CI) 102 [043 240]
5 Number of deaths related
to rejection at maximum
follow-up
1 102 Risk Ratio (M-H Fixed 95 CI) 030 [001 712]
51 UDCA versus placebo 1 102 Risk Ratio (M-H Fixed 95 CI) 030 [001 712]
6 Number of retransplantations at
maximum follow-up
2 132 Risk Ratio (M-H Fixed 95 CI) 076 [020 286]
7 Number of patients with acute
cellular rejection at maximum
follow-up
7 339 Risk Ratio (M-H Fixed 95 CI) 089 [074 106]
71 UDCA versus placebo or
no treatment
6 306 Risk Ratio (M-H Fixed 95 CI) 089 [074 108]
72 TUDCA versus no
treatment
1 33 Risk Ratio (M-H Fixed 95 CI) 085 [045 160]
8 Subgroup analysis number of
patients with acute cellular
rejection according to time of
start of bile acid
7 339 Risk Ratio (M-H Fixed 95 CI) 089 [074 106]
32Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
81 Less than three days after
transplantation
2 134 Risk Ratio (M-H Fixed 95 CI) 084 [063 111]
82 Three days or more after
liver transplantation
5 205 Risk Ratio (M-H Fixed 95 CI) 092 [072 117]
9 Subgroup analysis number
of patients with acute
cellular rejection according to
treatment duration
7 339 Risk Ratio (M-H Fixed 95 CI) 089 [074 106]
91 Less than six months 5 266 Risk Ratio (M-H Fixed 95 CI) 087 [071 107]
92 Six months or more 2 73 Risk Ratio (M-H Fixed 95 CI) 094 [065 136]
10 Number of patients with
chronic rejection at maximum
follow-up
3 184 Risk Ratio (M-H Fixed 95 CI) 028 [008 095]
11 Number of patients with
steroid-resistant rejection at
maximum follow-up
4 234 Risk Ratio (M-H Fixed 95 CI) 077 [047 127]
12 Serum bilirubin (mgdl) at the
end of treatment
1 30 Mean Difference (IV Fixed 95 CI) 26 [-096 616]
13 Number of days of
hospitalisation after liver
transplantation
1 52 Mean Difference (IV Fixed 95 CI) -85 [-1667 -033]
14 Adverse events 3 187 Risk Ratio (M-H Fixed 95 CI) 088 [030 260]
Analysis 11 Comparison 1 Bile acids for liver-transplanted patients Outcome 1 All-cause mortality at
maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 1 All-cause mortality at maximum follow-up
Study or subgroup Favours bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 UDCA versus placebo or no treatment
Barnes 1997 228 724 253 024 [ 006 107 ]
Fleckenstein 1998 214 416 125 057 [ 012 266 ]
Keiding 1997 1454 1048 355 124 [ 061 254 ]
Sama 1991 520 620 201 083 [ 030 229 ]
Subtotal (95 CI) 116 108 935 080 [ 049 130 ]
Total events 23 (Favours bile acids) 27 (Control)
Heterogeneity Chi2 = 416 df = 3 (P = 025) I2 =28
Test for overall effect Z = 091 (P = 036)
01 02 05 1 2 5 10
Favours bile acids Favours control
(Continued )
33Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Favours bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
2 TUDCA versus no treatment
Angelico 1999 316 217 65 159 [ 030 833 ]
Subtotal (95 CI) 16 17 65 159 [ 030 833 ]
Total events 3 (Favours bile acids) 2 (Control)
Heterogeneity not applicable
Test for overall effect Z = 055 (P = 058)
Total (95 CI) 132 125 1000 085 [ 053 136 ]
Total events 26 (Favours bile acids) 29 (Control)
Heterogeneity Chi2 = 466 df = 4 (P = 032) I2 =14
Test for overall effect Z = 069 (P = 049)
01 02 05 1 2 5 10
Favours bile acids Favours control
Analysis 12 Comparison 1 Bile acids for liver-transplanted patients Outcome 2 All-cause mortality worst-
best case and best-worst case scenarios
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 2 All-cause mortality worst-best case and best-worst case scenarios
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 Worst-best case scenario
Angelico 1999 516 217 65 266 [ 060 1180 ]
Barnes 1997 828 724 253 098 [ 042 230 ]
Fleckenstein 1998 314 416 125 086 [ 023 319 ]
Keiding 1997 1954 1048 355 169 [ 087 327 ]
Sama 1991 520 620 201 083 [ 030 229 ]
Subtotal (95 CI) 132 125 1000 130 [ 086 196 ]
Total events 40 (Bile acids) 29 (Control)
Heterogeneity Chi2 = 303 df = 4 (P = 055) I2 =00
Test for overall effect Z = 123 (P = 022)
2 Best-worst case scenario
005 02 1 5 20
Favours bile acids Favours control
(Continued )
34Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Angelico 1999 316 417 90 080 [ 021 302 ]
Barnes 1997 228 1124 274 016 [ 004 063 ]
Fleckenstein 1998 214 616 130 038 [ 009 159 ]
Keiding 1997 1454 1548 368 083 [ 045 154 ]
Sama 1991 520 620 139 083 [ 030 229 ]
Subtotal (95 CI) 132 125 1000 058 [ 038 090 ]
Total events 26 (Bile acids) 42 (Control)
Heterogeneity Chi2 = 567 df = 4 (P = 023) I2 =29
Test for overall effect Z = 247 (P = 0014)
005 02 1 5 20
Favours bile acids Favours control
Analysis 13 Comparison 1 Bile acids for liver-transplanted patients Outcome 3 Subgroup analyses all-
cause mortality at maximum follow-up according to time of start of bile acids
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 3 Subgroup analyses all-cause mortality at maximum follow-up according to time of start of bile acids
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 Less than three days after transplantation
Keiding 1997 1454 1048 355 124 [ 061 254 ]
Subtotal (95 CI) 54 48 355 124 [ 061 254 ]
Total events 14 (Bile acids) 10 (Control)
Heterogeneity not applicable
Test for overall effect Z = 060 (P = 055)
2 Three days or more after transplantation
Angelico 1999 316 217 65 159 [ 030 833 ]
Barnes 1997 228 724 253 024 [ 006 107 ]
Fleckenstein 1998 214 416 125 057 [ 012 266 ]
Sama 1991 520 620 201 083 [ 030 229 ]
005 02 1 5 20
Favours bile acids Favours control
(Continued )
35Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Subtotal (95 CI) 78 77 645 063 [ 033 120 ]
Total events 12 (Bile acids) 19 (Control)
Heterogeneity Chi2 = 310 df = 3 (P = 038) I2 =3
Test for overall effect Z = 141 (P = 016)
Total (95 CI) 132 125 1000 085 [ 053 136 ]
Total events 26 (Bile acids) 29 (Control)
Heterogeneity Chi2 = 466 df = 4 (P = 032) I2 =14
Test for overall effect Z = 069 (P = 049)
005 02 1 5 20
Favours bile acids Favours control
Analysis 14 Comparison 1 Bile acids for liver-transplanted patients Outcome 4 Subgroup analyses all
cause mortality at maximum follow-up according to treatment duration
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 4 Subgroup analyses all cause mortality at maximum follow-up according to treatment duration
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 Less than six months
Barnes 1997 228 724 253 024 [ 006 107 ]
Fleckenstein 1998 214 416 125 057 [ 012 266 ]
Keiding 1997 1454 1048 355 124 [ 061 254 ]
Subtotal (95 CI) 96 88 734 078 [ 045 138 ]
Total events 18 (Bile acids) 21 (Control)
Heterogeneity Chi2 = 417 df = 2 (P = 012) I2 =52
Test for overall effect Z = 084 (P = 040)
2 Six months or more
Angelico 1999 316 217 65 159 [ 030 833 ]
Sama 1991 520 620 201 083 [ 030 229 ]
Subtotal (95 CI) 36 37 266 102 [ 043 240 ]
Total events 8 (Bile acids) 8 (Control)
Heterogeneity Chi2 = 043 df = 1 (P = 051) I2 =00
005 02 1 5 20
Favours bile acids Favours control
(Continued )
36Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Test for overall effect Z = 004 (P = 097)
Total (95 CI) 132 125 1000 085 [ 053 136 ]
Total events 26 (Bile acids) 29 (Control)
Heterogeneity Chi2 = 466 df = 4 (P = 032) I2 =14
Test for overall effect Z = 069 (P = 049)
005 02 1 5 20
Favours bile acids Favours control
Analysis 15 Comparison 1 Bile acids for liver-transplanted patients Outcome 5 Number of deaths related
to rejection at maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 5 Number of deaths related to rejection at maximum follow-up
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 UDCA versus placebo
Keiding 1997 054 148 1000 030 [ 001 712 ]
Total (95 CI) 54 48 1000 030 [ 001 712 ]
Total events 0 (Bile acids) 1 (Control)
Heterogeneity not applicable
Test for overall effect Z = 075 (P = 045)
0001 001 01 1 10 100 1000
Favours bile acids Favours control
37Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 16 Comparison 1 Bile acids for liver-transplanted patients Outcome 6 Number of
retransplantations at maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 6 Number of retransplantations at maximum follow-up
Study or subgroup Bile acids Placebo Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Fleckenstein 1998 214 016 100 567 [ 029 10891 ]
Keiding 1997 154 448 900 022 [ 003 192 ]
Total (95 CI) 68 64 1000 076 [ 020 286 ]
Total events 3 (Bile acids) 4 (Placebo)
Heterogeneity Chi2 = 303 df = 1 (P = 008) I2 =67
Test for overall effect Z = 040 (P = 069)
0001 001 01 1 10 100 1000
Favours bile acids Favours placebo
Analysis 17 Comparison 1 Bile acids for liver-transplanted patients Outcome 7 Number of patients with
acute cellular rejection at maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 7 Number of patients with acute cellular rejection at maximum follow-up
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 UDCA versus placebo or no treatment
Barnes 1997 1728 1724 180 086 [ 058 127 ]
Fleckenstein 1998 814 916 83 102 [ 054 190 ]
Keiding 1997 3554 3248 333 097 [ 073 129 ]
Koneru 1993 316 916 89 033 [ 011 101 ]
Pageaux 1995 926 924 92 092 [ 044 193 ]
Sama 1991 1320 1320 128 100 [ 063 158 ]
Subtotal (95 CI) 158 148 905 089 [ 074 108 ]
01 02 05 1 2 5 10
Favours bile acids Favours control
(Continued )
38Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Total events 85 (Bile acids) 89 (Control)
Heterogeneity Chi2 = 387 df = 5 (P = 057) I2 =00
Test for overall effect Z = 120 (P = 023)
2 TUDCA versus no treatment
Angelico 1999 816 1017 95 085 [ 045 160 ]
Subtotal (95 CI) 16 17 95 085 [ 045 160 ]
Total events 8 (Bile acids) 10 (Control)
Heterogeneity not applicable
Test for overall effect Z = 050 (P = 061)
Total (95 CI) 174 165 1000 089 [ 074 106 ]
Total events 93 (Bile acids) 99 (Control)
Heterogeneity Chi2 = 392 df = 6 (P = 069) I2 =00
Test for overall effect Z = 130 (P = 019)
01 02 05 1 2 5 10
Favours bile acids Favours control
Analysis 18 Comparison 1 Bile acids for liver-transplanted patients Outcome 8 Subgroup analysis
number of patients with acute cellular rejection according to time of start of bile acid
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 8 Subgroup analysis number of patients with acute cellular rejection according to time of start of bile acid
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 Less than three days after transplantation
Keiding 1997 3554 3248 333 097 [ 073 129 ]
Koneru 1993 316 916 89 033 [ 011 101 ]
Subtotal (95 CI) 70 64 422 084 [ 063 111 ]
Total events 38 (Bile acids) 41 (Control)
Heterogeneity Chi2 = 374 df = 1 (P = 005) I2 =73
Test for overall effect Z = 124 (P = 022)
2 Three days or more after liver transplantation
Angelico 1999 816 1017 95 085 [ 045 160 ]
01 02 05 1 2 5 10
Favours bile acids Favours control
(Continued )
39Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Barnes 1997 1728 1724 180 086 [ 058 127 ]
Fleckenstein 1998 814 916 83 102 [ 054 190 ]
Pageaux 1995 926 924 92 092 [ 044 193 ]
Sama 1991 1320 1320 128 100 [ 063 158 ]
Subtotal (95 CI) 104 101 578 092 [ 072 117 ]
Total events 55 (Bile acids) 58 (Control)
Heterogeneity Chi2 = 041 df = 4 (P = 098) I2 =00
Test for overall effect Z = 067 (P = 050)
Total (95 CI) 174 165 1000 089 [ 074 106 ]
Total events 93 (Bile acids) 99 (Control)
Heterogeneity Chi2 = 392 df = 6 (P = 069) I2 =00
Test for overall effect Z = 130 (P = 019)
01 02 05 1 2 5 10
Favours bile acids Favours control
40Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 19 Comparison 1 Bile acids for liver-transplanted patients Outcome 9 Subgroup analysis
number of patients with acute cellular rejection according to treatment duration
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 9 Subgroup analysis number of patients with acute cellular rejection according to treatment duration
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 Less than six months
Barnes 1997 1728 1724 180 086 [ 058 127 ]
Fleckenstein 1998 814 916 83 102 [ 054 190 ]
Keiding 1997 3554 3248 333 097 [ 073 129 ]
Koneru 1993 316 916 89 033 [ 011 101 ]
Pageaux 1995 926 924 92 092 [ 044 193 ]
Subtotal (95 CI) 138 128 777 087 [ 071 107 ]
Total events 72 (Bile acids) 76 (Control)
Heterogeneity Chi2 = 374 df = 4 (P = 044) I2 =00
Test for overall effect Z = 129 (P = 020)
2 Six months or more
Angelico 1999 816 1017 95 085 [ 045 160 ]
Sama 1991 1320 1320 128 100 [ 063 158 ]
Subtotal (95 CI) 36 37 223 094 [ 065 136 ]
Total events 21 (Bile acids) 23 (Control)
Heterogeneity Chi2 = 017 df = 1 (P = 068) I2 =00
Test for overall effect Z = 035 (P = 073)
Total (95 CI) 174 165 1000 089 [ 074 106 ]
Total events 93 (Bile acids) 99 (Control)
Heterogeneity Chi2 = 392 df = 6 (P = 069) I2 =00
Test for overall effect Z = 130 (P = 019)
01 02 05 1 2 5 10
Favours bile acids Favours control
41Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 110 Comparison 1 Bile acids for liver-transplanted patients Outcome 10 Number of patients
with chronic rejection at maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 10 Number of patients with chronic rejection at maximum follow-up
Study or subgroup Bile acids Placebo Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Barnes 1997 128 624 611 014 [ 002 110 ]
Fleckenstein 1998 114 116 88 114 [ 008 1663 ]
Keiding 1997 154 348 300 030 [ 003 275 ]
Total (95 CI) 96 88 1000 028 [ 008 095 ]
Total events 3 (Bile acids) 10 (Placebo)
Heterogeneity Chi2 = 148 df = 2 (P = 048) I2 =00
Test for overall effect Z = 204 (P = 0041)
0001 001 01 1 10 100 1000
Favours bile acids Favours placebo
Analysis 111 Comparison 1 Bile acids for liver-transplanted patients Outcome 11 Number of patients
with steroid-resistant rejection at maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 11 Number of patients with steroid-resistant rejection at maximum follow-up
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Barnes 1997 328 724 277 037 [ 011 127 ]
Fleckenstein 1998 314 316 103 114 [ 027 478 ]
Keiding 1997 1454 1548 583 083 [ 045 154 ]
Pageaux 1995 226 124 38 185 [ 018 1908 ]
Total (95 CI) 122 112 1000 077 [ 047 127 ]
Total events 22 (Bile acids) 26 (Control)
Heterogeneity Chi2 = 226 df = 3 (P = 052) I2 =00
Test for overall effect Z = 102 (P = 031)
001 01 1 10 100
Favours bile acids Favours placebo
42Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 112 Comparison 1 Bile acids for liver-transplanted patients Outcome 12 Serum bilirubin (mgdl)
at the end of treatment
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 12 Serum bilirubin (mgdl) at the end of treatment
Study or subgroup Bile acids Placebo Mean Difference Weight Mean Difference
N Mean(SD) N Mean(SD) IVFixed95 CI IVFixed95 CI
Fleckenstein 1998 14 319 (68) 16 059 (022) 1000 260 [ -096 616 ]
Total (95 CI) 14 16 1000 260 [ -096 616 ]
Heterogeneity not applicable
Test for overall effect Z = 143 (P = 015)
-10 -5 0 5 10
Favours bile acids Favours placebo
Analysis 113 Comparison 1 Bile acids for liver-transplanted patients Outcome 13 Number of days of
hospitalisation after liver transplantation
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 13 Number of days of hospitalisation after liver transplantation
Study or subgroup Bile acids Placebo Mean Difference Weight Mean Difference
N Mean(SD) N Mean(SD) IVFixed95 CI IVFixed95 CI
Barnes 1997 28 25 (17) 24 335 (13) 1000 -850 [ -1667 -033 ]
Total (95 CI) 28 24 1000 -850 [ -1667 -033 ]
Heterogeneity not applicable
Test for overall effect Z = 204 (P = 0041)
-100 -50 0 50 100
Favours bile acids Favours placebo
43Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 114 Comparison 1 Bile acids for liver-transplanted patients Outcome 14 Adverse events
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 14 Adverse events
Study or subgroup Bile acids Placebo Risk Ratio Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Angelico 1999 016 017 00 [ 00 00 ]
Barnes 1997 128 124 086 [ 006 1298 ]
Keiding 1997 554 548 089 [ 027 288 ]
Total (95 CI) 98 89 088 [ 030 260 ]
Total events 6 (Bile acids) 6 (Placebo)
Heterogeneity Chi2 = 000 df = 1 (P = 098) I2 =00
Test for overall effect Z = 022 (P = 082)
001 01 1 10 100
Favours bile acids Favours placebo
A P P E N D I C E S
Appendix 1 Search strategies
Data Base Date of Search Search Strategy
The Cochrane Hepato-Biliary Group Con-
trolled Trials Register
September 2009 1 rsquoliver transplantationrsquo and rsquochenodeoxy-
cholicrsquo
2 rsquoliver transplantationrsquo and rsquocholicrsquo
3 rsquoliver transplantationrsquo and rsquodeoxycholicrsquo
4 rsquoliver transplantationrsquo and rsquoglycochen-
odeoxycholicrsquo
5 rsquoliver transplantationrsquo and rsquoglycocholicrsquo
6 rsquoliver transplantationrsquo and rsquoglycodeoxy-
cholicrsquo
7 rsquoliver transplantationrsquo and rsquoglycolitho-
cholicrsquo
8 rsquoliver transplantationrsquo and rsquohyodeoxy-
cholicrsquo
9 rsquoliver transplantationrsquo and rsquolithocholicrsquo
10 rsquoliver transplantationrsquo and rsquotaurochen-
odeoxycholicrsquo
44Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
11 rsquoliver transplantationrsquo and rsquotauro-
cholicrsquo
12 rsquoliver transplantationrsquo and rsquotaurodehy-
drocholicrsquo
13 rsquoliver transplantationrsquo and rsquotau-
rodeoxycholicrsquo
14 rsquoliver transplantationrsquo and rsquotauroglyco-
cholicrsquo
15 rsquoliver transplantationrsquo and rsquotaurolitho-
cholicrsquo
16 rsquoliver transplantationrsquo and rsquotaurosel-
cholicrsquo
17 rsquoliver transplantationrsquo and rsquotaurourso-
cholicrsquo
18 rsquoliver transplantationrsquo and rsquotaurour-
sodeoxycholicrsquo
19 rsquoliver transplantationrsquo and rsquoursocholicrsquo
20 rsquoliver transplantationrsquo and rsquoursodeoxy-
cholicrsquo
The Cochrane Central Register of Con-
trolled Trials in The Cochrane Library
Issue 3 2009 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
6 3 or 4
7 5 and 6
MEDLINE September 2009 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
45Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
6 3 or 4
7 5 and 6
8 RANDOMIZED-CONTROLLED-
TRIAL ME
9 RANDOM
10 8 or 9
11 7 and 10
EMBASE September 2009 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
6 3 or 4
7 5 and 6
8 RANDOMIZED-CONTROLLED-
TRIAL ME
9 RANDOM
10 8 or 9
11 7 and 10
46Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
Science Citation Index Expanded September 2009 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
6 3 or 4
7 5 and 6
8 RANDOMIZED-CONTROLLED-
TRIAL ME
9 RANDOM
10 8 or 9
11 7 and 10
The Chinese Biomedical Database Searched from January 1980 to April 2002 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
47Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
6 3 or 4
7 5 and 6
8 RANDOMIZED-CONTROLLED-
TRIAL ME
9 RANDOM
10 8 or 9
11 7 and 10
W H A T rsquo S N E W
Last assessed as up-to-date 8 February 2010
18 September 2009 New citation required but conclusions have not
changed
This review is an updated version of a review that was
published for the first time in Issue 3 2005 of TheCochrane Library by Chen 2003b
18 September 2009 New search has been performed No new studies fulfilled the inclusion criteria
H I S T O R Y
Protocol first published Issue 3 2003
Review first published Issue 3 2005
C O N T R I B U T I O N S O F A U T H O R S
GP and VG independently performed searches of relevant databases GP validated the search selected trials for inclusion contacted
the authors of the trials performed data extraction and data analysis and drafted the systematic review VG revised the review update
CG and DS revised the review update solved discrepancies of data extraction validated data analyses and provided consultation
D E C L A R A T I O N S O F I N T E R E S T
None known
48Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
S O U R C E S O F S U P P O R T
Internal sources
bull Copenhagen Trial Unit Denmark
External sources
bull Danish Medical Research Councilrsquos Grant on Getting Research into Practice (GRIP) Denmark
D I F F E R E N C E S B E T W E E N P R O T O C O L A N D R E V I E W
We assessed the risk of bias in the included studies for another four domains that were added to the review protocol (incomplete
outcome data selective outcome reporting baseline imbalance and early stopping of trial) In general the text of the risk of bias
domains were updated following Higgins 2008 Trials were considered at low risk of bias when judged as adequate in all domains
Quasi-randomised studies observational and case-control studies were included for the report of adverse events
We performed trial sequential analysis for outcomes demonstrating a statistically significant result
I N D E X T E R M S
Medical Subject Headings (MeSH)
lowastLiver Transplantation Cholagogues and Choleretics [lowasttherapeutic use] Graft Rejection [lowastprevention amp control] Randomized Con-
trolled Trials as Topic Taurochenodeoxycholic Acid [lowasttherapeutic use] Ursodeoxycholic Acid [lowasttherapeutic use]
MeSH check words
Humans
49Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
Heathcote 1999 Observational study From 1987 to 1996 37 UDCA treated and 53 placebo treated patients with primary biliary
cirrhosis were referred for transplantation Posttransplantation survival rates at one month were 939 in the
UDCA group and 884 in the placebo group and one year survival rates were 903 and 784 respectively
(no significant differences) However rejection (type not defined - a secondary outcome measure) occurred
significantly less often in the UDCA group (429) than in placebo group (688)
Henriksson 1991 Observational study All patients in this study were given sequential quadruple immunosuppression with anti-
lymphocyte globulin azathioprine steroids and cyclosporine All patients with primary graft function (n = 11)
were treated with 10 mg UDCAkg body weightday starting during the first postoperative week Patients who
received liver transplantation in the first 6 months of 1989 (n = 8) served as controls In the control group one
patient died after 9 months with chronic graft dysfunction and six patients had rejection episodes during the
first postoperative month All patients in the UDCA group were alive without rejection episodes
Persson 1990 Observational study All 11 adult patients transplanted between August 1989 and January 1990 with primary
graft function were treated with 10 mg UDCA kg body weightday Eight patients transplanted during the first
half of 1989 served as control UDCA was started during the first postoperative week and the treatment was
continued for six months All patients in the UDCA treated group survived with satisfactory graft function In
the control group six patients had at least one rejection episode needing treatment during the first postoperative
month
Rafael 1995 Observational study Seventeen patients who underwent liver transplantation between February 1990 and April
1993 and developed biliary complications after transplantation were retrospectively analysed regarding treatment
with UDCA UDCA was given in a dose of 500 to 1000 mgday Ten patients were treated for at least one year while
seven patients were treated for 14 to 250 days UDCA significantly improved gammaglutamyl transpeptidase in
liver graft recipients with biliary complications There was also a trend towards improvement in serum bilirubin
and alanine transaminase values
Sama 1998 Observational study Thirty-four patients who underwent liver transplantation between January 1995 and June
1996 were included in the study Seventeen were treated with UDCA 10 mgkg body weightday during 6
months while 17 served as controls on the basis of having undergone liver transplantation closest to UDCA
patients A significant decrease in serum bilirubin levels was observed in UDCA patients There was a significantly
higher incidence of recurrent hepatitis in the control group
UDCA ursodeoxycholic acid
31Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
D A T A A N D A N A L Y S E S
Comparison 1 Bile acids for liver-transplanted patients
Outcome or subgroup titleNo of
studies
No of
participants Statistical method Effect size
1 All-cause mortality at maximum
follow-up
5 257 Risk Ratio (M-H Fixed 95 CI) 085 [053 136]
11 UDCA versus placebo or
no treatment
4 224 Risk Ratio (M-H Fixed 95 CI) 080 [049 130]
12 TUDCA versus no
treatment
1 33 Risk Ratio (M-H Fixed 95 CI) 159 [030 833]
2 All-cause mortality worst-best
case and best-worst case
scenarios
5 Risk Ratio (M-H Fixed 95 CI) Subtotals only
21 Worst-best case scenario 5 257 Risk Ratio (M-H Fixed 95 CI) 130 [086 196]
22 Best-worst case scenario 5 257 Risk Ratio (M-H Fixed 95 CI) 058 [038 090]
3 Subgroup analyses all-cause
mortality at maximum
follow-up according to time of
start of bile acids
5 257 Risk Ratio (M-H Fixed 95 CI) 085 [053 136]
31 Less than three days after
transplantation
1 102 Risk Ratio (M-H Fixed 95 CI) 124 [061 254]
32 Three days or more after
transplantation
4 155 Risk Ratio (M-H Fixed 95 CI) 063 [033 120]
4 Subgroup analyses all cause
mortality at maximum
follow-up according to
treatment duration
5 257 Risk Ratio (M-H Fixed 95 CI) 085 [053 136]
41 Less than six months 3 184 Risk Ratio (M-H Fixed 95 CI) 078 [045 138]
42 Six months or more 2 73 Risk Ratio (M-H Fixed 95 CI) 102 [043 240]
5 Number of deaths related
to rejection at maximum
follow-up
1 102 Risk Ratio (M-H Fixed 95 CI) 030 [001 712]
51 UDCA versus placebo 1 102 Risk Ratio (M-H Fixed 95 CI) 030 [001 712]
6 Number of retransplantations at
maximum follow-up
2 132 Risk Ratio (M-H Fixed 95 CI) 076 [020 286]
7 Number of patients with acute
cellular rejection at maximum
follow-up
7 339 Risk Ratio (M-H Fixed 95 CI) 089 [074 106]
71 UDCA versus placebo or
no treatment
6 306 Risk Ratio (M-H Fixed 95 CI) 089 [074 108]
72 TUDCA versus no
treatment
1 33 Risk Ratio (M-H Fixed 95 CI) 085 [045 160]
8 Subgroup analysis number of
patients with acute cellular
rejection according to time of
start of bile acid
7 339 Risk Ratio (M-H Fixed 95 CI) 089 [074 106]
32Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
81 Less than three days after
transplantation
2 134 Risk Ratio (M-H Fixed 95 CI) 084 [063 111]
82 Three days or more after
liver transplantation
5 205 Risk Ratio (M-H Fixed 95 CI) 092 [072 117]
9 Subgroup analysis number
of patients with acute
cellular rejection according to
treatment duration
7 339 Risk Ratio (M-H Fixed 95 CI) 089 [074 106]
91 Less than six months 5 266 Risk Ratio (M-H Fixed 95 CI) 087 [071 107]
92 Six months or more 2 73 Risk Ratio (M-H Fixed 95 CI) 094 [065 136]
10 Number of patients with
chronic rejection at maximum
follow-up
3 184 Risk Ratio (M-H Fixed 95 CI) 028 [008 095]
11 Number of patients with
steroid-resistant rejection at
maximum follow-up
4 234 Risk Ratio (M-H Fixed 95 CI) 077 [047 127]
12 Serum bilirubin (mgdl) at the
end of treatment
1 30 Mean Difference (IV Fixed 95 CI) 26 [-096 616]
13 Number of days of
hospitalisation after liver
transplantation
1 52 Mean Difference (IV Fixed 95 CI) -85 [-1667 -033]
14 Adverse events 3 187 Risk Ratio (M-H Fixed 95 CI) 088 [030 260]
Analysis 11 Comparison 1 Bile acids for liver-transplanted patients Outcome 1 All-cause mortality at
maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 1 All-cause mortality at maximum follow-up
Study or subgroup Favours bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 UDCA versus placebo or no treatment
Barnes 1997 228 724 253 024 [ 006 107 ]
Fleckenstein 1998 214 416 125 057 [ 012 266 ]
Keiding 1997 1454 1048 355 124 [ 061 254 ]
Sama 1991 520 620 201 083 [ 030 229 ]
Subtotal (95 CI) 116 108 935 080 [ 049 130 ]
Total events 23 (Favours bile acids) 27 (Control)
Heterogeneity Chi2 = 416 df = 3 (P = 025) I2 =28
Test for overall effect Z = 091 (P = 036)
01 02 05 1 2 5 10
Favours bile acids Favours control
(Continued )
33Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Favours bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
2 TUDCA versus no treatment
Angelico 1999 316 217 65 159 [ 030 833 ]
Subtotal (95 CI) 16 17 65 159 [ 030 833 ]
Total events 3 (Favours bile acids) 2 (Control)
Heterogeneity not applicable
Test for overall effect Z = 055 (P = 058)
Total (95 CI) 132 125 1000 085 [ 053 136 ]
Total events 26 (Favours bile acids) 29 (Control)
Heterogeneity Chi2 = 466 df = 4 (P = 032) I2 =14
Test for overall effect Z = 069 (P = 049)
01 02 05 1 2 5 10
Favours bile acids Favours control
Analysis 12 Comparison 1 Bile acids for liver-transplanted patients Outcome 2 All-cause mortality worst-
best case and best-worst case scenarios
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 2 All-cause mortality worst-best case and best-worst case scenarios
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 Worst-best case scenario
Angelico 1999 516 217 65 266 [ 060 1180 ]
Barnes 1997 828 724 253 098 [ 042 230 ]
Fleckenstein 1998 314 416 125 086 [ 023 319 ]
Keiding 1997 1954 1048 355 169 [ 087 327 ]
Sama 1991 520 620 201 083 [ 030 229 ]
Subtotal (95 CI) 132 125 1000 130 [ 086 196 ]
Total events 40 (Bile acids) 29 (Control)
Heterogeneity Chi2 = 303 df = 4 (P = 055) I2 =00
Test for overall effect Z = 123 (P = 022)
2 Best-worst case scenario
005 02 1 5 20
Favours bile acids Favours control
(Continued )
34Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Angelico 1999 316 417 90 080 [ 021 302 ]
Barnes 1997 228 1124 274 016 [ 004 063 ]
Fleckenstein 1998 214 616 130 038 [ 009 159 ]
Keiding 1997 1454 1548 368 083 [ 045 154 ]
Sama 1991 520 620 139 083 [ 030 229 ]
Subtotal (95 CI) 132 125 1000 058 [ 038 090 ]
Total events 26 (Bile acids) 42 (Control)
Heterogeneity Chi2 = 567 df = 4 (P = 023) I2 =29
Test for overall effect Z = 247 (P = 0014)
005 02 1 5 20
Favours bile acids Favours control
Analysis 13 Comparison 1 Bile acids for liver-transplanted patients Outcome 3 Subgroup analyses all-
cause mortality at maximum follow-up according to time of start of bile acids
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 3 Subgroup analyses all-cause mortality at maximum follow-up according to time of start of bile acids
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 Less than three days after transplantation
Keiding 1997 1454 1048 355 124 [ 061 254 ]
Subtotal (95 CI) 54 48 355 124 [ 061 254 ]
Total events 14 (Bile acids) 10 (Control)
Heterogeneity not applicable
Test for overall effect Z = 060 (P = 055)
2 Three days or more after transplantation
Angelico 1999 316 217 65 159 [ 030 833 ]
Barnes 1997 228 724 253 024 [ 006 107 ]
Fleckenstein 1998 214 416 125 057 [ 012 266 ]
Sama 1991 520 620 201 083 [ 030 229 ]
005 02 1 5 20
Favours bile acids Favours control
(Continued )
35Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Subtotal (95 CI) 78 77 645 063 [ 033 120 ]
Total events 12 (Bile acids) 19 (Control)
Heterogeneity Chi2 = 310 df = 3 (P = 038) I2 =3
Test for overall effect Z = 141 (P = 016)
Total (95 CI) 132 125 1000 085 [ 053 136 ]
Total events 26 (Bile acids) 29 (Control)
Heterogeneity Chi2 = 466 df = 4 (P = 032) I2 =14
Test for overall effect Z = 069 (P = 049)
005 02 1 5 20
Favours bile acids Favours control
Analysis 14 Comparison 1 Bile acids for liver-transplanted patients Outcome 4 Subgroup analyses all
cause mortality at maximum follow-up according to treatment duration
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 4 Subgroup analyses all cause mortality at maximum follow-up according to treatment duration
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 Less than six months
Barnes 1997 228 724 253 024 [ 006 107 ]
Fleckenstein 1998 214 416 125 057 [ 012 266 ]
Keiding 1997 1454 1048 355 124 [ 061 254 ]
Subtotal (95 CI) 96 88 734 078 [ 045 138 ]
Total events 18 (Bile acids) 21 (Control)
Heterogeneity Chi2 = 417 df = 2 (P = 012) I2 =52
Test for overall effect Z = 084 (P = 040)
2 Six months or more
Angelico 1999 316 217 65 159 [ 030 833 ]
Sama 1991 520 620 201 083 [ 030 229 ]
Subtotal (95 CI) 36 37 266 102 [ 043 240 ]
Total events 8 (Bile acids) 8 (Control)
Heterogeneity Chi2 = 043 df = 1 (P = 051) I2 =00
005 02 1 5 20
Favours bile acids Favours control
(Continued )
36Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Test for overall effect Z = 004 (P = 097)
Total (95 CI) 132 125 1000 085 [ 053 136 ]
Total events 26 (Bile acids) 29 (Control)
Heterogeneity Chi2 = 466 df = 4 (P = 032) I2 =14
Test for overall effect Z = 069 (P = 049)
005 02 1 5 20
Favours bile acids Favours control
Analysis 15 Comparison 1 Bile acids for liver-transplanted patients Outcome 5 Number of deaths related
to rejection at maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 5 Number of deaths related to rejection at maximum follow-up
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 UDCA versus placebo
Keiding 1997 054 148 1000 030 [ 001 712 ]
Total (95 CI) 54 48 1000 030 [ 001 712 ]
Total events 0 (Bile acids) 1 (Control)
Heterogeneity not applicable
Test for overall effect Z = 075 (P = 045)
0001 001 01 1 10 100 1000
Favours bile acids Favours control
37Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 16 Comparison 1 Bile acids for liver-transplanted patients Outcome 6 Number of
retransplantations at maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 6 Number of retransplantations at maximum follow-up
Study or subgroup Bile acids Placebo Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Fleckenstein 1998 214 016 100 567 [ 029 10891 ]
Keiding 1997 154 448 900 022 [ 003 192 ]
Total (95 CI) 68 64 1000 076 [ 020 286 ]
Total events 3 (Bile acids) 4 (Placebo)
Heterogeneity Chi2 = 303 df = 1 (P = 008) I2 =67
Test for overall effect Z = 040 (P = 069)
0001 001 01 1 10 100 1000
Favours bile acids Favours placebo
Analysis 17 Comparison 1 Bile acids for liver-transplanted patients Outcome 7 Number of patients with
acute cellular rejection at maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 7 Number of patients with acute cellular rejection at maximum follow-up
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 UDCA versus placebo or no treatment
Barnes 1997 1728 1724 180 086 [ 058 127 ]
Fleckenstein 1998 814 916 83 102 [ 054 190 ]
Keiding 1997 3554 3248 333 097 [ 073 129 ]
Koneru 1993 316 916 89 033 [ 011 101 ]
Pageaux 1995 926 924 92 092 [ 044 193 ]
Sama 1991 1320 1320 128 100 [ 063 158 ]
Subtotal (95 CI) 158 148 905 089 [ 074 108 ]
01 02 05 1 2 5 10
Favours bile acids Favours control
(Continued )
38Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Total events 85 (Bile acids) 89 (Control)
Heterogeneity Chi2 = 387 df = 5 (P = 057) I2 =00
Test for overall effect Z = 120 (P = 023)
2 TUDCA versus no treatment
Angelico 1999 816 1017 95 085 [ 045 160 ]
Subtotal (95 CI) 16 17 95 085 [ 045 160 ]
Total events 8 (Bile acids) 10 (Control)
Heterogeneity not applicable
Test for overall effect Z = 050 (P = 061)
Total (95 CI) 174 165 1000 089 [ 074 106 ]
Total events 93 (Bile acids) 99 (Control)
Heterogeneity Chi2 = 392 df = 6 (P = 069) I2 =00
Test for overall effect Z = 130 (P = 019)
01 02 05 1 2 5 10
Favours bile acids Favours control
Analysis 18 Comparison 1 Bile acids for liver-transplanted patients Outcome 8 Subgroup analysis
number of patients with acute cellular rejection according to time of start of bile acid
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 8 Subgroup analysis number of patients with acute cellular rejection according to time of start of bile acid
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 Less than three days after transplantation
Keiding 1997 3554 3248 333 097 [ 073 129 ]
Koneru 1993 316 916 89 033 [ 011 101 ]
Subtotal (95 CI) 70 64 422 084 [ 063 111 ]
Total events 38 (Bile acids) 41 (Control)
Heterogeneity Chi2 = 374 df = 1 (P = 005) I2 =73
Test for overall effect Z = 124 (P = 022)
2 Three days or more after liver transplantation
Angelico 1999 816 1017 95 085 [ 045 160 ]
01 02 05 1 2 5 10
Favours bile acids Favours control
(Continued )
39Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Barnes 1997 1728 1724 180 086 [ 058 127 ]
Fleckenstein 1998 814 916 83 102 [ 054 190 ]
Pageaux 1995 926 924 92 092 [ 044 193 ]
Sama 1991 1320 1320 128 100 [ 063 158 ]
Subtotal (95 CI) 104 101 578 092 [ 072 117 ]
Total events 55 (Bile acids) 58 (Control)
Heterogeneity Chi2 = 041 df = 4 (P = 098) I2 =00
Test for overall effect Z = 067 (P = 050)
Total (95 CI) 174 165 1000 089 [ 074 106 ]
Total events 93 (Bile acids) 99 (Control)
Heterogeneity Chi2 = 392 df = 6 (P = 069) I2 =00
Test for overall effect Z = 130 (P = 019)
01 02 05 1 2 5 10
Favours bile acids Favours control
40Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 19 Comparison 1 Bile acids for liver-transplanted patients Outcome 9 Subgroup analysis
number of patients with acute cellular rejection according to treatment duration
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 9 Subgroup analysis number of patients with acute cellular rejection according to treatment duration
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 Less than six months
Barnes 1997 1728 1724 180 086 [ 058 127 ]
Fleckenstein 1998 814 916 83 102 [ 054 190 ]
Keiding 1997 3554 3248 333 097 [ 073 129 ]
Koneru 1993 316 916 89 033 [ 011 101 ]
Pageaux 1995 926 924 92 092 [ 044 193 ]
Subtotal (95 CI) 138 128 777 087 [ 071 107 ]
Total events 72 (Bile acids) 76 (Control)
Heterogeneity Chi2 = 374 df = 4 (P = 044) I2 =00
Test for overall effect Z = 129 (P = 020)
2 Six months or more
Angelico 1999 816 1017 95 085 [ 045 160 ]
Sama 1991 1320 1320 128 100 [ 063 158 ]
Subtotal (95 CI) 36 37 223 094 [ 065 136 ]
Total events 21 (Bile acids) 23 (Control)
Heterogeneity Chi2 = 017 df = 1 (P = 068) I2 =00
Test for overall effect Z = 035 (P = 073)
Total (95 CI) 174 165 1000 089 [ 074 106 ]
Total events 93 (Bile acids) 99 (Control)
Heterogeneity Chi2 = 392 df = 6 (P = 069) I2 =00
Test for overall effect Z = 130 (P = 019)
01 02 05 1 2 5 10
Favours bile acids Favours control
41Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 110 Comparison 1 Bile acids for liver-transplanted patients Outcome 10 Number of patients
with chronic rejection at maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 10 Number of patients with chronic rejection at maximum follow-up
Study or subgroup Bile acids Placebo Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Barnes 1997 128 624 611 014 [ 002 110 ]
Fleckenstein 1998 114 116 88 114 [ 008 1663 ]
Keiding 1997 154 348 300 030 [ 003 275 ]
Total (95 CI) 96 88 1000 028 [ 008 095 ]
Total events 3 (Bile acids) 10 (Placebo)
Heterogeneity Chi2 = 148 df = 2 (P = 048) I2 =00
Test for overall effect Z = 204 (P = 0041)
0001 001 01 1 10 100 1000
Favours bile acids Favours placebo
Analysis 111 Comparison 1 Bile acids for liver-transplanted patients Outcome 11 Number of patients
with steroid-resistant rejection at maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 11 Number of patients with steroid-resistant rejection at maximum follow-up
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Barnes 1997 328 724 277 037 [ 011 127 ]
Fleckenstein 1998 314 316 103 114 [ 027 478 ]
Keiding 1997 1454 1548 583 083 [ 045 154 ]
Pageaux 1995 226 124 38 185 [ 018 1908 ]
Total (95 CI) 122 112 1000 077 [ 047 127 ]
Total events 22 (Bile acids) 26 (Control)
Heterogeneity Chi2 = 226 df = 3 (P = 052) I2 =00
Test for overall effect Z = 102 (P = 031)
001 01 1 10 100
Favours bile acids Favours placebo
42Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 112 Comparison 1 Bile acids for liver-transplanted patients Outcome 12 Serum bilirubin (mgdl)
at the end of treatment
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 12 Serum bilirubin (mgdl) at the end of treatment
Study or subgroup Bile acids Placebo Mean Difference Weight Mean Difference
N Mean(SD) N Mean(SD) IVFixed95 CI IVFixed95 CI
Fleckenstein 1998 14 319 (68) 16 059 (022) 1000 260 [ -096 616 ]
Total (95 CI) 14 16 1000 260 [ -096 616 ]
Heterogeneity not applicable
Test for overall effect Z = 143 (P = 015)
-10 -5 0 5 10
Favours bile acids Favours placebo
Analysis 113 Comparison 1 Bile acids for liver-transplanted patients Outcome 13 Number of days of
hospitalisation after liver transplantation
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 13 Number of days of hospitalisation after liver transplantation
Study or subgroup Bile acids Placebo Mean Difference Weight Mean Difference
N Mean(SD) N Mean(SD) IVFixed95 CI IVFixed95 CI
Barnes 1997 28 25 (17) 24 335 (13) 1000 -850 [ -1667 -033 ]
Total (95 CI) 28 24 1000 -850 [ -1667 -033 ]
Heterogeneity not applicable
Test for overall effect Z = 204 (P = 0041)
-100 -50 0 50 100
Favours bile acids Favours placebo
43Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 114 Comparison 1 Bile acids for liver-transplanted patients Outcome 14 Adverse events
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 14 Adverse events
Study or subgroup Bile acids Placebo Risk Ratio Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Angelico 1999 016 017 00 [ 00 00 ]
Barnes 1997 128 124 086 [ 006 1298 ]
Keiding 1997 554 548 089 [ 027 288 ]
Total (95 CI) 98 89 088 [ 030 260 ]
Total events 6 (Bile acids) 6 (Placebo)
Heterogeneity Chi2 = 000 df = 1 (P = 098) I2 =00
Test for overall effect Z = 022 (P = 082)
001 01 1 10 100
Favours bile acids Favours placebo
A P P E N D I C E S
Appendix 1 Search strategies
Data Base Date of Search Search Strategy
The Cochrane Hepato-Biliary Group Con-
trolled Trials Register
September 2009 1 rsquoliver transplantationrsquo and rsquochenodeoxy-
cholicrsquo
2 rsquoliver transplantationrsquo and rsquocholicrsquo
3 rsquoliver transplantationrsquo and rsquodeoxycholicrsquo
4 rsquoliver transplantationrsquo and rsquoglycochen-
odeoxycholicrsquo
5 rsquoliver transplantationrsquo and rsquoglycocholicrsquo
6 rsquoliver transplantationrsquo and rsquoglycodeoxy-
cholicrsquo
7 rsquoliver transplantationrsquo and rsquoglycolitho-
cholicrsquo
8 rsquoliver transplantationrsquo and rsquohyodeoxy-
cholicrsquo
9 rsquoliver transplantationrsquo and rsquolithocholicrsquo
10 rsquoliver transplantationrsquo and rsquotaurochen-
odeoxycholicrsquo
44Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
11 rsquoliver transplantationrsquo and rsquotauro-
cholicrsquo
12 rsquoliver transplantationrsquo and rsquotaurodehy-
drocholicrsquo
13 rsquoliver transplantationrsquo and rsquotau-
rodeoxycholicrsquo
14 rsquoliver transplantationrsquo and rsquotauroglyco-
cholicrsquo
15 rsquoliver transplantationrsquo and rsquotaurolitho-
cholicrsquo
16 rsquoliver transplantationrsquo and rsquotaurosel-
cholicrsquo
17 rsquoliver transplantationrsquo and rsquotaurourso-
cholicrsquo
18 rsquoliver transplantationrsquo and rsquotaurour-
sodeoxycholicrsquo
19 rsquoliver transplantationrsquo and rsquoursocholicrsquo
20 rsquoliver transplantationrsquo and rsquoursodeoxy-
cholicrsquo
The Cochrane Central Register of Con-
trolled Trials in The Cochrane Library
Issue 3 2009 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
6 3 or 4
7 5 and 6
MEDLINE September 2009 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
45Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
6 3 or 4
7 5 and 6
8 RANDOMIZED-CONTROLLED-
TRIAL ME
9 RANDOM
10 8 or 9
11 7 and 10
EMBASE September 2009 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
6 3 or 4
7 5 and 6
8 RANDOMIZED-CONTROLLED-
TRIAL ME
9 RANDOM
10 8 or 9
11 7 and 10
46Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
Science Citation Index Expanded September 2009 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
6 3 or 4
7 5 and 6
8 RANDOMIZED-CONTROLLED-
TRIAL ME
9 RANDOM
10 8 or 9
11 7 and 10
The Chinese Biomedical Database Searched from January 1980 to April 2002 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
47Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
6 3 or 4
7 5 and 6
8 RANDOMIZED-CONTROLLED-
TRIAL ME
9 RANDOM
10 8 or 9
11 7 and 10
W H A T rsquo S N E W
Last assessed as up-to-date 8 February 2010
18 September 2009 New citation required but conclusions have not
changed
This review is an updated version of a review that was
published for the first time in Issue 3 2005 of TheCochrane Library by Chen 2003b
18 September 2009 New search has been performed No new studies fulfilled the inclusion criteria
H I S T O R Y
Protocol first published Issue 3 2003
Review first published Issue 3 2005
C O N T R I B U T I O N S O F A U T H O R S
GP and VG independently performed searches of relevant databases GP validated the search selected trials for inclusion contacted
the authors of the trials performed data extraction and data analysis and drafted the systematic review VG revised the review update
CG and DS revised the review update solved discrepancies of data extraction validated data analyses and provided consultation
D E C L A R A T I O N S O F I N T E R E S T
None known
48Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
S O U R C E S O F S U P P O R T
Internal sources
bull Copenhagen Trial Unit Denmark
External sources
bull Danish Medical Research Councilrsquos Grant on Getting Research into Practice (GRIP) Denmark
D I F F E R E N C E S B E T W E E N P R O T O C O L A N D R E V I E W
We assessed the risk of bias in the included studies for another four domains that were added to the review protocol (incomplete
outcome data selective outcome reporting baseline imbalance and early stopping of trial) In general the text of the risk of bias
domains were updated following Higgins 2008 Trials were considered at low risk of bias when judged as adequate in all domains
Quasi-randomised studies observational and case-control studies were included for the report of adverse events
We performed trial sequential analysis for outcomes demonstrating a statistically significant result
I N D E X T E R M S
Medical Subject Headings (MeSH)
lowastLiver Transplantation Cholagogues and Choleretics [lowasttherapeutic use] Graft Rejection [lowastprevention amp control] Randomized Con-
trolled Trials as Topic Taurochenodeoxycholic Acid [lowasttherapeutic use] Ursodeoxycholic Acid [lowasttherapeutic use]
MeSH check words
Humans
49Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
D A T A A N D A N A L Y S E S
Comparison 1 Bile acids for liver-transplanted patients
Outcome or subgroup titleNo of
studies
No of
participants Statistical method Effect size
1 All-cause mortality at maximum
follow-up
5 257 Risk Ratio (M-H Fixed 95 CI) 085 [053 136]
11 UDCA versus placebo or
no treatment
4 224 Risk Ratio (M-H Fixed 95 CI) 080 [049 130]
12 TUDCA versus no
treatment
1 33 Risk Ratio (M-H Fixed 95 CI) 159 [030 833]
2 All-cause mortality worst-best
case and best-worst case
scenarios
5 Risk Ratio (M-H Fixed 95 CI) Subtotals only
21 Worst-best case scenario 5 257 Risk Ratio (M-H Fixed 95 CI) 130 [086 196]
22 Best-worst case scenario 5 257 Risk Ratio (M-H Fixed 95 CI) 058 [038 090]
3 Subgroup analyses all-cause
mortality at maximum
follow-up according to time of
start of bile acids
5 257 Risk Ratio (M-H Fixed 95 CI) 085 [053 136]
31 Less than three days after
transplantation
1 102 Risk Ratio (M-H Fixed 95 CI) 124 [061 254]
32 Three days or more after
transplantation
4 155 Risk Ratio (M-H Fixed 95 CI) 063 [033 120]
4 Subgroup analyses all cause
mortality at maximum
follow-up according to
treatment duration
5 257 Risk Ratio (M-H Fixed 95 CI) 085 [053 136]
41 Less than six months 3 184 Risk Ratio (M-H Fixed 95 CI) 078 [045 138]
42 Six months or more 2 73 Risk Ratio (M-H Fixed 95 CI) 102 [043 240]
5 Number of deaths related
to rejection at maximum
follow-up
1 102 Risk Ratio (M-H Fixed 95 CI) 030 [001 712]
51 UDCA versus placebo 1 102 Risk Ratio (M-H Fixed 95 CI) 030 [001 712]
6 Number of retransplantations at
maximum follow-up
2 132 Risk Ratio (M-H Fixed 95 CI) 076 [020 286]
7 Number of patients with acute
cellular rejection at maximum
follow-up
7 339 Risk Ratio (M-H Fixed 95 CI) 089 [074 106]
71 UDCA versus placebo or
no treatment
6 306 Risk Ratio (M-H Fixed 95 CI) 089 [074 108]
72 TUDCA versus no
treatment
1 33 Risk Ratio (M-H Fixed 95 CI) 085 [045 160]
8 Subgroup analysis number of
patients with acute cellular
rejection according to time of
start of bile acid
7 339 Risk Ratio (M-H Fixed 95 CI) 089 [074 106]
32Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
81 Less than three days after
transplantation
2 134 Risk Ratio (M-H Fixed 95 CI) 084 [063 111]
82 Three days or more after
liver transplantation
5 205 Risk Ratio (M-H Fixed 95 CI) 092 [072 117]
9 Subgroup analysis number
of patients with acute
cellular rejection according to
treatment duration
7 339 Risk Ratio (M-H Fixed 95 CI) 089 [074 106]
91 Less than six months 5 266 Risk Ratio (M-H Fixed 95 CI) 087 [071 107]
92 Six months or more 2 73 Risk Ratio (M-H Fixed 95 CI) 094 [065 136]
10 Number of patients with
chronic rejection at maximum
follow-up
3 184 Risk Ratio (M-H Fixed 95 CI) 028 [008 095]
11 Number of patients with
steroid-resistant rejection at
maximum follow-up
4 234 Risk Ratio (M-H Fixed 95 CI) 077 [047 127]
12 Serum bilirubin (mgdl) at the
end of treatment
1 30 Mean Difference (IV Fixed 95 CI) 26 [-096 616]
13 Number of days of
hospitalisation after liver
transplantation
1 52 Mean Difference (IV Fixed 95 CI) -85 [-1667 -033]
14 Adverse events 3 187 Risk Ratio (M-H Fixed 95 CI) 088 [030 260]
Analysis 11 Comparison 1 Bile acids for liver-transplanted patients Outcome 1 All-cause mortality at
maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 1 All-cause mortality at maximum follow-up
Study or subgroup Favours bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 UDCA versus placebo or no treatment
Barnes 1997 228 724 253 024 [ 006 107 ]
Fleckenstein 1998 214 416 125 057 [ 012 266 ]
Keiding 1997 1454 1048 355 124 [ 061 254 ]
Sama 1991 520 620 201 083 [ 030 229 ]
Subtotal (95 CI) 116 108 935 080 [ 049 130 ]
Total events 23 (Favours bile acids) 27 (Control)
Heterogeneity Chi2 = 416 df = 3 (P = 025) I2 =28
Test for overall effect Z = 091 (P = 036)
01 02 05 1 2 5 10
Favours bile acids Favours control
(Continued )
33Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Favours bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
2 TUDCA versus no treatment
Angelico 1999 316 217 65 159 [ 030 833 ]
Subtotal (95 CI) 16 17 65 159 [ 030 833 ]
Total events 3 (Favours bile acids) 2 (Control)
Heterogeneity not applicable
Test for overall effect Z = 055 (P = 058)
Total (95 CI) 132 125 1000 085 [ 053 136 ]
Total events 26 (Favours bile acids) 29 (Control)
Heterogeneity Chi2 = 466 df = 4 (P = 032) I2 =14
Test for overall effect Z = 069 (P = 049)
01 02 05 1 2 5 10
Favours bile acids Favours control
Analysis 12 Comparison 1 Bile acids for liver-transplanted patients Outcome 2 All-cause mortality worst-
best case and best-worst case scenarios
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 2 All-cause mortality worst-best case and best-worst case scenarios
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 Worst-best case scenario
Angelico 1999 516 217 65 266 [ 060 1180 ]
Barnes 1997 828 724 253 098 [ 042 230 ]
Fleckenstein 1998 314 416 125 086 [ 023 319 ]
Keiding 1997 1954 1048 355 169 [ 087 327 ]
Sama 1991 520 620 201 083 [ 030 229 ]
Subtotal (95 CI) 132 125 1000 130 [ 086 196 ]
Total events 40 (Bile acids) 29 (Control)
Heterogeneity Chi2 = 303 df = 4 (P = 055) I2 =00
Test for overall effect Z = 123 (P = 022)
2 Best-worst case scenario
005 02 1 5 20
Favours bile acids Favours control
(Continued )
34Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Angelico 1999 316 417 90 080 [ 021 302 ]
Barnes 1997 228 1124 274 016 [ 004 063 ]
Fleckenstein 1998 214 616 130 038 [ 009 159 ]
Keiding 1997 1454 1548 368 083 [ 045 154 ]
Sama 1991 520 620 139 083 [ 030 229 ]
Subtotal (95 CI) 132 125 1000 058 [ 038 090 ]
Total events 26 (Bile acids) 42 (Control)
Heterogeneity Chi2 = 567 df = 4 (P = 023) I2 =29
Test for overall effect Z = 247 (P = 0014)
005 02 1 5 20
Favours bile acids Favours control
Analysis 13 Comparison 1 Bile acids for liver-transplanted patients Outcome 3 Subgroup analyses all-
cause mortality at maximum follow-up according to time of start of bile acids
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 3 Subgroup analyses all-cause mortality at maximum follow-up according to time of start of bile acids
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 Less than three days after transplantation
Keiding 1997 1454 1048 355 124 [ 061 254 ]
Subtotal (95 CI) 54 48 355 124 [ 061 254 ]
Total events 14 (Bile acids) 10 (Control)
Heterogeneity not applicable
Test for overall effect Z = 060 (P = 055)
2 Three days or more after transplantation
Angelico 1999 316 217 65 159 [ 030 833 ]
Barnes 1997 228 724 253 024 [ 006 107 ]
Fleckenstein 1998 214 416 125 057 [ 012 266 ]
Sama 1991 520 620 201 083 [ 030 229 ]
005 02 1 5 20
Favours bile acids Favours control
(Continued )
35Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Subtotal (95 CI) 78 77 645 063 [ 033 120 ]
Total events 12 (Bile acids) 19 (Control)
Heterogeneity Chi2 = 310 df = 3 (P = 038) I2 =3
Test for overall effect Z = 141 (P = 016)
Total (95 CI) 132 125 1000 085 [ 053 136 ]
Total events 26 (Bile acids) 29 (Control)
Heterogeneity Chi2 = 466 df = 4 (P = 032) I2 =14
Test for overall effect Z = 069 (P = 049)
005 02 1 5 20
Favours bile acids Favours control
Analysis 14 Comparison 1 Bile acids for liver-transplanted patients Outcome 4 Subgroup analyses all
cause mortality at maximum follow-up according to treatment duration
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 4 Subgroup analyses all cause mortality at maximum follow-up according to treatment duration
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 Less than six months
Barnes 1997 228 724 253 024 [ 006 107 ]
Fleckenstein 1998 214 416 125 057 [ 012 266 ]
Keiding 1997 1454 1048 355 124 [ 061 254 ]
Subtotal (95 CI) 96 88 734 078 [ 045 138 ]
Total events 18 (Bile acids) 21 (Control)
Heterogeneity Chi2 = 417 df = 2 (P = 012) I2 =52
Test for overall effect Z = 084 (P = 040)
2 Six months or more
Angelico 1999 316 217 65 159 [ 030 833 ]
Sama 1991 520 620 201 083 [ 030 229 ]
Subtotal (95 CI) 36 37 266 102 [ 043 240 ]
Total events 8 (Bile acids) 8 (Control)
Heterogeneity Chi2 = 043 df = 1 (P = 051) I2 =00
005 02 1 5 20
Favours bile acids Favours control
(Continued )
36Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Test for overall effect Z = 004 (P = 097)
Total (95 CI) 132 125 1000 085 [ 053 136 ]
Total events 26 (Bile acids) 29 (Control)
Heterogeneity Chi2 = 466 df = 4 (P = 032) I2 =14
Test for overall effect Z = 069 (P = 049)
005 02 1 5 20
Favours bile acids Favours control
Analysis 15 Comparison 1 Bile acids for liver-transplanted patients Outcome 5 Number of deaths related
to rejection at maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 5 Number of deaths related to rejection at maximum follow-up
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 UDCA versus placebo
Keiding 1997 054 148 1000 030 [ 001 712 ]
Total (95 CI) 54 48 1000 030 [ 001 712 ]
Total events 0 (Bile acids) 1 (Control)
Heterogeneity not applicable
Test for overall effect Z = 075 (P = 045)
0001 001 01 1 10 100 1000
Favours bile acids Favours control
37Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 16 Comparison 1 Bile acids for liver-transplanted patients Outcome 6 Number of
retransplantations at maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 6 Number of retransplantations at maximum follow-up
Study or subgroup Bile acids Placebo Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Fleckenstein 1998 214 016 100 567 [ 029 10891 ]
Keiding 1997 154 448 900 022 [ 003 192 ]
Total (95 CI) 68 64 1000 076 [ 020 286 ]
Total events 3 (Bile acids) 4 (Placebo)
Heterogeneity Chi2 = 303 df = 1 (P = 008) I2 =67
Test for overall effect Z = 040 (P = 069)
0001 001 01 1 10 100 1000
Favours bile acids Favours placebo
Analysis 17 Comparison 1 Bile acids for liver-transplanted patients Outcome 7 Number of patients with
acute cellular rejection at maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 7 Number of patients with acute cellular rejection at maximum follow-up
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 UDCA versus placebo or no treatment
Barnes 1997 1728 1724 180 086 [ 058 127 ]
Fleckenstein 1998 814 916 83 102 [ 054 190 ]
Keiding 1997 3554 3248 333 097 [ 073 129 ]
Koneru 1993 316 916 89 033 [ 011 101 ]
Pageaux 1995 926 924 92 092 [ 044 193 ]
Sama 1991 1320 1320 128 100 [ 063 158 ]
Subtotal (95 CI) 158 148 905 089 [ 074 108 ]
01 02 05 1 2 5 10
Favours bile acids Favours control
(Continued )
38Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Total events 85 (Bile acids) 89 (Control)
Heterogeneity Chi2 = 387 df = 5 (P = 057) I2 =00
Test for overall effect Z = 120 (P = 023)
2 TUDCA versus no treatment
Angelico 1999 816 1017 95 085 [ 045 160 ]
Subtotal (95 CI) 16 17 95 085 [ 045 160 ]
Total events 8 (Bile acids) 10 (Control)
Heterogeneity not applicable
Test for overall effect Z = 050 (P = 061)
Total (95 CI) 174 165 1000 089 [ 074 106 ]
Total events 93 (Bile acids) 99 (Control)
Heterogeneity Chi2 = 392 df = 6 (P = 069) I2 =00
Test for overall effect Z = 130 (P = 019)
01 02 05 1 2 5 10
Favours bile acids Favours control
Analysis 18 Comparison 1 Bile acids for liver-transplanted patients Outcome 8 Subgroup analysis
number of patients with acute cellular rejection according to time of start of bile acid
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 8 Subgroup analysis number of patients with acute cellular rejection according to time of start of bile acid
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 Less than three days after transplantation
Keiding 1997 3554 3248 333 097 [ 073 129 ]
Koneru 1993 316 916 89 033 [ 011 101 ]
Subtotal (95 CI) 70 64 422 084 [ 063 111 ]
Total events 38 (Bile acids) 41 (Control)
Heterogeneity Chi2 = 374 df = 1 (P = 005) I2 =73
Test for overall effect Z = 124 (P = 022)
2 Three days or more after liver transplantation
Angelico 1999 816 1017 95 085 [ 045 160 ]
01 02 05 1 2 5 10
Favours bile acids Favours control
(Continued )
39Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Barnes 1997 1728 1724 180 086 [ 058 127 ]
Fleckenstein 1998 814 916 83 102 [ 054 190 ]
Pageaux 1995 926 924 92 092 [ 044 193 ]
Sama 1991 1320 1320 128 100 [ 063 158 ]
Subtotal (95 CI) 104 101 578 092 [ 072 117 ]
Total events 55 (Bile acids) 58 (Control)
Heterogeneity Chi2 = 041 df = 4 (P = 098) I2 =00
Test for overall effect Z = 067 (P = 050)
Total (95 CI) 174 165 1000 089 [ 074 106 ]
Total events 93 (Bile acids) 99 (Control)
Heterogeneity Chi2 = 392 df = 6 (P = 069) I2 =00
Test for overall effect Z = 130 (P = 019)
01 02 05 1 2 5 10
Favours bile acids Favours control
40Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 19 Comparison 1 Bile acids for liver-transplanted patients Outcome 9 Subgroup analysis
number of patients with acute cellular rejection according to treatment duration
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 9 Subgroup analysis number of patients with acute cellular rejection according to treatment duration
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 Less than six months
Barnes 1997 1728 1724 180 086 [ 058 127 ]
Fleckenstein 1998 814 916 83 102 [ 054 190 ]
Keiding 1997 3554 3248 333 097 [ 073 129 ]
Koneru 1993 316 916 89 033 [ 011 101 ]
Pageaux 1995 926 924 92 092 [ 044 193 ]
Subtotal (95 CI) 138 128 777 087 [ 071 107 ]
Total events 72 (Bile acids) 76 (Control)
Heterogeneity Chi2 = 374 df = 4 (P = 044) I2 =00
Test for overall effect Z = 129 (P = 020)
2 Six months or more
Angelico 1999 816 1017 95 085 [ 045 160 ]
Sama 1991 1320 1320 128 100 [ 063 158 ]
Subtotal (95 CI) 36 37 223 094 [ 065 136 ]
Total events 21 (Bile acids) 23 (Control)
Heterogeneity Chi2 = 017 df = 1 (P = 068) I2 =00
Test for overall effect Z = 035 (P = 073)
Total (95 CI) 174 165 1000 089 [ 074 106 ]
Total events 93 (Bile acids) 99 (Control)
Heterogeneity Chi2 = 392 df = 6 (P = 069) I2 =00
Test for overall effect Z = 130 (P = 019)
01 02 05 1 2 5 10
Favours bile acids Favours control
41Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 110 Comparison 1 Bile acids for liver-transplanted patients Outcome 10 Number of patients
with chronic rejection at maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 10 Number of patients with chronic rejection at maximum follow-up
Study or subgroup Bile acids Placebo Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Barnes 1997 128 624 611 014 [ 002 110 ]
Fleckenstein 1998 114 116 88 114 [ 008 1663 ]
Keiding 1997 154 348 300 030 [ 003 275 ]
Total (95 CI) 96 88 1000 028 [ 008 095 ]
Total events 3 (Bile acids) 10 (Placebo)
Heterogeneity Chi2 = 148 df = 2 (P = 048) I2 =00
Test for overall effect Z = 204 (P = 0041)
0001 001 01 1 10 100 1000
Favours bile acids Favours placebo
Analysis 111 Comparison 1 Bile acids for liver-transplanted patients Outcome 11 Number of patients
with steroid-resistant rejection at maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 11 Number of patients with steroid-resistant rejection at maximum follow-up
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Barnes 1997 328 724 277 037 [ 011 127 ]
Fleckenstein 1998 314 316 103 114 [ 027 478 ]
Keiding 1997 1454 1548 583 083 [ 045 154 ]
Pageaux 1995 226 124 38 185 [ 018 1908 ]
Total (95 CI) 122 112 1000 077 [ 047 127 ]
Total events 22 (Bile acids) 26 (Control)
Heterogeneity Chi2 = 226 df = 3 (P = 052) I2 =00
Test for overall effect Z = 102 (P = 031)
001 01 1 10 100
Favours bile acids Favours placebo
42Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 112 Comparison 1 Bile acids for liver-transplanted patients Outcome 12 Serum bilirubin (mgdl)
at the end of treatment
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 12 Serum bilirubin (mgdl) at the end of treatment
Study or subgroup Bile acids Placebo Mean Difference Weight Mean Difference
N Mean(SD) N Mean(SD) IVFixed95 CI IVFixed95 CI
Fleckenstein 1998 14 319 (68) 16 059 (022) 1000 260 [ -096 616 ]
Total (95 CI) 14 16 1000 260 [ -096 616 ]
Heterogeneity not applicable
Test for overall effect Z = 143 (P = 015)
-10 -5 0 5 10
Favours bile acids Favours placebo
Analysis 113 Comparison 1 Bile acids for liver-transplanted patients Outcome 13 Number of days of
hospitalisation after liver transplantation
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 13 Number of days of hospitalisation after liver transplantation
Study or subgroup Bile acids Placebo Mean Difference Weight Mean Difference
N Mean(SD) N Mean(SD) IVFixed95 CI IVFixed95 CI
Barnes 1997 28 25 (17) 24 335 (13) 1000 -850 [ -1667 -033 ]
Total (95 CI) 28 24 1000 -850 [ -1667 -033 ]
Heterogeneity not applicable
Test for overall effect Z = 204 (P = 0041)
-100 -50 0 50 100
Favours bile acids Favours placebo
43Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 114 Comparison 1 Bile acids for liver-transplanted patients Outcome 14 Adverse events
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 14 Adverse events
Study or subgroup Bile acids Placebo Risk Ratio Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Angelico 1999 016 017 00 [ 00 00 ]
Barnes 1997 128 124 086 [ 006 1298 ]
Keiding 1997 554 548 089 [ 027 288 ]
Total (95 CI) 98 89 088 [ 030 260 ]
Total events 6 (Bile acids) 6 (Placebo)
Heterogeneity Chi2 = 000 df = 1 (P = 098) I2 =00
Test for overall effect Z = 022 (P = 082)
001 01 1 10 100
Favours bile acids Favours placebo
A P P E N D I C E S
Appendix 1 Search strategies
Data Base Date of Search Search Strategy
The Cochrane Hepato-Biliary Group Con-
trolled Trials Register
September 2009 1 rsquoliver transplantationrsquo and rsquochenodeoxy-
cholicrsquo
2 rsquoliver transplantationrsquo and rsquocholicrsquo
3 rsquoliver transplantationrsquo and rsquodeoxycholicrsquo
4 rsquoliver transplantationrsquo and rsquoglycochen-
odeoxycholicrsquo
5 rsquoliver transplantationrsquo and rsquoglycocholicrsquo
6 rsquoliver transplantationrsquo and rsquoglycodeoxy-
cholicrsquo
7 rsquoliver transplantationrsquo and rsquoglycolitho-
cholicrsquo
8 rsquoliver transplantationrsquo and rsquohyodeoxy-
cholicrsquo
9 rsquoliver transplantationrsquo and rsquolithocholicrsquo
10 rsquoliver transplantationrsquo and rsquotaurochen-
odeoxycholicrsquo
44Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
11 rsquoliver transplantationrsquo and rsquotauro-
cholicrsquo
12 rsquoliver transplantationrsquo and rsquotaurodehy-
drocholicrsquo
13 rsquoliver transplantationrsquo and rsquotau-
rodeoxycholicrsquo
14 rsquoliver transplantationrsquo and rsquotauroglyco-
cholicrsquo
15 rsquoliver transplantationrsquo and rsquotaurolitho-
cholicrsquo
16 rsquoliver transplantationrsquo and rsquotaurosel-
cholicrsquo
17 rsquoliver transplantationrsquo and rsquotaurourso-
cholicrsquo
18 rsquoliver transplantationrsquo and rsquotaurour-
sodeoxycholicrsquo
19 rsquoliver transplantationrsquo and rsquoursocholicrsquo
20 rsquoliver transplantationrsquo and rsquoursodeoxy-
cholicrsquo
The Cochrane Central Register of Con-
trolled Trials in The Cochrane Library
Issue 3 2009 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
6 3 or 4
7 5 and 6
MEDLINE September 2009 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
45Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
6 3 or 4
7 5 and 6
8 RANDOMIZED-CONTROLLED-
TRIAL ME
9 RANDOM
10 8 or 9
11 7 and 10
EMBASE September 2009 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
6 3 or 4
7 5 and 6
8 RANDOMIZED-CONTROLLED-
TRIAL ME
9 RANDOM
10 8 or 9
11 7 and 10
46Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
Science Citation Index Expanded September 2009 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
6 3 or 4
7 5 and 6
8 RANDOMIZED-CONTROLLED-
TRIAL ME
9 RANDOM
10 8 or 9
11 7 and 10
The Chinese Biomedical Database Searched from January 1980 to April 2002 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
47Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
6 3 or 4
7 5 and 6
8 RANDOMIZED-CONTROLLED-
TRIAL ME
9 RANDOM
10 8 or 9
11 7 and 10
W H A T rsquo S N E W
Last assessed as up-to-date 8 February 2010
18 September 2009 New citation required but conclusions have not
changed
This review is an updated version of a review that was
published for the first time in Issue 3 2005 of TheCochrane Library by Chen 2003b
18 September 2009 New search has been performed No new studies fulfilled the inclusion criteria
H I S T O R Y
Protocol first published Issue 3 2003
Review first published Issue 3 2005
C O N T R I B U T I O N S O F A U T H O R S
GP and VG independently performed searches of relevant databases GP validated the search selected trials for inclusion contacted
the authors of the trials performed data extraction and data analysis and drafted the systematic review VG revised the review update
CG and DS revised the review update solved discrepancies of data extraction validated data analyses and provided consultation
D E C L A R A T I O N S O F I N T E R E S T
None known
48Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
S O U R C E S O F S U P P O R T
Internal sources
bull Copenhagen Trial Unit Denmark
External sources
bull Danish Medical Research Councilrsquos Grant on Getting Research into Practice (GRIP) Denmark
D I F F E R E N C E S B E T W E E N P R O T O C O L A N D R E V I E W
We assessed the risk of bias in the included studies for another four domains that were added to the review protocol (incomplete
outcome data selective outcome reporting baseline imbalance and early stopping of trial) In general the text of the risk of bias
domains were updated following Higgins 2008 Trials were considered at low risk of bias when judged as adequate in all domains
Quasi-randomised studies observational and case-control studies were included for the report of adverse events
We performed trial sequential analysis for outcomes demonstrating a statistically significant result
I N D E X T E R M S
Medical Subject Headings (MeSH)
lowastLiver Transplantation Cholagogues and Choleretics [lowasttherapeutic use] Graft Rejection [lowastprevention amp control] Randomized Con-
trolled Trials as Topic Taurochenodeoxycholic Acid [lowasttherapeutic use] Ursodeoxycholic Acid [lowasttherapeutic use]
MeSH check words
Humans
49Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
81 Less than three days after
transplantation
2 134 Risk Ratio (M-H Fixed 95 CI) 084 [063 111]
82 Three days or more after
liver transplantation
5 205 Risk Ratio (M-H Fixed 95 CI) 092 [072 117]
9 Subgroup analysis number
of patients with acute
cellular rejection according to
treatment duration
7 339 Risk Ratio (M-H Fixed 95 CI) 089 [074 106]
91 Less than six months 5 266 Risk Ratio (M-H Fixed 95 CI) 087 [071 107]
92 Six months or more 2 73 Risk Ratio (M-H Fixed 95 CI) 094 [065 136]
10 Number of patients with
chronic rejection at maximum
follow-up
3 184 Risk Ratio (M-H Fixed 95 CI) 028 [008 095]
11 Number of patients with
steroid-resistant rejection at
maximum follow-up
4 234 Risk Ratio (M-H Fixed 95 CI) 077 [047 127]
12 Serum bilirubin (mgdl) at the
end of treatment
1 30 Mean Difference (IV Fixed 95 CI) 26 [-096 616]
13 Number of days of
hospitalisation after liver
transplantation
1 52 Mean Difference (IV Fixed 95 CI) -85 [-1667 -033]
14 Adverse events 3 187 Risk Ratio (M-H Fixed 95 CI) 088 [030 260]
Analysis 11 Comparison 1 Bile acids for liver-transplanted patients Outcome 1 All-cause mortality at
maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 1 All-cause mortality at maximum follow-up
Study or subgroup Favours bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 UDCA versus placebo or no treatment
Barnes 1997 228 724 253 024 [ 006 107 ]
Fleckenstein 1998 214 416 125 057 [ 012 266 ]
Keiding 1997 1454 1048 355 124 [ 061 254 ]
Sama 1991 520 620 201 083 [ 030 229 ]
Subtotal (95 CI) 116 108 935 080 [ 049 130 ]
Total events 23 (Favours bile acids) 27 (Control)
Heterogeneity Chi2 = 416 df = 3 (P = 025) I2 =28
Test for overall effect Z = 091 (P = 036)
01 02 05 1 2 5 10
Favours bile acids Favours control
(Continued )
33Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Favours bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
2 TUDCA versus no treatment
Angelico 1999 316 217 65 159 [ 030 833 ]
Subtotal (95 CI) 16 17 65 159 [ 030 833 ]
Total events 3 (Favours bile acids) 2 (Control)
Heterogeneity not applicable
Test for overall effect Z = 055 (P = 058)
Total (95 CI) 132 125 1000 085 [ 053 136 ]
Total events 26 (Favours bile acids) 29 (Control)
Heterogeneity Chi2 = 466 df = 4 (P = 032) I2 =14
Test for overall effect Z = 069 (P = 049)
01 02 05 1 2 5 10
Favours bile acids Favours control
Analysis 12 Comparison 1 Bile acids for liver-transplanted patients Outcome 2 All-cause mortality worst-
best case and best-worst case scenarios
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 2 All-cause mortality worst-best case and best-worst case scenarios
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 Worst-best case scenario
Angelico 1999 516 217 65 266 [ 060 1180 ]
Barnes 1997 828 724 253 098 [ 042 230 ]
Fleckenstein 1998 314 416 125 086 [ 023 319 ]
Keiding 1997 1954 1048 355 169 [ 087 327 ]
Sama 1991 520 620 201 083 [ 030 229 ]
Subtotal (95 CI) 132 125 1000 130 [ 086 196 ]
Total events 40 (Bile acids) 29 (Control)
Heterogeneity Chi2 = 303 df = 4 (P = 055) I2 =00
Test for overall effect Z = 123 (P = 022)
2 Best-worst case scenario
005 02 1 5 20
Favours bile acids Favours control
(Continued )
34Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Angelico 1999 316 417 90 080 [ 021 302 ]
Barnes 1997 228 1124 274 016 [ 004 063 ]
Fleckenstein 1998 214 616 130 038 [ 009 159 ]
Keiding 1997 1454 1548 368 083 [ 045 154 ]
Sama 1991 520 620 139 083 [ 030 229 ]
Subtotal (95 CI) 132 125 1000 058 [ 038 090 ]
Total events 26 (Bile acids) 42 (Control)
Heterogeneity Chi2 = 567 df = 4 (P = 023) I2 =29
Test for overall effect Z = 247 (P = 0014)
005 02 1 5 20
Favours bile acids Favours control
Analysis 13 Comparison 1 Bile acids for liver-transplanted patients Outcome 3 Subgroup analyses all-
cause mortality at maximum follow-up according to time of start of bile acids
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 3 Subgroup analyses all-cause mortality at maximum follow-up according to time of start of bile acids
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 Less than three days after transplantation
Keiding 1997 1454 1048 355 124 [ 061 254 ]
Subtotal (95 CI) 54 48 355 124 [ 061 254 ]
Total events 14 (Bile acids) 10 (Control)
Heterogeneity not applicable
Test for overall effect Z = 060 (P = 055)
2 Three days or more after transplantation
Angelico 1999 316 217 65 159 [ 030 833 ]
Barnes 1997 228 724 253 024 [ 006 107 ]
Fleckenstein 1998 214 416 125 057 [ 012 266 ]
Sama 1991 520 620 201 083 [ 030 229 ]
005 02 1 5 20
Favours bile acids Favours control
(Continued )
35Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Subtotal (95 CI) 78 77 645 063 [ 033 120 ]
Total events 12 (Bile acids) 19 (Control)
Heterogeneity Chi2 = 310 df = 3 (P = 038) I2 =3
Test for overall effect Z = 141 (P = 016)
Total (95 CI) 132 125 1000 085 [ 053 136 ]
Total events 26 (Bile acids) 29 (Control)
Heterogeneity Chi2 = 466 df = 4 (P = 032) I2 =14
Test for overall effect Z = 069 (P = 049)
005 02 1 5 20
Favours bile acids Favours control
Analysis 14 Comparison 1 Bile acids for liver-transplanted patients Outcome 4 Subgroup analyses all
cause mortality at maximum follow-up according to treatment duration
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 4 Subgroup analyses all cause mortality at maximum follow-up according to treatment duration
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 Less than six months
Barnes 1997 228 724 253 024 [ 006 107 ]
Fleckenstein 1998 214 416 125 057 [ 012 266 ]
Keiding 1997 1454 1048 355 124 [ 061 254 ]
Subtotal (95 CI) 96 88 734 078 [ 045 138 ]
Total events 18 (Bile acids) 21 (Control)
Heterogeneity Chi2 = 417 df = 2 (P = 012) I2 =52
Test for overall effect Z = 084 (P = 040)
2 Six months or more
Angelico 1999 316 217 65 159 [ 030 833 ]
Sama 1991 520 620 201 083 [ 030 229 ]
Subtotal (95 CI) 36 37 266 102 [ 043 240 ]
Total events 8 (Bile acids) 8 (Control)
Heterogeneity Chi2 = 043 df = 1 (P = 051) I2 =00
005 02 1 5 20
Favours bile acids Favours control
(Continued )
36Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Test for overall effect Z = 004 (P = 097)
Total (95 CI) 132 125 1000 085 [ 053 136 ]
Total events 26 (Bile acids) 29 (Control)
Heterogeneity Chi2 = 466 df = 4 (P = 032) I2 =14
Test for overall effect Z = 069 (P = 049)
005 02 1 5 20
Favours bile acids Favours control
Analysis 15 Comparison 1 Bile acids for liver-transplanted patients Outcome 5 Number of deaths related
to rejection at maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 5 Number of deaths related to rejection at maximum follow-up
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 UDCA versus placebo
Keiding 1997 054 148 1000 030 [ 001 712 ]
Total (95 CI) 54 48 1000 030 [ 001 712 ]
Total events 0 (Bile acids) 1 (Control)
Heterogeneity not applicable
Test for overall effect Z = 075 (P = 045)
0001 001 01 1 10 100 1000
Favours bile acids Favours control
37Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 16 Comparison 1 Bile acids for liver-transplanted patients Outcome 6 Number of
retransplantations at maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 6 Number of retransplantations at maximum follow-up
Study or subgroup Bile acids Placebo Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Fleckenstein 1998 214 016 100 567 [ 029 10891 ]
Keiding 1997 154 448 900 022 [ 003 192 ]
Total (95 CI) 68 64 1000 076 [ 020 286 ]
Total events 3 (Bile acids) 4 (Placebo)
Heterogeneity Chi2 = 303 df = 1 (P = 008) I2 =67
Test for overall effect Z = 040 (P = 069)
0001 001 01 1 10 100 1000
Favours bile acids Favours placebo
Analysis 17 Comparison 1 Bile acids for liver-transplanted patients Outcome 7 Number of patients with
acute cellular rejection at maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 7 Number of patients with acute cellular rejection at maximum follow-up
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 UDCA versus placebo or no treatment
Barnes 1997 1728 1724 180 086 [ 058 127 ]
Fleckenstein 1998 814 916 83 102 [ 054 190 ]
Keiding 1997 3554 3248 333 097 [ 073 129 ]
Koneru 1993 316 916 89 033 [ 011 101 ]
Pageaux 1995 926 924 92 092 [ 044 193 ]
Sama 1991 1320 1320 128 100 [ 063 158 ]
Subtotal (95 CI) 158 148 905 089 [ 074 108 ]
01 02 05 1 2 5 10
Favours bile acids Favours control
(Continued )
38Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Total events 85 (Bile acids) 89 (Control)
Heterogeneity Chi2 = 387 df = 5 (P = 057) I2 =00
Test for overall effect Z = 120 (P = 023)
2 TUDCA versus no treatment
Angelico 1999 816 1017 95 085 [ 045 160 ]
Subtotal (95 CI) 16 17 95 085 [ 045 160 ]
Total events 8 (Bile acids) 10 (Control)
Heterogeneity not applicable
Test for overall effect Z = 050 (P = 061)
Total (95 CI) 174 165 1000 089 [ 074 106 ]
Total events 93 (Bile acids) 99 (Control)
Heterogeneity Chi2 = 392 df = 6 (P = 069) I2 =00
Test for overall effect Z = 130 (P = 019)
01 02 05 1 2 5 10
Favours bile acids Favours control
Analysis 18 Comparison 1 Bile acids for liver-transplanted patients Outcome 8 Subgroup analysis
number of patients with acute cellular rejection according to time of start of bile acid
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 8 Subgroup analysis number of patients with acute cellular rejection according to time of start of bile acid
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 Less than three days after transplantation
Keiding 1997 3554 3248 333 097 [ 073 129 ]
Koneru 1993 316 916 89 033 [ 011 101 ]
Subtotal (95 CI) 70 64 422 084 [ 063 111 ]
Total events 38 (Bile acids) 41 (Control)
Heterogeneity Chi2 = 374 df = 1 (P = 005) I2 =73
Test for overall effect Z = 124 (P = 022)
2 Three days or more after liver transplantation
Angelico 1999 816 1017 95 085 [ 045 160 ]
01 02 05 1 2 5 10
Favours bile acids Favours control
(Continued )
39Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Barnes 1997 1728 1724 180 086 [ 058 127 ]
Fleckenstein 1998 814 916 83 102 [ 054 190 ]
Pageaux 1995 926 924 92 092 [ 044 193 ]
Sama 1991 1320 1320 128 100 [ 063 158 ]
Subtotal (95 CI) 104 101 578 092 [ 072 117 ]
Total events 55 (Bile acids) 58 (Control)
Heterogeneity Chi2 = 041 df = 4 (P = 098) I2 =00
Test for overall effect Z = 067 (P = 050)
Total (95 CI) 174 165 1000 089 [ 074 106 ]
Total events 93 (Bile acids) 99 (Control)
Heterogeneity Chi2 = 392 df = 6 (P = 069) I2 =00
Test for overall effect Z = 130 (P = 019)
01 02 05 1 2 5 10
Favours bile acids Favours control
40Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 19 Comparison 1 Bile acids for liver-transplanted patients Outcome 9 Subgroup analysis
number of patients with acute cellular rejection according to treatment duration
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 9 Subgroup analysis number of patients with acute cellular rejection according to treatment duration
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 Less than six months
Barnes 1997 1728 1724 180 086 [ 058 127 ]
Fleckenstein 1998 814 916 83 102 [ 054 190 ]
Keiding 1997 3554 3248 333 097 [ 073 129 ]
Koneru 1993 316 916 89 033 [ 011 101 ]
Pageaux 1995 926 924 92 092 [ 044 193 ]
Subtotal (95 CI) 138 128 777 087 [ 071 107 ]
Total events 72 (Bile acids) 76 (Control)
Heterogeneity Chi2 = 374 df = 4 (P = 044) I2 =00
Test for overall effect Z = 129 (P = 020)
2 Six months or more
Angelico 1999 816 1017 95 085 [ 045 160 ]
Sama 1991 1320 1320 128 100 [ 063 158 ]
Subtotal (95 CI) 36 37 223 094 [ 065 136 ]
Total events 21 (Bile acids) 23 (Control)
Heterogeneity Chi2 = 017 df = 1 (P = 068) I2 =00
Test for overall effect Z = 035 (P = 073)
Total (95 CI) 174 165 1000 089 [ 074 106 ]
Total events 93 (Bile acids) 99 (Control)
Heterogeneity Chi2 = 392 df = 6 (P = 069) I2 =00
Test for overall effect Z = 130 (P = 019)
01 02 05 1 2 5 10
Favours bile acids Favours control
41Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 110 Comparison 1 Bile acids for liver-transplanted patients Outcome 10 Number of patients
with chronic rejection at maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 10 Number of patients with chronic rejection at maximum follow-up
Study or subgroup Bile acids Placebo Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Barnes 1997 128 624 611 014 [ 002 110 ]
Fleckenstein 1998 114 116 88 114 [ 008 1663 ]
Keiding 1997 154 348 300 030 [ 003 275 ]
Total (95 CI) 96 88 1000 028 [ 008 095 ]
Total events 3 (Bile acids) 10 (Placebo)
Heterogeneity Chi2 = 148 df = 2 (P = 048) I2 =00
Test for overall effect Z = 204 (P = 0041)
0001 001 01 1 10 100 1000
Favours bile acids Favours placebo
Analysis 111 Comparison 1 Bile acids for liver-transplanted patients Outcome 11 Number of patients
with steroid-resistant rejection at maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 11 Number of patients with steroid-resistant rejection at maximum follow-up
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Barnes 1997 328 724 277 037 [ 011 127 ]
Fleckenstein 1998 314 316 103 114 [ 027 478 ]
Keiding 1997 1454 1548 583 083 [ 045 154 ]
Pageaux 1995 226 124 38 185 [ 018 1908 ]
Total (95 CI) 122 112 1000 077 [ 047 127 ]
Total events 22 (Bile acids) 26 (Control)
Heterogeneity Chi2 = 226 df = 3 (P = 052) I2 =00
Test for overall effect Z = 102 (P = 031)
001 01 1 10 100
Favours bile acids Favours placebo
42Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 112 Comparison 1 Bile acids for liver-transplanted patients Outcome 12 Serum bilirubin (mgdl)
at the end of treatment
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 12 Serum bilirubin (mgdl) at the end of treatment
Study or subgroup Bile acids Placebo Mean Difference Weight Mean Difference
N Mean(SD) N Mean(SD) IVFixed95 CI IVFixed95 CI
Fleckenstein 1998 14 319 (68) 16 059 (022) 1000 260 [ -096 616 ]
Total (95 CI) 14 16 1000 260 [ -096 616 ]
Heterogeneity not applicable
Test for overall effect Z = 143 (P = 015)
-10 -5 0 5 10
Favours bile acids Favours placebo
Analysis 113 Comparison 1 Bile acids for liver-transplanted patients Outcome 13 Number of days of
hospitalisation after liver transplantation
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 13 Number of days of hospitalisation after liver transplantation
Study or subgroup Bile acids Placebo Mean Difference Weight Mean Difference
N Mean(SD) N Mean(SD) IVFixed95 CI IVFixed95 CI
Barnes 1997 28 25 (17) 24 335 (13) 1000 -850 [ -1667 -033 ]
Total (95 CI) 28 24 1000 -850 [ -1667 -033 ]
Heterogeneity not applicable
Test for overall effect Z = 204 (P = 0041)
-100 -50 0 50 100
Favours bile acids Favours placebo
43Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 114 Comparison 1 Bile acids for liver-transplanted patients Outcome 14 Adverse events
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 14 Adverse events
Study or subgroup Bile acids Placebo Risk Ratio Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Angelico 1999 016 017 00 [ 00 00 ]
Barnes 1997 128 124 086 [ 006 1298 ]
Keiding 1997 554 548 089 [ 027 288 ]
Total (95 CI) 98 89 088 [ 030 260 ]
Total events 6 (Bile acids) 6 (Placebo)
Heterogeneity Chi2 = 000 df = 1 (P = 098) I2 =00
Test for overall effect Z = 022 (P = 082)
001 01 1 10 100
Favours bile acids Favours placebo
A P P E N D I C E S
Appendix 1 Search strategies
Data Base Date of Search Search Strategy
The Cochrane Hepato-Biliary Group Con-
trolled Trials Register
September 2009 1 rsquoliver transplantationrsquo and rsquochenodeoxy-
cholicrsquo
2 rsquoliver transplantationrsquo and rsquocholicrsquo
3 rsquoliver transplantationrsquo and rsquodeoxycholicrsquo
4 rsquoliver transplantationrsquo and rsquoglycochen-
odeoxycholicrsquo
5 rsquoliver transplantationrsquo and rsquoglycocholicrsquo
6 rsquoliver transplantationrsquo and rsquoglycodeoxy-
cholicrsquo
7 rsquoliver transplantationrsquo and rsquoglycolitho-
cholicrsquo
8 rsquoliver transplantationrsquo and rsquohyodeoxy-
cholicrsquo
9 rsquoliver transplantationrsquo and rsquolithocholicrsquo
10 rsquoliver transplantationrsquo and rsquotaurochen-
odeoxycholicrsquo
44Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
11 rsquoliver transplantationrsquo and rsquotauro-
cholicrsquo
12 rsquoliver transplantationrsquo and rsquotaurodehy-
drocholicrsquo
13 rsquoliver transplantationrsquo and rsquotau-
rodeoxycholicrsquo
14 rsquoliver transplantationrsquo and rsquotauroglyco-
cholicrsquo
15 rsquoliver transplantationrsquo and rsquotaurolitho-
cholicrsquo
16 rsquoliver transplantationrsquo and rsquotaurosel-
cholicrsquo
17 rsquoliver transplantationrsquo and rsquotaurourso-
cholicrsquo
18 rsquoliver transplantationrsquo and rsquotaurour-
sodeoxycholicrsquo
19 rsquoliver transplantationrsquo and rsquoursocholicrsquo
20 rsquoliver transplantationrsquo and rsquoursodeoxy-
cholicrsquo
The Cochrane Central Register of Con-
trolled Trials in The Cochrane Library
Issue 3 2009 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
6 3 or 4
7 5 and 6
MEDLINE September 2009 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
45Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
6 3 or 4
7 5 and 6
8 RANDOMIZED-CONTROLLED-
TRIAL ME
9 RANDOM
10 8 or 9
11 7 and 10
EMBASE September 2009 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
6 3 or 4
7 5 and 6
8 RANDOMIZED-CONTROLLED-
TRIAL ME
9 RANDOM
10 8 or 9
11 7 and 10
46Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
Science Citation Index Expanded September 2009 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
6 3 or 4
7 5 and 6
8 RANDOMIZED-CONTROLLED-
TRIAL ME
9 RANDOM
10 8 or 9
11 7 and 10
The Chinese Biomedical Database Searched from January 1980 to April 2002 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
47Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
6 3 or 4
7 5 and 6
8 RANDOMIZED-CONTROLLED-
TRIAL ME
9 RANDOM
10 8 or 9
11 7 and 10
W H A T rsquo S N E W
Last assessed as up-to-date 8 February 2010
18 September 2009 New citation required but conclusions have not
changed
This review is an updated version of a review that was
published for the first time in Issue 3 2005 of TheCochrane Library by Chen 2003b
18 September 2009 New search has been performed No new studies fulfilled the inclusion criteria
H I S T O R Y
Protocol first published Issue 3 2003
Review first published Issue 3 2005
C O N T R I B U T I O N S O F A U T H O R S
GP and VG independently performed searches of relevant databases GP validated the search selected trials for inclusion contacted
the authors of the trials performed data extraction and data analysis and drafted the systematic review VG revised the review update
CG and DS revised the review update solved discrepancies of data extraction validated data analyses and provided consultation
D E C L A R A T I O N S O F I N T E R E S T
None known
48Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
S O U R C E S O F S U P P O R T
Internal sources
bull Copenhagen Trial Unit Denmark
External sources
bull Danish Medical Research Councilrsquos Grant on Getting Research into Practice (GRIP) Denmark
D I F F E R E N C E S B E T W E E N P R O T O C O L A N D R E V I E W
We assessed the risk of bias in the included studies for another four domains that were added to the review protocol (incomplete
outcome data selective outcome reporting baseline imbalance and early stopping of trial) In general the text of the risk of bias
domains were updated following Higgins 2008 Trials were considered at low risk of bias when judged as adequate in all domains
Quasi-randomised studies observational and case-control studies were included for the report of adverse events
We performed trial sequential analysis for outcomes demonstrating a statistically significant result
I N D E X T E R M S
Medical Subject Headings (MeSH)
lowastLiver Transplantation Cholagogues and Choleretics [lowasttherapeutic use] Graft Rejection [lowastprevention amp control] Randomized Con-
trolled Trials as Topic Taurochenodeoxycholic Acid [lowasttherapeutic use] Ursodeoxycholic Acid [lowasttherapeutic use]
MeSH check words
Humans
49Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Favours bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
2 TUDCA versus no treatment
Angelico 1999 316 217 65 159 [ 030 833 ]
Subtotal (95 CI) 16 17 65 159 [ 030 833 ]
Total events 3 (Favours bile acids) 2 (Control)
Heterogeneity not applicable
Test for overall effect Z = 055 (P = 058)
Total (95 CI) 132 125 1000 085 [ 053 136 ]
Total events 26 (Favours bile acids) 29 (Control)
Heterogeneity Chi2 = 466 df = 4 (P = 032) I2 =14
Test for overall effect Z = 069 (P = 049)
01 02 05 1 2 5 10
Favours bile acids Favours control
Analysis 12 Comparison 1 Bile acids for liver-transplanted patients Outcome 2 All-cause mortality worst-
best case and best-worst case scenarios
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 2 All-cause mortality worst-best case and best-worst case scenarios
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 Worst-best case scenario
Angelico 1999 516 217 65 266 [ 060 1180 ]
Barnes 1997 828 724 253 098 [ 042 230 ]
Fleckenstein 1998 314 416 125 086 [ 023 319 ]
Keiding 1997 1954 1048 355 169 [ 087 327 ]
Sama 1991 520 620 201 083 [ 030 229 ]
Subtotal (95 CI) 132 125 1000 130 [ 086 196 ]
Total events 40 (Bile acids) 29 (Control)
Heterogeneity Chi2 = 303 df = 4 (P = 055) I2 =00
Test for overall effect Z = 123 (P = 022)
2 Best-worst case scenario
005 02 1 5 20
Favours bile acids Favours control
(Continued )
34Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Angelico 1999 316 417 90 080 [ 021 302 ]
Barnes 1997 228 1124 274 016 [ 004 063 ]
Fleckenstein 1998 214 616 130 038 [ 009 159 ]
Keiding 1997 1454 1548 368 083 [ 045 154 ]
Sama 1991 520 620 139 083 [ 030 229 ]
Subtotal (95 CI) 132 125 1000 058 [ 038 090 ]
Total events 26 (Bile acids) 42 (Control)
Heterogeneity Chi2 = 567 df = 4 (P = 023) I2 =29
Test for overall effect Z = 247 (P = 0014)
005 02 1 5 20
Favours bile acids Favours control
Analysis 13 Comparison 1 Bile acids for liver-transplanted patients Outcome 3 Subgroup analyses all-
cause mortality at maximum follow-up according to time of start of bile acids
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 3 Subgroup analyses all-cause mortality at maximum follow-up according to time of start of bile acids
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 Less than three days after transplantation
Keiding 1997 1454 1048 355 124 [ 061 254 ]
Subtotal (95 CI) 54 48 355 124 [ 061 254 ]
Total events 14 (Bile acids) 10 (Control)
Heterogeneity not applicable
Test for overall effect Z = 060 (P = 055)
2 Three days or more after transplantation
Angelico 1999 316 217 65 159 [ 030 833 ]
Barnes 1997 228 724 253 024 [ 006 107 ]
Fleckenstein 1998 214 416 125 057 [ 012 266 ]
Sama 1991 520 620 201 083 [ 030 229 ]
005 02 1 5 20
Favours bile acids Favours control
(Continued )
35Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Subtotal (95 CI) 78 77 645 063 [ 033 120 ]
Total events 12 (Bile acids) 19 (Control)
Heterogeneity Chi2 = 310 df = 3 (P = 038) I2 =3
Test for overall effect Z = 141 (P = 016)
Total (95 CI) 132 125 1000 085 [ 053 136 ]
Total events 26 (Bile acids) 29 (Control)
Heterogeneity Chi2 = 466 df = 4 (P = 032) I2 =14
Test for overall effect Z = 069 (P = 049)
005 02 1 5 20
Favours bile acids Favours control
Analysis 14 Comparison 1 Bile acids for liver-transplanted patients Outcome 4 Subgroup analyses all
cause mortality at maximum follow-up according to treatment duration
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 4 Subgroup analyses all cause mortality at maximum follow-up according to treatment duration
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 Less than six months
Barnes 1997 228 724 253 024 [ 006 107 ]
Fleckenstein 1998 214 416 125 057 [ 012 266 ]
Keiding 1997 1454 1048 355 124 [ 061 254 ]
Subtotal (95 CI) 96 88 734 078 [ 045 138 ]
Total events 18 (Bile acids) 21 (Control)
Heterogeneity Chi2 = 417 df = 2 (P = 012) I2 =52
Test for overall effect Z = 084 (P = 040)
2 Six months or more
Angelico 1999 316 217 65 159 [ 030 833 ]
Sama 1991 520 620 201 083 [ 030 229 ]
Subtotal (95 CI) 36 37 266 102 [ 043 240 ]
Total events 8 (Bile acids) 8 (Control)
Heterogeneity Chi2 = 043 df = 1 (P = 051) I2 =00
005 02 1 5 20
Favours bile acids Favours control
(Continued )
36Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Test for overall effect Z = 004 (P = 097)
Total (95 CI) 132 125 1000 085 [ 053 136 ]
Total events 26 (Bile acids) 29 (Control)
Heterogeneity Chi2 = 466 df = 4 (P = 032) I2 =14
Test for overall effect Z = 069 (P = 049)
005 02 1 5 20
Favours bile acids Favours control
Analysis 15 Comparison 1 Bile acids for liver-transplanted patients Outcome 5 Number of deaths related
to rejection at maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 5 Number of deaths related to rejection at maximum follow-up
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 UDCA versus placebo
Keiding 1997 054 148 1000 030 [ 001 712 ]
Total (95 CI) 54 48 1000 030 [ 001 712 ]
Total events 0 (Bile acids) 1 (Control)
Heterogeneity not applicable
Test for overall effect Z = 075 (P = 045)
0001 001 01 1 10 100 1000
Favours bile acids Favours control
37Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 16 Comparison 1 Bile acids for liver-transplanted patients Outcome 6 Number of
retransplantations at maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 6 Number of retransplantations at maximum follow-up
Study or subgroup Bile acids Placebo Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Fleckenstein 1998 214 016 100 567 [ 029 10891 ]
Keiding 1997 154 448 900 022 [ 003 192 ]
Total (95 CI) 68 64 1000 076 [ 020 286 ]
Total events 3 (Bile acids) 4 (Placebo)
Heterogeneity Chi2 = 303 df = 1 (P = 008) I2 =67
Test for overall effect Z = 040 (P = 069)
0001 001 01 1 10 100 1000
Favours bile acids Favours placebo
Analysis 17 Comparison 1 Bile acids for liver-transplanted patients Outcome 7 Number of patients with
acute cellular rejection at maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 7 Number of patients with acute cellular rejection at maximum follow-up
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 UDCA versus placebo or no treatment
Barnes 1997 1728 1724 180 086 [ 058 127 ]
Fleckenstein 1998 814 916 83 102 [ 054 190 ]
Keiding 1997 3554 3248 333 097 [ 073 129 ]
Koneru 1993 316 916 89 033 [ 011 101 ]
Pageaux 1995 926 924 92 092 [ 044 193 ]
Sama 1991 1320 1320 128 100 [ 063 158 ]
Subtotal (95 CI) 158 148 905 089 [ 074 108 ]
01 02 05 1 2 5 10
Favours bile acids Favours control
(Continued )
38Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Total events 85 (Bile acids) 89 (Control)
Heterogeneity Chi2 = 387 df = 5 (P = 057) I2 =00
Test for overall effect Z = 120 (P = 023)
2 TUDCA versus no treatment
Angelico 1999 816 1017 95 085 [ 045 160 ]
Subtotal (95 CI) 16 17 95 085 [ 045 160 ]
Total events 8 (Bile acids) 10 (Control)
Heterogeneity not applicable
Test for overall effect Z = 050 (P = 061)
Total (95 CI) 174 165 1000 089 [ 074 106 ]
Total events 93 (Bile acids) 99 (Control)
Heterogeneity Chi2 = 392 df = 6 (P = 069) I2 =00
Test for overall effect Z = 130 (P = 019)
01 02 05 1 2 5 10
Favours bile acids Favours control
Analysis 18 Comparison 1 Bile acids for liver-transplanted patients Outcome 8 Subgroup analysis
number of patients with acute cellular rejection according to time of start of bile acid
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 8 Subgroup analysis number of patients with acute cellular rejection according to time of start of bile acid
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 Less than three days after transplantation
Keiding 1997 3554 3248 333 097 [ 073 129 ]
Koneru 1993 316 916 89 033 [ 011 101 ]
Subtotal (95 CI) 70 64 422 084 [ 063 111 ]
Total events 38 (Bile acids) 41 (Control)
Heterogeneity Chi2 = 374 df = 1 (P = 005) I2 =73
Test for overall effect Z = 124 (P = 022)
2 Three days or more after liver transplantation
Angelico 1999 816 1017 95 085 [ 045 160 ]
01 02 05 1 2 5 10
Favours bile acids Favours control
(Continued )
39Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Barnes 1997 1728 1724 180 086 [ 058 127 ]
Fleckenstein 1998 814 916 83 102 [ 054 190 ]
Pageaux 1995 926 924 92 092 [ 044 193 ]
Sama 1991 1320 1320 128 100 [ 063 158 ]
Subtotal (95 CI) 104 101 578 092 [ 072 117 ]
Total events 55 (Bile acids) 58 (Control)
Heterogeneity Chi2 = 041 df = 4 (P = 098) I2 =00
Test for overall effect Z = 067 (P = 050)
Total (95 CI) 174 165 1000 089 [ 074 106 ]
Total events 93 (Bile acids) 99 (Control)
Heterogeneity Chi2 = 392 df = 6 (P = 069) I2 =00
Test for overall effect Z = 130 (P = 019)
01 02 05 1 2 5 10
Favours bile acids Favours control
40Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 19 Comparison 1 Bile acids for liver-transplanted patients Outcome 9 Subgroup analysis
number of patients with acute cellular rejection according to treatment duration
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 9 Subgroup analysis number of patients with acute cellular rejection according to treatment duration
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 Less than six months
Barnes 1997 1728 1724 180 086 [ 058 127 ]
Fleckenstein 1998 814 916 83 102 [ 054 190 ]
Keiding 1997 3554 3248 333 097 [ 073 129 ]
Koneru 1993 316 916 89 033 [ 011 101 ]
Pageaux 1995 926 924 92 092 [ 044 193 ]
Subtotal (95 CI) 138 128 777 087 [ 071 107 ]
Total events 72 (Bile acids) 76 (Control)
Heterogeneity Chi2 = 374 df = 4 (P = 044) I2 =00
Test for overall effect Z = 129 (P = 020)
2 Six months or more
Angelico 1999 816 1017 95 085 [ 045 160 ]
Sama 1991 1320 1320 128 100 [ 063 158 ]
Subtotal (95 CI) 36 37 223 094 [ 065 136 ]
Total events 21 (Bile acids) 23 (Control)
Heterogeneity Chi2 = 017 df = 1 (P = 068) I2 =00
Test for overall effect Z = 035 (P = 073)
Total (95 CI) 174 165 1000 089 [ 074 106 ]
Total events 93 (Bile acids) 99 (Control)
Heterogeneity Chi2 = 392 df = 6 (P = 069) I2 =00
Test for overall effect Z = 130 (P = 019)
01 02 05 1 2 5 10
Favours bile acids Favours control
41Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 110 Comparison 1 Bile acids for liver-transplanted patients Outcome 10 Number of patients
with chronic rejection at maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 10 Number of patients with chronic rejection at maximum follow-up
Study or subgroup Bile acids Placebo Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Barnes 1997 128 624 611 014 [ 002 110 ]
Fleckenstein 1998 114 116 88 114 [ 008 1663 ]
Keiding 1997 154 348 300 030 [ 003 275 ]
Total (95 CI) 96 88 1000 028 [ 008 095 ]
Total events 3 (Bile acids) 10 (Placebo)
Heterogeneity Chi2 = 148 df = 2 (P = 048) I2 =00
Test for overall effect Z = 204 (P = 0041)
0001 001 01 1 10 100 1000
Favours bile acids Favours placebo
Analysis 111 Comparison 1 Bile acids for liver-transplanted patients Outcome 11 Number of patients
with steroid-resistant rejection at maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 11 Number of patients with steroid-resistant rejection at maximum follow-up
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Barnes 1997 328 724 277 037 [ 011 127 ]
Fleckenstein 1998 314 316 103 114 [ 027 478 ]
Keiding 1997 1454 1548 583 083 [ 045 154 ]
Pageaux 1995 226 124 38 185 [ 018 1908 ]
Total (95 CI) 122 112 1000 077 [ 047 127 ]
Total events 22 (Bile acids) 26 (Control)
Heterogeneity Chi2 = 226 df = 3 (P = 052) I2 =00
Test for overall effect Z = 102 (P = 031)
001 01 1 10 100
Favours bile acids Favours placebo
42Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 112 Comparison 1 Bile acids for liver-transplanted patients Outcome 12 Serum bilirubin (mgdl)
at the end of treatment
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 12 Serum bilirubin (mgdl) at the end of treatment
Study or subgroup Bile acids Placebo Mean Difference Weight Mean Difference
N Mean(SD) N Mean(SD) IVFixed95 CI IVFixed95 CI
Fleckenstein 1998 14 319 (68) 16 059 (022) 1000 260 [ -096 616 ]
Total (95 CI) 14 16 1000 260 [ -096 616 ]
Heterogeneity not applicable
Test for overall effect Z = 143 (P = 015)
-10 -5 0 5 10
Favours bile acids Favours placebo
Analysis 113 Comparison 1 Bile acids for liver-transplanted patients Outcome 13 Number of days of
hospitalisation after liver transplantation
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 13 Number of days of hospitalisation after liver transplantation
Study or subgroup Bile acids Placebo Mean Difference Weight Mean Difference
N Mean(SD) N Mean(SD) IVFixed95 CI IVFixed95 CI
Barnes 1997 28 25 (17) 24 335 (13) 1000 -850 [ -1667 -033 ]
Total (95 CI) 28 24 1000 -850 [ -1667 -033 ]
Heterogeneity not applicable
Test for overall effect Z = 204 (P = 0041)
-100 -50 0 50 100
Favours bile acids Favours placebo
43Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 114 Comparison 1 Bile acids for liver-transplanted patients Outcome 14 Adverse events
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 14 Adverse events
Study or subgroup Bile acids Placebo Risk Ratio Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Angelico 1999 016 017 00 [ 00 00 ]
Barnes 1997 128 124 086 [ 006 1298 ]
Keiding 1997 554 548 089 [ 027 288 ]
Total (95 CI) 98 89 088 [ 030 260 ]
Total events 6 (Bile acids) 6 (Placebo)
Heterogeneity Chi2 = 000 df = 1 (P = 098) I2 =00
Test for overall effect Z = 022 (P = 082)
001 01 1 10 100
Favours bile acids Favours placebo
A P P E N D I C E S
Appendix 1 Search strategies
Data Base Date of Search Search Strategy
The Cochrane Hepato-Biliary Group Con-
trolled Trials Register
September 2009 1 rsquoliver transplantationrsquo and rsquochenodeoxy-
cholicrsquo
2 rsquoliver transplantationrsquo and rsquocholicrsquo
3 rsquoliver transplantationrsquo and rsquodeoxycholicrsquo
4 rsquoliver transplantationrsquo and rsquoglycochen-
odeoxycholicrsquo
5 rsquoliver transplantationrsquo and rsquoglycocholicrsquo
6 rsquoliver transplantationrsquo and rsquoglycodeoxy-
cholicrsquo
7 rsquoliver transplantationrsquo and rsquoglycolitho-
cholicrsquo
8 rsquoliver transplantationrsquo and rsquohyodeoxy-
cholicrsquo
9 rsquoliver transplantationrsquo and rsquolithocholicrsquo
10 rsquoliver transplantationrsquo and rsquotaurochen-
odeoxycholicrsquo
44Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
11 rsquoliver transplantationrsquo and rsquotauro-
cholicrsquo
12 rsquoliver transplantationrsquo and rsquotaurodehy-
drocholicrsquo
13 rsquoliver transplantationrsquo and rsquotau-
rodeoxycholicrsquo
14 rsquoliver transplantationrsquo and rsquotauroglyco-
cholicrsquo
15 rsquoliver transplantationrsquo and rsquotaurolitho-
cholicrsquo
16 rsquoliver transplantationrsquo and rsquotaurosel-
cholicrsquo
17 rsquoliver transplantationrsquo and rsquotaurourso-
cholicrsquo
18 rsquoliver transplantationrsquo and rsquotaurour-
sodeoxycholicrsquo
19 rsquoliver transplantationrsquo and rsquoursocholicrsquo
20 rsquoliver transplantationrsquo and rsquoursodeoxy-
cholicrsquo
The Cochrane Central Register of Con-
trolled Trials in The Cochrane Library
Issue 3 2009 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
6 3 or 4
7 5 and 6
MEDLINE September 2009 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
45Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
6 3 or 4
7 5 and 6
8 RANDOMIZED-CONTROLLED-
TRIAL ME
9 RANDOM
10 8 or 9
11 7 and 10
EMBASE September 2009 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
6 3 or 4
7 5 and 6
8 RANDOMIZED-CONTROLLED-
TRIAL ME
9 RANDOM
10 8 or 9
11 7 and 10
46Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
Science Citation Index Expanded September 2009 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
6 3 or 4
7 5 and 6
8 RANDOMIZED-CONTROLLED-
TRIAL ME
9 RANDOM
10 8 or 9
11 7 and 10
The Chinese Biomedical Database Searched from January 1980 to April 2002 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
47Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
6 3 or 4
7 5 and 6
8 RANDOMIZED-CONTROLLED-
TRIAL ME
9 RANDOM
10 8 or 9
11 7 and 10
W H A T rsquo S N E W
Last assessed as up-to-date 8 February 2010
18 September 2009 New citation required but conclusions have not
changed
This review is an updated version of a review that was
published for the first time in Issue 3 2005 of TheCochrane Library by Chen 2003b
18 September 2009 New search has been performed No new studies fulfilled the inclusion criteria
H I S T O R Y
Protocol first published Issue 3 2003
Review first published Issue 3 2005
C O N T R I B U T I O N S O F A U T H O R S
GP and VG independently performed searches of relevant databases GP validated the search selected trials for inclusion contacted
the authors of the trials performed data extraction and data analysis and drafted the systematic review VG revised the review update
CG and DS revised the review update solved discrepancies of data extraction validated data analyses and provided consultation
D E C L A R A T I O N S O F I N T E R E S T
None known
48Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
S O U R C E S O F S U P P O R T
Internal sources
bull Copenhagen Trial Unit Denmark
External sources
bull Danish Medical Research Councilrsquos Grant on Getting Research into Practice (GRIP) Denmark
D I F F E R E N C E S B E T W E E N P R O T O C O L A N D R E V I E W
We assessed the risk of bias in the included studies for another four domains that were added to the review protocol (incomplete
outcome data selective outcome reporting baseline imbalance and early stopping of trial) In general the text of the risk of bias
domains were updated following Higgins 2008 Trials were considered at low risk of bias when judged as adequate in all domains
Quasi-randomised studies observational and case-control studies were included for the report of adverse events
We performed trial sequential analysis for outcomes demonstrating a statistically significant result
I N D E X T E R M S
Medical Subject Headings (MeSH)
lowastLiver Transplantation Cholagogues and Choleretics [lowasttherapeutic use] Graft Rejection [lowastprevention amp control] Randomized Con-
trolled Trials as Topic Taurochenodeoxycholic Acid [lowasttherapeutic use] Ursodeoxycholic Acid [lowasttherapeutic use]
MeSH check words
Humans
49Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Angelico 1999 316 417 90 080 [ 021 302 ]
Barnes 1997 228 1124 274 016 [ 004 063 ]
Fleckenstein 1998 214 616 130 038 [ 009 159 ]
Keiding 1997 1454 1548 368 083 [ 045 154 ]
Sama 1991 520 620 139 083 [ 030 229 ]
Subtotal (95 CI) 132 125 1000 058 [ 038 090 ]
Total events 26 (Bile acids) 42 (Control)
Heterogeneity Chi2 = 567 df = 4 (P = 023) I2 =29
Test for overall effect Z = 247 (P = 0014)
005 02 1 5 20
Favours bile acids Favours control
Analysis 13 Comparison 1 Bile acids for liver-transplanted patients Outcome 3 Subgroup analyses all-
cause mortality at maximum follow-up according to time of start of bile acids
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 3 Subgroup analyses all-cause mortality at maximum follow-up according to time of start of bile acids
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 Less than three days after transplantation
Keiding 1997 1454 1048 355 124 [ 061 254 ]
Subtotal (95 CI) 54 48 355 124 [ 061 254 ]
Total events 14 (Bile acids) 10 (Control)
Heterogeneity not applicable
Test for overall effect Z = 060 (P = 055)
2 Three days or more after transplantation
Angelico 1999 316 217 65 159 [ 030 833 ]
Barnes 1997 228 724 253 024 [ 006 107 ]
Fleckenstein 1998 214 416 125 057 [ 012 266 ]
Sama 1991 520 620 201 083 [ 030 229 ]
005 02 1 5 20
Favours bile acids Favours control
(Continued )
35Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Subtotal (95 CI) 78 77 645 063 [ 033 120 ]
Total events 12 (Bile acids) 19 (Control)
Heterogeneity Chi2 = 310 df = 3 (P = 038) I2 =3
Test for overall effect Z = 141 (P = 016)
Total (95 CI) 132 125 1000 085 [ 053 136 ]
Total events 26 (Bile acids) 29 (Control)
Heterogeneity Chi2 = 466 df = 4 (P = 032) I2 =14
Test for overall effect Z = 069 (P = 049)
005 02 1 5 20
Favours bile acids Favours control
Analysis 14 Comparison 1 Bile acids for liver-transplanted patients Outcome 4 Subgroup analyses all
cause mortality at maximum follow-up according to treatment duration
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 4 Subgroup analyses all cause mortality at maximum follow-up according to treatment duration
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 Less than six months
Barnes 1997 228 724 253 024 [ 006 107 ]
Fleckenstein 1998 214 416 125 057 [ 012 266 ]
Keiding 1997 1454 1048 355 124 [ 061 254 ]
Subtotal (95 CI) 96 88 734 078 [ 045 138 ]
Total events 18 (Bile acids) 21 (Control)
Heterogeneity Chi2 = 417 df = 2 (P = 012) I2 =52
Test for overall effect Z = 084 (P = 040)
2 Six months or more
Angelico 1999 316 217 65 159 [ 030 833 ]
Sama 1991 520 620 201 083 [ 030 229 ]
Subtotal (95 CI) 36 37 266 102 [ 043 240 ]
Total events 8 (Bile acids) 8 (Control)
Heterogeneity Chi2 = 043 df = 1 (P = 051) I2 =00
005 02 1 5 20
Favours bile acids Favours control
(Continued )
36Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Test for overall effect Z = 004 (P = 097)
Total (95 CI) 132 125 1000 085 [ 053 136 ]
Total events 26 (Bile acids) 29 (Control)
Heterogeneity Chi2 = 466 df = 4 (P = 032) I2 =14
Test for overall effect Z = 069 (P = 049)
005 02 1 5 20
Favours bile acids Favours control
Analysis 15 Comparison 1 Bile acids for liver-transplanted patients Outcome 5 Number of deaths related
to rejection at maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 5 Number of deaths related to rejection at maximum follow-up
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 UDCA versus placebo
Keiding 1997 054 148 1000 030 [ 001 712 ]
Total (95 CI) 54 48 1000 030 [ 001 712 ]
Total events 0 (Bile acids) 1 (Control)
Heterogeneity not applicable
Test for overall effect Z = 075 (P = 045)
0001 001 01 1 10 100 1000
Favours bile acids Favours control
37Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 16 Comparison 1 Bile acids for liver-transplanted patients Outcome 6 Number of
retransplantations at maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 6 Number of retransplantations at maximum follow-up
Study or subgroup Bile acids Placebo Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Fleckenstein 1998 214 016 100 567 [ 029 10891 ]
Keiding 1997 154 448 900 022 [ 003 192 ]
Total (95 CI) 68 64 1000 076 [ 020 286 ]
Total events 3 (Bile acids) 4 (Placebo)
Heterogeneity Chi2 = 303 df = 1 (P = 008) I2 =67
Test for overall effect Z = 040 (P = 069)
0001 001 01 1 10 100 1000
Favours bile acids Favours placebo
Analysis 17 Comparison 1 Bile acids for liver-transplanted patients Outcome 7 Number of patients with
acute cellular rejection at maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 7 Number of patients with acute cellular rejection at maximum follow-up
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 UDCA versus placebo or no treatment
Barnes 1997 1728 1724 180 086 [ 058 127 ]
Fleckenstein 1998 814 916 83 102 [ 054 190 ]
Keiding 1997 3554 3248 333 097 [ 073 129 ]
Koneru 1993 316 916 89 033 [ 011 101 ]
Pageaux 1995 926 924 92 092 [ 044 193 ]
Sama 1991 1320 1320 128 100 [ 063 158 ]
Subtotal (95 CI) 158 148 905 089 [ 074 108 ]
01 02 05 1 2 5 10
Favours bile acids Favours control
(Continued )
38Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Total events 85 (Bile acids) 89 (Control)
Heterogeneity Chi2 = 387 df = 5 (P = 057) I2 =00
Test for overall effect Z = 120 (P = 023)
2 TUDCA versus no treatment
Angelico 1999 816 1017 95 085 [ 045 160 ]
Subtotal (95 CI) 16 17 95 085 [ 045 160 ]
Total events 8 (Bile acids) 10 (Control)
Heterogeneity not applicable
Test for overall effect Z = 050 (P = 061)
Total (95 CI) 174 165 1000 089 [ 074 106 ]
Total events 93 (Bile acids) 99 (Control)
Heterogeneity Chi2 = 392 df = 6 (P = 069) I2 =00
Test for overall effect Z = 130 (P = 019)
01 02 05 1 2 5 10
Favours bile acids Favours control
Analysis 18 Comparison 1 Bile acids for liver-transplanted patients Outcome 8 Subgroup analysis
number of patients with acute cellular rejection according to time of start of bile acid
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 8 Subgroup analysis number of patients with acute cellular rejection according to time of start of bile acid
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 Less than three days after transplantation
Keiding 1997 3554 3248 333 097 [ 073 129 ]
Koneru 1993 316 916 89 033 [ 011 101 ]
Subtotal (95 CI) 70 64 422 084 [ 063 111 ]
Total events 38 (Bile acids) 41 (Control)
Heterogeneity Chi2 = 374 df = 1 (P = 005) I2 =73
Test for overall effect Z = 124 (P = 022)
2 Three days or more after liver transplantation
Angelico 1999 816 1017 95 085 [ 045 160 ]
01 02 05 1 2 5 10
Favours bile acids Favours control
(Continued )
39Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Barnes 1997 1728 1724 180 086 [ 058 127 ]
Fleckenstein 1998 814 916 83 102 [ 054 190 ]
Pageaux 1995 926 924 92 092 [ 044 193 ]
Sama 1991 1320 1320 128 100 [ 063 158 ]
Subtotal (95 CI) 104 101 578 092 [ 072 117 ]
Total events 55 (Bile acids) 58 (Control)
Heterogeneity Chi2 = 041 df = 4 (P = 098) I2 =00
Test for overall effect Z = 067 (P = 050)
Total (95 CI) 174 165 1000 089 [ 074 106 ]
Total events 93 (Bile acids) 99 (Control)
Heterogeneity Chi2 = 392 df = 6 (P = 069) I2 =00
Test for overall effect Z = 130 (P = 019)
01 02 05 1 2 5 10
Favours bile acids Favours control
40Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 19 Comparison 1 Bile acids for liver-transplanted patients Outcome 9 Subgroup analysis
number of patients with acute cellular rejection according to treatment duration
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 9 Subgroup analysis number of patients with acute cellular rejection according to treatment duration
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 Less than six months
Barnes 1997 1728 1724 180 086 [ 058 127 ]
Fleckenstein 1998 814 916 83 102 [ 054 190 ]
Keiding 1997 3554 3248 333 097 [ 073 129 ]
Koneru 1993 316 916 89 033 [ 011 101 ]
Pageaux 1995 926 924 92 092 [ 044 193 ]
Subtotal (95 CI) 138 128 777 087 [ 071 107 ]
Total events 72 (Bile acids) 76 (Control)
Heterogeneity Chi2 = 374 df = 4 (P = 044) I2 =00
Test for overall effect Z = 129 (P = 020)
2 Six months or more
Angelico 1999 816 1017 95 085 [ 045 160 ]
Sama 1991 1320 1320 128 100 [ 063 158 ]
Subtotal (95 CI) 36 37 223 094 [ 065 136 ]
Total events 21 (Bile acids) 23 (Control)
Heterogeneity Chi2 = 017 df = 1 (P = 068) I2 =00
Test for overall effect Z = 035 (P = 073)
Total (95 CI) 174 165 1000 089 [ 074 106 ]
Total events 93 (Bile acids) 99 (Control)
Heterogeneity Chi2 = 392 df = 6 (P = 069) I2 =00
Test for overall effect Z = 130 (P = 019)
01 02 05 1 2 5 10
Favours bile acids Favours control
41Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 110 Comparison 1 Bile acids for liver-transplanted patients Outcome 10 Number of patients
with chronic rejection at maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 10 Number of patients with chronic rejection at maximum follow-up
Study or subgroup Bile acids Placebo Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Barnes 1997 128 624 611 014 [ 002 110 ]
Fleckenstein 1998 114 116 88 114 [ 008 1663 ]
Keiding 1997 154 348 300 030 [ 003 275 ]
Total (95 CI) 96 88 1000 028 [ 008 095 ]
Total events 3 (Bile acids) 10 (Placebo)
Heterogeneity Chi2 = 148 df = 2 (P = 048) I2 =00
Test for overall effect Z = 204 (P = 0041)
0001 001 01 1 10 100 1000
Favours bile acids Favours placebo
Analysis 111 Comparison 1 Bile acids for liver-transplanted patients Outcome 11 Number of patients
with steroid-resistant rejection at maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 11 Number of patients with steroid-resistant rejection at maximum follow-up
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Barnes 1997 328 724 277 037 [ 011 127 ]
Fleckenstein 1998 314 316 103 114 [ 027 478 ]
Keiding 1997 1454 1548 583 083 [ 045 154 ]
Pageaux 1995 226 124 38 185 [ 018 1908 ]
Total (95 CI) 122 112 1000 077 [ 047 127 ]
Total events 22 (Bile acids) 26 (Control)
Heterogeneity Chi2 = 226 df = 3 (P = 052) I2 =00
Test for overall effect Z = 102 (P = 031)
001 01 1 10 100
Favours bile acids Favours placebo
42Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 112 Comparison 1 Bile acids for liver-transplanted patients Outcome 12 Serum bilirubin (mgdl)
at the end of treatment
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 12 Serum bilirubin (mgdl) at the end of treatment
Study or subgroup Bile acids Placebo Mean Difference Weight Mean Difference
N Mean(SD) N Mean(SD) IVFixed95 CI IVFixed95 CI
Fleckenstein 1998 14 319 (68) 16 059 (022) 1000 260 [ -096 616 ]
Total (95 CI) 14 16 1000 260 [ -096 616 ]
Heterogeneity not applicable
Test for overall effect Z = 143 (P = 015)
-10 -5 0 5 10
Favours bile acids Favours placebo
Analysis 113 Comparison 1 Bile acids for liver-transplanted patients Outcome 13 Number of days of
hospitalisation after liver transplantation
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 13 Number of days of hospitalisation after liver transplantation
Study or subgroup Bile acids Placebo Mean Difference Weight Mean Difference
N Mean(SD) N Mean(SD) IVFixed95 CI IVFixed95 CI
Barnes 1997 28 25 (17) 24 335 (13) 1000 -850 [ -1667 -033 ]
Total (95 CI) 28 24 1000 -850 [ -1667 -033 ]
Heterogeneity not applicable
Test for overall effect Z = 204 (P = 0041)
-100 -50 0 50 100
Favours bile acids Favours placebo
43Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 114 Comparison 1 Bile acids for liver-transplanted patients Outcome 14 Adverse events
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 14 Adverse events
Study or subgroup Bile acids Placebo Risk Ratio Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Angelico 1999 016 017 00 [ 00 00 ]
Barnes 1997 128 124 086 [ 006 1298 ]
Keiding 1997 554 548 089 [ 027 288 ]
Total (95 CI) 98 89 088 [ 030 260 ]
Total events 6 (Bile acids) 6 (Placebo)
Heterogeneity Chi2 = 000 df = 1 (P = 098) I2 =00
Test for overall effect Z = 022 (P = 082)
001 01 1 10 100
Favours bile acids Favours placebo
A P P E N D I C E S
Appendix 1 Search strategies
Data Base Date of Search Search Strategy
The Cochrane Hepato-Biliary Group Con-
trolled Trials Register
September 2009 1 rsquoliver transplantationrsquo and rsquochenodeoxy-
cholicrsquo
2 rsquoliver transplantationrsquo and rsquocholicrsquo
3 rsquoliver transplantationrsquo and rsquodeoxycholicrsquo
4 rsquoliver transplantationrsquo and rsquoglycochen-
odeoxycholicrsquo
5 rsquoliver transplantationrsquo and rsquoglycocholicrsquo
6 rsquoliver transplantationrsquo and rsquoglycodeoxy-
cholicrsquo
7 rsquoliver transplantationrsquo and rsquoglycolitho-
cholicrsquo
8 rsquoliver transplantationrsquo and rsquohyodeoxy-
cholicrsquo
9 rsquoliver transplantationrsquo and rsquolithocholicrsquo
10 rsquoliver transplantationrsquo and rsquotaurochen-
odeoxycholicrsquo
44Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
11 rsquoliver transplantationrsquo and rsquotauro-
cholicrsquo
12 rsquoliver transplantationrsquo and rsquotaurodehy-
drocholicrsquo
13 rsquoliver transplantationrsquo and rsquotau-
rodeoxycholicrsquo
14 rsquoliver transplantationrsquo and rsquotauroglyco-
cholicrsquo
15 rsquoliver transplantationrsquo and rsquotaurolitho-
cholicrsquo
16 rsquoliver transplantationrsquo and rsquotaurosel-
cholicrsquo
17 rsquoliver transplantationrsquo and rsquotaurourso-
cholicrsquo
18 rsquoliver transplantationrsquo and rsquotaurour-
sodeoxycholicrsquo
19 rsquoliver transplantationrsquo and rsquoursocholicrsquo
20 rsquoliver transplantationrsquo and rsquoursodeoxy-
cholicrsquo
The Cochrane Central Register of Con-
trolled Trials in The Cochrane Library
Issue 3 2009 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
6 3 or 4
7 5 and 6
MEDLINE September 2009 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
45Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
6 3 or 4
7 5 and 6
8 RANDOMIZED-CONTROLLED-
TRIAL ME
9 RANDOM
10 8 or 9
11 7 and 10
EMBASE September 2009 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
6 3 or 4
7 5 and 6
8 RANDOMIZED-CONTROLLED-
TRIAL ME
9 RANDOM
10 8 or 9
11 7 and 10
46Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
Science Citation Index Expanded September 2009 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
6 3 or 4
7 5 and 6
8 RANDOMIZED-CONTROLLED-
TRIAL ME
9 RANDOM
10 8 or 9
11 7 and 10
The Chinese Biomedical Database Searched from January 1980 to April 2002 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
47Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
6 3 or 4
7 5 and 6
8 RANDOMIZED-CONTROLLED-
TRIAL ME
9 RANDOM
10 8 or 9
11 7 and 10
W H A T rsquo S N E W
Last assessed as up-to-date 8 February 2010
18 September 2009 New citation required but conclusions have not
changed
This review is an updated version of a review that was
published for the first time in Issue 3 2005 of TheCochrane Library by Chen 2003b
18 September 2009 New search has been performed No new studies fulfilled the inclusion criteria
H I S T O R Y
Protocol first published Issue 3 2003
Review first published Issue 3 2005
C O N T R I B U T I O N S O F A U T H O R S
GP and VG independently performed searches of relevant databases GP validated the search selected trials for inclusion contacted
the authors of the trials performed data extraction and data analysis and drafted the systematic review VG revised the review update
CG and DS revised the review update solved discrepancies of data extraction validated data analyses and provided consultation
D E C L A R A T I O N S O F I N T E R E S T
None known
48Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
S O U R C E S O F S U P P O R T
Internal sources
bull Copenhagen Trial Unit Denmark
External sources
bull Danish Medical Research Councilrsquos Grant on Getting Research into Practice (GRIP) Denmark
D I F F E R E N C E S B E T W E E N P R O T O C O L A N D R E V I E W
We assessed the risk of bias in the included studies for another four domains that were added to the review protocol (incomplete
outcome data selective outcome reporting baseline imbalance and early stopping of trial) In general the text of the risk of bias
domains were updated following Higgins 2008 Trials were considered at low risk of bias when judged as adequate in all domains
Quasi-randomised studies observational and case-control studies were included for the report of adverse events
We performed trial sequential analysis for outcomes demonstrating a statistically significant result
I N D E X T E R M S
Medical Subject Headings (MeSH)
lowastLiver Transplantation Cholagogues and Choleretics [lowasttherapeutic use] Graft Rejection [lowastprevention amp control] Randomized Con-
trolled Trials as Topic Taurochenodeoxycholic Acid [lowasttherapeutic use] Ursodeoxycholic Acid [lowasttherapeutic use]
MeSH check words
Humans
49Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Subtotal (95 CI) 78 77 645 063 [ 033 120 ]
Total events 12 (Bile acids) 19 (Control)
Heterogeneity Chi2 = 310 df = 3 (P = 038) I2 =3
Test for overall effect Z = 141 (P = 016)
Total (95 CI) 132 125 1000 085 [ 053 136 ]
Total events 26 (Bile acids) 29 (Control)
Heterogeneity Chi2 = 466 df = 4 (P = 032) I2 =14
Test for overall effect Z = 069 (P = 049)
005 02 1 5 20
Favours bile acids Favours control
Analysis 14 Comparison 1 Bile acids for liver-transplanted patients Outcome 4 Subgroup analyses all
cause mortality at maximum follow-up according to treatment duration
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 4 Subgroup analyses all cause mortality at maximum follow-up according to treatment duration
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 Less than six months
Barnes 1997 228 724 253 024 [ 006 107 ]
Fleckenstein 1998 214 416 125 057 [ 012 266 ]
Keiding 1997 1454 1048 355 124 [ 061 254 ]
Subtotal (95 CI) 96 88 734 078 [ 045 138 ]
Total events 18 (Bile acids) 21 (Control)
Heterogeneity Chi2 = 417 df = 2 (P = 012) I2 =52
Test for overall effect Z = 084 (P = 040)
2 Six months or more
Angelico 1999 316 217 65 159 [ 030 833 ]
Sama 1991 520 620 201 083 [ 030 229 ]
Subtotal (95 CI) 36 37 266 102 [ 043 240 ]
Total events 8 (Bile acids) 8 (Control)
Heterogeneity Chi2 = 043 df = 1 (P = 051) I2 =00
005 02 1 5 20
Favours bile acids Favours control
(Continued )
36Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Test for overall effect Z = 004 (P = 097)
Total (95 CI) 132 125 1000 085 [ 053 136 ]
Total events 26 (Bile acids) 29 (Control)
Heterogeneity Chi2 = 466 df = 4 (P = 032) I2 =14
Test for overall effect Z = 069 (P = 049)
005 02 1 5 20
Favours bile acids Favours control
Analysis 15 Comparison 1 Bile acids for liver-transplanted patients Outcome 5 Number of deaths related
to rejection at maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 5 Number of deaths related to rejection at maximum follow-up
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 UDCA versus placebo
Keiding 1997 054 148 1000 030 [ 001 712 ]
Total (95 CI) 54 48 1000 030 [ 001 712 ]
Total events 0 (Bile acids) 1 (Control)
Heterogeneity not applicable
Test for overall effect Z = 075 (P = 045)
0001 001 01 1 10 100 1000
Favours bile acids Favours control
37Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 16 Comparison 1 Bile acids for liver-transplanted patients Outcome 6 Number of
retransplantations at maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 6 Number of retransplantations at maximum follow-up
Study or subgroup Bile acids Placebo Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Fleckenstein 1998 214 016 100 567 [ 029 10891 ]
Keiding 1997 154 448 900 022 [ 003 192 ]
Total (95 CI) 68 64 1000 076 [ 020 286 ]
Total events 3 (Bile acids) 4 (Placebo)
Heterogeneity Chi2 = 303 df = 1 (P = 008) I2 =67
Test for overall effect Z = 040 (P = 069)
0001 001 01 1 10 100 1000
Favours bile acids Favours placebo
Analysis 17 Comparison 1 Bile acids for liver-transplanted patients Outcome 7 Number of patients with
acute cellular rejection at maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 7 Number of patients with acute cellular rejection at maximum follow-up
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 UDCA versus placebo or no treatment
Barnes 1997 1728 1724 180 086 [ 058 127 ]
Fleckenstein 1998 814 916 83 102 [ 054 190 ]
Keiding 1997 3554 3248 333 097 [ 073 129 ]
Koneru 1993 316 916 89 033 [ 011 101 ]
Pageaux 1995 926 924 92 092 [ 044 193 ]
Sama 1991 1320 1320 128 100 [ 063 158 ]
Subtotal (95 CI) 158 148 905 089 [ 074 108 ]
01 02 05 1 2 5 10
Favours bile acids Favours control
(Continued )
38Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Total events 85 (Bile acids) 89 (Control)
Heterogeneity Chi2 = 387 df = 5 (P = 057) I2 =00
Test for overall effect Z = 120 (P = 023)
2 TUDCA versus no treatment
Angelico 1999 816 1017 95 085 [ 045 160 ]
Subtotal (95 CI) 16 17 95 085 [ 045 160 ]
Total events 8 (Bile acids) 10 (Control)
Heterogeneity not applicable
Test for overall effect Z = 050 (P = 061)
Total (95 CI) 174 165 1000 089 [ 074 106 ]
Total events 93 (Bile acids) 99 (Control)
Heterogeneity Chi2 = 392 df = 6 (P = 069) I2 =00
Test for overall effect Z = 130 (P = 019)
01 02 05 1 2 5 10
Favours bile acids Favours control
Analysis 18 Comparison 1 Bile acids for liver-transplanted patients Outcome 8 Subgroup analysis
number of patients with acute cellular rejection according to time of start of bile acid
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 8 Subgroup analysis number of patients with acute cellular rejection according to time of start of bile acid
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 Less than three days after transplantation
Keiding 1997 3554 3248 333 097 [ 073 129 ]
Koneru 1993 316 916 89 033 [ 011 101 ]
Subtotal (95 CI) 70 64 422 084 [ 063 111 ]
Total events 38 (Bile acids) 41 (Control)
Heterogeneity Chi2 = 374 df = 1 (P = 005) I2 =73
Test for overall effect Z = 124 (P = 022)
2 Three days or more after liver transplantation
Angelico 1999 816 1017 95 085 [ 045 160 ]
01 02 05 1 2 5 10
Favours bile acids Favours control
(Continued )
39Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Barnes 1997 1728 1724 180 086 [ 058 127 ]
Fleckenstein 1998 814 916 83 102 [ 054 190 ]
Pageaux 1995 926 924 92 092 [ 044 193 ]
Sama 1991 1320 1320 128 100 [ 063 158 ]
Subtotal (95 CI) 104 101 578 092 [ 072 117 ]
Total events 55 (Bile acids) 58 (Control)
Heterogeneity Chi2 = 041 df = 4 (P = 098) I2 =00
Test for overall effect Z = 067 (P = 050)
Total (95 CI) 174 165 1000 089 [ 074 106 ]
Total events 93 (Bile acids) 99 (Control)
Heterogeneity Chi2 = 392 df = 6 (P = 069) I2 =00
Test for overall effect Z = 130 (P = 019)
01 02 05 1 2 5 10
Favours bile acids Favours control
40Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 19 Comparison 1 Bile acids for liver-transplanted patients Outcome 9 Subgroup analysis
number of patients with acute cellular rejection according to treatment duration
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 9 Subgroup analysis number of patients with acute cellular rejection according to treatment duration
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 Less than six months
Barnes 1997 1728 1724 180 086 [ 058 127 ]
Fleckenstein 1998 814 916 83 102 [ 054 190 ]
Keiding 1997 3554 3248 333 097 [ 073 129 ]
Koneru 1993 316 916 89 033 [ 011 101 ]
Pageaux 1995 926 924 92 092 [ 044 193 ]
Subtotal (95 CI) 138 128 777 087 [ 071 107 ]
Total events 72 (Bile acids) 76 (Control)
Heterogeneity Chi2 = 374 df = 4 (P = 044) I2 =00
Test for overall effect Z = 129 (P = 020)
2 Six months or more
Angelico 1999 816 1017 95 085 [ 045 160 ]
Sama 1991 1320 1320 128 100 [ 063 158 ]
Subtotal (95 CI) 36 37 223 094 [ 065 136 ]
Total events 21 (Bile acids) 23 (Control)
Heterogeneity Chi2 = 017 df = 1 (P = 068) I2 =00
Test for overall effect Z = 035 (P = 073)
Total (95 CI) 174 165 1000 089 [ 074 106 ]
Total events 93 (Bile acids) 99 (Control)
Heterogeneity Chi2 = 392 df = 6 (P = 069) I2 =00
Test for overall effect Z = 130 (P = 019)
01 02 05 1 2 5 10
Favours bile acids Favours control
41Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 110 Comparison 1 Bile acids for liver-transplanted patients Outcome 10 Number of patients
with chronic rejection at maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 10 Number of patients with chronic rejection at maximum follow-up
Study or subgroup Bile acids Placebo Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Barnes 1997 128 624 611 014 [ 002 110 ]
Fleckenstein 1998 114 116 88 114 [ 008 1663 ]
Keiding 1997 154 348 300 030 [ 003 275 ]
Total (95 CI) 96 88 1000 028 [ 008 095 ]
Total events 3 (Bile acids) 10 (Placebo)
Heterogeneity Chi2 = 148 df = 2 (P = 048) I2 =00
Test for overall effect Z = 204 (P = 0041)
0001 001 01 1 10 100 1000
Favours bile acids Favours placebo
Analysis 111 Comparison 1 Bile acids for liver-transplanted patients Outcome 11 Number of patients
with steroid-resistant rejection at maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 11 Number of patients with steroid-resistant rejection at maximum follow-up
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Barnes 1997 328 724 277 037 [ 011 127 ]
Fleckenstein 1998 314 316 103 114 [ 027 478 ]
Keiding 1997 1454 1548 583 083 [ 045 154 ]
Pageaux 1995 226 124 38 185 [ 018 1908 ]
Total (95 CI) 122 112 1000 077 [ 047 127 ]
Total events 22 (Bile acids) 26 (Control)
Heterogeneity Chi2 = 226 df = 3 (P = 052) I2 =00
Test for overall effect Z = 102 (P = 031)
001 01 1 10 100
Favours bile acids Favours placebo
42Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 112 Comparison 1 Bile acids for liver-transplanted patients Outcome 12 Serum bilirubin (mgdl)
at the end of treatment
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 12 Serum bilirubin (mgdl) at the end of treatment
Study or subgroup Bile acids Placebo Mean Difference Weight Mean Difference
N Mean(SD) N Mean(SD) IVFixed95 CI IVFixed95 CI
Fleckenstein 1998 14 319 (68) 16 059 (022) 1000 260 [ -096 616 ]
Total (95 CI) 14 16 1000 260 [ -096 616 ]
Heterogeneity not applicable
Test for overall effect Z = 143 (P = 015)
-10 -5 0 5 10
Favours bile acids Favours placebo
Analysis 113 Comparison 1 Bile acids for liver-transplanted patients Outcome 13 Number of days of
hospitalisation after liver transplantation
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 13 Number of days of hospitalisation after liver transplantation
Study or subgroup Bile acids Placebo Mean Difference Weight Mean Difference
N Mean(SD) N Mean(SD) IVFixed95 CI IVFixed95 CI
Barnes 1997 28 25 (17) 24 335 (13) 1000 -850 [ -1667 -033 ]
Total (95 CI) 28 24 1000 -850 [ -1667 -033 ]
Heterogeneity not applicable
Test for overall effect Z = 204 (P = 0041)
-100 -50 0 50 100
Favours bile acids Favours placebo
43Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 114 Comparison 1 Bile acids for liver-transplanted patients Outcome 14 Adverse events
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 14 Adverse events
Study or subgroup Bile acids Placebo Risk Ratio Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Angelico 1999 016 017 00 [ 00 00 ]
Barnes 1997 128 124 086 [ 006 1298 ]
Keiding 1997 554 548 089 [ 027 288 ]
Total (95 CI) 98 89 088 [ 030 260 ]
Total events 6 (Bile acids) 6 (Placebo)
Heterogeneity Chi2 = 000 df = 1 (P = 098) I2 =00
Test for overall effect Z = 022 (P = 082)
001 01 1 10 100
Favours bile acids Favours placebo
A P P E N D I C E S
Appendix 1 Search strategies
Data Base Date of Search Search Strategy
The Cochrane Hepato-Biliary Group Con-
trolled Trials Register
September 2009 1 rsquoliver transplantationrsquo and rsquochenodeoxy-
cholicrsquo
2 rsquoliver transplantationrsquo and rsquocholicrsquo
3 rsquoliver transplantationrsquo and rsquodeoxycholicrsquo
4 rsquoliver transplantationrsquo and rsquoglycochen-
odeoxycholicrsquo
5 rsquoliver transplantationrsquo and rsquoglycocholicrsquo
6 rsquoliver transplantationrsquo and rsquoglycodeoxy-
cholicrsquo
7 rsquoliver transplantationrsquo and rsquoglycolitho-
cholicrsquo
8 rsquoliver transplantationrsquo and rsquohyodeoxy-
cholicrsquo
9 rsquoliver transplantationrsquo and rsquolithocholicrsquo
10 rsquoliver transplantationrsquo and rsquotaurochen-
odeoxycholicrsquo
44Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
11 rsquoliver transplantationrsquo and rsquotauro-
cholicrsquo
12 rsquoliver transplantationrsquo and rsquotaurodehy-
drocholicrsquo
13 rsquoliver transplantationrsquo and rsquotau-
rodeoxycholicrsquo
14 rsquoliver transplantationrsquo and rsquotauroglyco-
cholicrsquo
15 rsquoliver transplantationrsquo and rsquotaurolitho-
cholicrsquo
16 rsquoliver transplantationrsquo and rsquotaurosel-
cholicrsquo
17 rsquoliver transplantationrsquo and rsquotaurourso-
cholicrsquo
18 rsquoliver transplantationrsquo and rsquotaurour-
sodeoxycholicrsquo
19 rsquoliver transplantationrsquo and rsquoursocholicrsquo
20 rsquoliver transplantationrsquo and rsquoursodeoxy-
cholicrsquo
The Cochrane Central Register of Con-
trolled Trials in The Cochrane Library
Issue 3 2009 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
6 3 or 4
7 5 and 6
MEDLINE September 2009 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
45Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
6 3 or 4
7 5 and 6
8 RANDOMIZED-CONTROLLED-
TRIAL ME
9 RANDOM
10 8 or 9
11 7 and 10
EMBASE September 2009 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
6 3 or 4
7 5 and 6
8 RANDOMIZED-CONTROLLED-
TRIAL ME
9 RANDOM
10 8 or 9
11 7 and 10
46Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
Science Citation Index Expanded September 2009 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
6 3 or 4
7 5 and 6
8 RANDOMIZED-CONTROLLED-
TRIAL ME
9 RANDOM
10 8 or 9
11 7 and 10
The Chinese Biomedical Database Searched from January 1980 to April 2002 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
47Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
6 3 or 4
7 5 and 6
8 RANDOMIZED-CONTROLLED-
TRIAL ME
9 RANDOM
10 8 or 9
11 7 and 10
W H A T rsquo S N E W
Last assessed as up-to-date 8 February 2010
18 September 2009 New citation required but conclusions have not
changed
This review is an updated version of a review that was
published for the first time in Issue 3 2005 of TheCochrane Library by Chen 2003b
18 September 2009 New search has been performed No new studies fulfilled the inclusion criteria
H I S T O R Y
Protocol first published Issue 3 2003
Review first published Issue 3 2005
C O N T R I B U T I O N S O F A U T H O R S
GP and VG independently performed searches of relevant databases GP validated the search selected trials for inclusion contacted
the authors of the trials performed data extraction and data analysis and drafted the systematic review VG revised the review update
CG and DS revised the review update solved discrepancies of data extraction validated data analyses and provided consultation
D E C L A R A T I O N S O F I N T E R E S T
None known
48Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
S O U R C E S O F S U P P O R T
Internal sources
bull Copenhagen Trial Unit Denmark
External sources
bull Danish Medical Research Councilrsquos Grant on Getting Research into Practice (GRIP) Denmark
D I F F E R E N C E S B E T W E E N P R O T O C O L A N D R E V I E W
We assessed the risk of bias in the included studies for another four domains that were added to the review protocol (incomplete
outcome data selective outcome reporting baseline imbalance and early stopping of trial) In general the text of the risk of bias
domains were updated following Higgins 2008 Trials were considered at low risk of bias when judged as adequate in all domains
Quasi-randomised studies observational and case-control studies were included for the report of adverse events
We performed trial sequential analysis for outcomes demonstrating a statistically significant result
I N D E X T E R M S
Medical Subject Headings (MeSH)
lowastLiver Transplantation Cholagogues and Choleretics [lowasttherapeutic use] Graft Rejection [lowastprevention amp control] Randomized Con-
trolled Trials as Topic Taurochenodeoxycholic Acid [lowasttherapeutic use] Ursodeoxycholic Acid [lowasttherapeutic use]
MeSH check words
Humans
49Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Test for overall effect Z = 004 (P = 097)
Total (95 CI) 132 125 1000 085 [ 053 136 ]
Total events 26 (Bile acids) 29 (Control)
Heterogeneity Chi2 = 466 df = 4 (P = 032) I2 =14
Test for overall effect Z = 069 (P = 049)
005 02 1 5 20
Favours bile acids Favours control
Analysis 15 Comparison 1 Bile acids for liver-transplanted patients Outcome 5 Number of deaths related
to rejection at maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 5 Number of deaths related to rejection at maximum follow-up
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 UDCA versus placebo
Keiding 1997 054 148 1000 030 [ 001 712 ]
Total (95 CI) 54 48 1000 030 [ 001 712 ]
Total events 0 (Bile acids) 1 (Control)
Heterogeneity not applicable
Test for overall effect Z = 075 (P = 045)
0001 001 01 1 10 100 1000
Favours bile acids Favours control
37Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 16 Comparison 1 Bile acids for liver-transplanted patients Outcome 6 Number of
retransplantations at maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 6 Number of retransplantations at maximum follow-up
Study or subgroup Bile acids Placebo Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Fleckenstein 1998 214 016 100 567 [ 029 10891 ]
Keiding 1997 154 448 900 022 [ 003 192 ]
Total (95 CI) 68 64 1000 076 [ 020 286 ]
Total events 3 (Bile acids) 4 (Placebo)
Heterogeneity Chi2 = 303 df = 1 (P = 008) I2 =67
Test for overall effect Z = 040 (P = 069)
0001 001 01 1 10 100 1000
Favours bile acids Favours placebo
Analysis 17 Comparison 1 Bile acids for liver-transplanted patients Outcome 7 Number of patients with
acute cellular rejection at maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 7 Number of patients with acute cellular rejection at maximum follow-up
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 UDCA versus placebo or no treatment
Barnes 1997 1728 1724 180 086 [ 058 127 ]
Fleckenstein 1998 814 916 83 102 [ 054 190 ]
Keiding 1997 3554 3248 333 097 [ 073 129 ]
Koneru 1993 316 916 89 033 [ 011 101 ]
Pageaux 1995 926 924 92 092 [ 044 193 ]
Sama 1991 1320 1320 128 100 [ 063 158 ]
Subtotal (95 CI) 158 148 905 089 [ 074 108 ]
01 02 05 1 2 5 10
Favours bile acids Favours control
(Continued )
38Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Total events 85 (Bile acids) 89 (Control)
Heterogeneity Chi2 = 387 df = 5 (P = 057) I2 =00
Test for overall effect Z = 120 (P = 023)
2 TUDCA versus no treatment
Angelico 1999 816 1017 95 085 [ 045 160 ]
Subtotal (95 CI) 16 17 95 085 [ 045 160 ]
Total events 8 (Bile acids) 10 (Control)
Heterogeneity not applicable
Test for overall effect Z = 050 (P = 061)
Total (95 CI) 174 165 1000 089 [ 074 106 ]
Total events 93 (Bile acids) 99 (Control)
Heterogeneity Chi2 = 392 df = 6 (P = 069) I2 =00
Test for overall effect Z = 130 (P = 019)
01 02 05 1 2 5 10
Favours bile acids Favours control
Analysis 18 Comparison 1 Bile acids for liver-transplanted patients Outcome 8 Subgroup analysis
number of patients with acute cellular rejection according to time of start of bile acid
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 8 Subgroup analysis number of patients with acute cellular rejection according to time of start of bile acid
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 Less than three days after transplantation
Keiding 1997 3554 3248 333 097 [ 073 129 ]
Koneru 1993 316 916 89 033 [ 011 101 ]
Subtotal (95 CI) 70 64 422 084 [ 063 111 ]
Total events 38 (Bile acids) 41 (Control)
Heterogeneity Chi2 = 374 df = 1 (P = 005) I2 =73
Test for overall effect Z = 124 (P = 022)
2 Three days or more after liver transplantation
Angelico 1999 816 1017 95 085 [ 045 160 ]
01 02 05 1 2 5 10
Favours bile acids Favours control
(Continued )
39Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Barnes 1997 1728 1724 180 086 [ 058 127 ]
Fleckenstein 1998 814 916 83 102 [ 054 190 ]
Pageaux 1995 926 924 92 092 [ 044 193 ]
Sama 1991 1320 1320 128 100 [ 063 158 ]
Subtotal (95 CI) 104 101 578 092 [ 072 117 ]
Total events 55 (Bile acids) 58 (Control)
Heterogeneity Chi2 = 041 df = 4 (P = 098) I2 =00
Test for overall effect Z = 067 (P = 050)
Total (95 CI) 174 165 1000 089 [ 074 106 ]
Total events 93 (Bile acids) 99 (Control)
Heterogeneity Chi2 = 392 df = 6 (P = 069) I2 =00
Test for overall effect Z = 130 (P = 019)
01 02 05 1 2 5 10
Favours bile acids Favours control
40Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 19 Comparison 1 Bile acids for liver-transplanted patients Outcome 9 Subgroup analysis
number of patients with acute cellular rejection according to treatment duration
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 9 Subgroup analysis number of patients with acute cellular rejection according to treatment duration
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 Less than six months
Barnes 1997 1728 1724 180 086 [ 058 127 ]
Fleckenstein 1998 814 916 83 102 [ 054 190 ]
Keiding 1997 3554 3248 333 097 [ 073 129 ]
Koneru 1993 316 916 89 033 [ 011 101 ]
Pageaux 1995 926 924 92 092 [ 044 193 ]
Subtotal (95 CI) 138 128 777 087 [ 071 107 ]
Total events 72 (Bile acids) 76 (Control)
Heterogeneity Chi2 = 374 df = 4 (P = 044) I2 =00
Test for overall effect Z = 129 (P = 020)
2 Six months or more
Angelico 1999 816 1017 95 085 [ 045 160 ]
Sama 1991 1320 1320 128 100 [ 063 158 ]
Subtotal (95 CI) 36 37 223 094 [ 065 136 ]
Total events 21 (Bile acids) 23 (Control)
Heterogeneity Chi2 = 017 df = 1 (P = 068) I2 =00
Test for overall effect Z = 035 (P = 073)
Total (95 CI) 174 165 1000 089 [ 074 106 ]
Total events 93 (Bile acids) 99 (Control)
Heterogeneity Chi2 = 392 df = 6 (P = 069) I2 =00
Test for overall effect Z = 130 (P = 019)
01 02 05 1 2 5 10
Favours bile acids Favours control
41Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 110 Comparison 1 Bile acids for liver-transplanted patients Outcome 10 Number of patients
with chronic rejection at maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 10 Number of patients with chronic rejection at maximum follow-up
Study or subgroup Bile acids Placebo Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Barnes 1997 128 624 611 014 [ 002 110 ]
Fleckenstein 1998 114 116 88 114 [ 008 1663 ]
Keiding 1997 154 348 300 030 [ 003 275 ]
Total (95 CI) 96 88 1000 028 [ 008 095 ]
Total events 3 (Bile acids) 10 (Placebo)
Heterogeneity Chi2 = 148 df = 2 (P = 048) I2 =00
Test for overall effect Z = 204 (P = 0041)
0001 001 01 1 10 100 1000
Favours bile acids Favours placebo
Analysis 111 Comparison 1 Bile acids for liver-transplanted patients Outcome 11 Number of patients
with steroid-resistant rejection at maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 11 Number of patients with steroid-resistant rejection at maximum follow-up
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Barnes 1997 328 724 277 037 [ 011 127 ]
Fleckenstein 1998 314 316 103 114 [ 027 478 ]
Keiding 1997 1454 1548 583 083 [ 045 154 ]
Pageaux 1995 226 124 38 185 [ 018 1908 ]
Total (95 CI) 122 112 1000 077 [ 047 127 ]
Total events 22 (Bile acids) 26 (Control)
Heterogeneity Chi2 = 226 df = 3 (P = 052) I2 =00
Test for overall effect Z = 102 (P = 031)
001 01 1 10 100
Favours bile acids Favours placebo
42Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 112 Comparison 1 Bile acids for liver-transplanted patients Outcome 12 Serum bilirubin (mgdl)
at the end of treatment
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 12 Serum bilirubin (mgdl) at the end of treatment
Study or subgroup Bile acids Placebo Mean Difference Weight Mean Difference
N Mean(SD) N Mean(SD) IVFixed95 CI IVFixed95 CI
Fleckenstein 1998 14 319 (68) 16 059 (022) 1000 260 [ -096 616 ]
Total (95 CI) 14 16 1000 260 [ -096 616 ]
Heterogeneity not applicable
Test for overall effect Z = 143 (P = 015)
-10 -5 0 5 10
Favours bile acids Favours placebo
Analysis 113 Comparison 1 Bile acids for liver-transplanted patients Outcome 13 Number of days of
hospitalisation after liver transplantation
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 13 Number of days of hospitalisation after liver transplantation
Study or subgroup Bile acids Placebo Mean Difference Weight Mean Difference
N Mean(SD) N Mean(SD) IVFixed95 CI IVFixed95 CI
Barnes 1997 28 25 (17) 24 335 (13) 1000 -850 [ -1667 -033 ]
Total (95 CI) 28 24 1000 -850 [ -1667 -033 ]
Heterogeneity not applicable
Test for overall effect Z = 204 (P = 0041)
-100 -50 0 50 100
Favours bile acids Favours placebo
43Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 114 Comparison 1 Bile acids for liver-transplanted patients Outcome 14 Adverse events
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 14 Adverse events
Study or subgroup Bile acids Placebo Risk Ratio Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Angelico 1999 016 017 00 [ 00 00 ]
Barnes 1997 128 124 086 [ 006 1298 ]
Keiding 1997 554 548 089 [ 027 288 ]
Total (95 CI) 98 89 088 [ 030 260 ]
Total events 6 (Bile acids) 6 (Placebo)
Heterogeneity Chi2 = 000 df = 1 (P = 098) I2 =00
Test for overall effect Z = 022 (P = 082)
001 01 1 10 100
Favours bile acids Favours placebo
A P P E N D I C E S
Appendix 1 Search strategies
Data Base Date of Search Search Strategy
The Cochrane Hepato-Biliary Group Con-
trolled Trials Register
September 2009 1 rsquoliver transplantationrsquo and rsquochenodeoxy-
cholicrsquo
2 rsquoliver transplantationrsquo and rsquocholicrsquo
3 rsquoliver transplantationrsquo and rsquodeoxycholicrsquo
4 rsquoliver transplantationrsquo and rsquoglycochen-
odeoxycholicrsquo
5 rsquoliver transplantationrsquo and rsquoglycocholicrsquo
6 rsquoliver transplantationrsquo and rsquoglycodeoxy-
cholicrsquo
7 rsquoliver transplantationrsquo and rsquoglycolitho-
cholicrsquo
8 rsquoliver transplantationrsquo and rsquohyodeoxy-
cholicrsquo
9 rsquoliver transplantationrsquo and rsquolithocholicrsquo
10 rsquoliver transplantationrsquo and rsquotaurochen-
odeoxycholicrsquo
44Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
11 rsquoliver transplantationrsquo and rsquotauro-
cholicrsquo
12 rsquoliver transplantationrsquo and rsquotaurodehy-
drocholicrsquo
13 rsquoliver transplantationrsquo and rsquotau-
rodeoxycholicrsquo
14 rsquoliver transplantationrsquo and rsquotauroglyco-
cholicrsquo
15 rsquoliver transplantationrsquo and rsquotaurolitho-
cholicrsquo
16 rsquoliver transplantationrsquo and rsquotaurosel-
cholicrsquo
17 rsquoliver transplantationrsquo and rsquotaurourso-
cholicrsquo
18 rsquoliver transplantationrsquo and rsquotaurour-
sodeoxycholicrsquo
19 rsquoliver transplantationrsquo and rsquoursocholicrsquo
20 rsquoliver transplantationrsquo and rsquoursodeoxy-
cholicrsquo
The Cochrane Central Register of Con-
trolled Trials in The Cochrane Library
Issue 3 2009 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
6 3 or 4
7 5 and 6
MEDLINE September 2009 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
45Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
6 3 or 4
7 5 and 6
8 RANDOMIZED-CONTROLLED-
TRIAL ME
9 RANDOM
10 8 or 9
11 7 and 10
EMBASE September 2009 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
6 3 or 4
7 5 and 6
8 RANDOMIZED-CONTROLLED-
TRIAL ME
9 RANDOM
10 8 or 9
11 7 and 10
46Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
Science Citation Index Expanded September 2009 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
6 3 or 4
7 5 and 6
8 RANDOMIZED-CONTROLLED-
TRIAL ME
9 RANDOM
10 8 or 9
11 7 and 10
The Chinese Biomedical Database Searched from January 1980 to April 2002 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
47Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
6 3 or 4
7 5 and 6
8 RANDOMIZED-CONTROLLED-
TRIAL ME
9 RANDOM
10 8 or 9
11 7 and 10
W H A T rsquo S N E W
Last assessed as up-to-date 8 February 2010
18 September 2009 New citation required but conclusions have not
changed
This review is an updated version of a review that was
published for the first time in Issue 3 2005 of TheCochrane Library by Chen 2003b
18 September 2009 New search has been performed No new studies fulfilled the inclusion criteria
H I S T O R Y
Protocol first published Issue 3 2003
Review first published Issue 3 2005
C O N T R I B U T I O N S O F A U T H O R S
GP and VG independently performed searches of relevant databases GP validated the search selected trials for inclusion contacted
the authors of the trials performed data extraction and data analysis and drafted the systematic review VG revised the review update
CG and DS revised the review update solved discrepancies of data extraction validated data analyses and provided consultation
D E C L A R A T I O N S O F I N T E R E S T
None known
48Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
S O U R C E S O F S U P P O R T
Internal sources
bull Copenhagen Trial Unit Denmark
External sources
bull Danish Medical Research Councilrsquos Grant on Getting Research into Practice (GRIP) Denmark
D I F F E R E N C E S B E T W E E N P R O T O C O L A N D R E V I E W
We assessed the risk of bias in the included studies for another four domains that were added to the review protocol (incomplete
outcome data selective outcome reporting baseline imbalance and early stopping of trial) In general the text of the risk of bias
domains were updated following Higgins 2008 Trials were considered at low risk of bias when judged as adequate in all domains
Quasi-randomised studies observational and case-control studies were included for the report of adverse events
We performed trial sequential analysis for outcomes demonstrating a statistically significant result
I N D E X T E R M S
Medical Subject Headings (MeSH)
lowastLiver Transplantation Cholagogues and Choleretics [lowasttherapeutic use] Graft Rejection [lowastprevention amp control] Randomized Con-
trolled Trials as Topic Taurochenodeoxycholic Acid [lowasttherapeutic use] Ursodeoxycholic Acid [lowasttherapeutic use]
MeSH check words
Humans
49Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 16 Comparison 1 Bile acids for liver-transplanted patients Outcome 6 Number of
retransplantations at maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 6 Number of retransplantations at maximum follow-up
Study or subgroup Bile acids Placebo Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Fleckenstein 1998 214 016 100 567 [ 029 10891 ]
Keiding 1997 154 448 900 022 [ 003 192 ]
Total (95 CI) 68 64 1000 076 [ 020 286 ]
Total events 3 (Bile acids) 4 (Placebo)
Heterogeneity Chi2 = 303 df = 1 (P = 008) I2 =67
Test for overall effect Z = 040 (P = 069)
0001 001 01 1 10 100 1000
Favours bile acids Favours placebo
Analysis 17 Comparison 1 Bile acids for liver-transplanted patients Outcome 7 Number of patients with
acute cellular rejection at maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 7 Number of patients with acute cellular rejection at maximum follow-up
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 UDCA versus placebo or no treatment
Barnes 1997 1728 1724 180 086 [ 058 127 ]
Fleckenstein 1998 814 916 83 102 [ 054 190 ]
Keiding 1997 3554 3248 333 097 [ 073 129 ]
Koneru 1993 316 916 89 033 [ 011 101 ]
Pageaux 1995 926 924 92 092 [ 044 193 ]
Sama 1991 1320 1320 128 100 [ 063 158 ]
Subtotal (95 CI) 158 148 905 089 [ 074 108 ]
01 02 05 1 2 5 10
Favours bile acids Favours control
(Continued )
38Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Total events 85 (Bile acids) 89 (Control)
Heterogeneity Chi2 = 387 df = 5 (P = 057) I2 =00
Test for overall effect Z = 120 (P = 023)
2 TUDCA versus no treatment
Angelico 1999 816 1017 95 085 [ 045 160 ]
Subtotal (95 CI) 16 17 95 085 [ 045 160 ]
Total events 8 (Bile acids) 10 (Control)
Heterogeneity not applicable
Test for overall effect Z = 050 (P = 061)
Total (95 CI) 174 165 1000 089 [ 074 106 ]
Total events 93 (Bile acids) 99 (Control)
Heterogeneity Chi2 = 392 df = 6 (P = 069) I2 =00
Test for overall effect Z = 130 (P = 019)
01 02 05 1 2 5 10
Favours bile acids Favours control
Analysis 18 Comparison 1 Bile acids for liver-transplanted patients Outcome 8 Subgroup analysis
number of patients with acute cellular rejection according to time of start of bile acid
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 8 Subgroup analysis number of patients with acute cellular rejection according to time of start of bile acid
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 Less than three days after transplantation
Keiding 1997 3554 3248 333 097 [ 073 129 ]
Koneru 1993 316 916 89 033 [ 011 101 ]
Subtotal (95 CI) 70 64 422 084 [ 063 111 ]
Total events 38 (Bile acids) 41 (Control)
Heterogeneity Chi2 = 374 df = 1 (P = 005) I2 =73
Test for overall effect Z = 124 (P = 022)
2 Three days or more after liver transplantation
Angelico 1999 816 1017 95 085 [ 045 160 ]
01 02 05 1 2 5 10
Favours bile acids Favours control
(Continued )
39Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Barnes 1997 1728 1724 180 086 [ 058 127 ]
Fleckenstein 1998 814 916 83 102 [ 054 190 ]
Pageaux 1995 926 924 92 092 [ 044 193 ]
Sama 1991 1320 1320 128 100 [ 063 158 ]
Subtotal (95 CI) 104 101 578 092 [ 072 117 ]
Total events 55 (Bile acids) 58 (Control)
Heterogeneity Chi2 = 041 df = 4 (P = 098) I2 =00
Test for overall effect Z = 067 (P = 050)
Total (95 CI) 174 165 1000 089 [ 074 106 ]
Total events 93 (Bile acids) 99 (Control)
Heterogeneity Chi2 = 392 df = 6 (P = 069) I2 =00
Test for overall effect Z = 130 (P = 019)
01 02 05 1 2 5 10
Favours bile acids Favours control
40Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 19 Comparison 1 Bile acids for liver-transplanted patients Outcome 9 Subgroup analysis
number of patients with acute cellular rejection according to treatment duration
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 9 Subgroup analysis number of patients with acute cellular rejection according to treatment duration
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 Less than six months
Barnes 1997 1728 1724 180 086 [ 058 127 ]
Fleckenstein 1998 814 916 83 102 [ 054 190 ]
Keiding 1997 3554 3248 333 097 [ 073 129 ]
Koneru 1993 316 916 89 033 [ 011 101 ]
Pageaux 1995 926 924 92 092 [ 044 193 ]
Subtotal (95 CI) 138 128 777 087 [ 071 107 ]
Total events 72 (Bile acids) 76 (Control)
Heterogeneity Chi2 = 374 df = 4 (P = 044) I2 =00
Test for overall effect Z = 129 (P = 020)
2 Six months or more
Angelico 1999 816 1017 95 085 [ 045 160 ]
Sama 1991 1320 1320 128 100 [ 063 158 ]
Subtotal (95 CI) 36 37 223 094 [ 065 136 ]
Total events 21 (Bile acids) 23 (Control)
Heterogeneity Chi2 = 017 df = 1 (P = 068) I2 =00
Test for overall effect Z = 035 (P = 073)
Total (95 CI) 174 165 1000 089 [ 074 106 ]
Total events 93 (Bile acids) 99 (Control)
Heterogeneity Chi2 = 392 df = 6 (P = 069) I2 =00
Test for overall effect Z = 130 (P = 019)
01 02 05 1 2 5 10
Favours bile acids Favours control
41Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 110 Comparison 1 Bile acids for liver-transplanted patients Outcome 10 Number of patients
with chronic rejection at maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 10 Number of patients with chronic rejection at maximum follow-up
Study or subgroup Bile acids Placebo Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Barnes 1997 128 624 611 014 [ 002 110 ]
Fleckenstein 1998 114 116 88 114 [ 008 1663 ]
Keiding 1997 154 348 300 030 [ 003 275 ]
Total (95 CI) 96 88 1000 028 [ 008 095 ]
Total events 3 (Bile acids) 10 (Placebo)
Heterogeneity Chi2 = 148 df = 2 (P = 048) I2 =00
Test for overall effect Z = 204 (P = 0041)
0001 001 01 1 10 100 1000
Favours bile acids Favours placebo
Analysis 111 Comparison 1 Bile acids for liver-transplanted patients Outcome 11 Number of patients
with steroid-resistant rejection at maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 11 Number of patients with steroid-resistant rejection at maximum follow-up
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Barnes 1997 328 724 277 037 [ 011 127 ]
Fleckenstein 1998 314 316 103 114 [ 027 478 ]
Keiding 1997 1454 1548 583 083 [ 045 154 ]
Pageaux 1995 226 124 38 185 [ 018 1908 ]
Total (95 CI) 122 112 1000 077 [ 047 127 ]
Total events 22 (Bile acids) 26 (Control)
Heterogeneity Chi2 = 226 df = 3 (P = 052) I2 =00
Test for overall effect Z = 102 (P = 031)
001 01 1 10 100
Favours bile acids Favours placebo
42Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 112 Comparison 1 Bile acids for liver-transplanted patients Outcome 12 Serum bilirubin (mgdl)
at the end of treatment
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 12 Serum bilirubin (mgdl) at the end of treatment
Study or subgroup Bile acids Placebo Mean Difference Weight Mean Difference
N Mean(SD) N Mean(SD) IVFixed95 CI IVFixed95 CI
Fleckenstein 1998 14 319 (68) 16 059 (022) 1000 260 [ -096 616 ]
Total (95 CI) 14 16 1000 260 [ -096 616 ]
Heterogeneity not applicable
Test for overall effect Z = 143 (P = 015)
-10 -5 0 5 10
Favours bile acids Favours placebo
Analysis 113 Comparison 1 Bile acids for liver-transplanted patients Outcome 13 Number of days of
hospitalisation after liver transplantation
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 13 Number of days of hospitalisation after liver transplantation
Study or subgroup Bile acids Placebo Mean Difference Weight Mean Difference
N Mean(SD) N Mean(SD) IVFixed95 CI IVFixed95 CI
Barnes 1997 28 25 (17) 24 335 (13) 1000 -850 [ -1667 -033 ]
Total (95 CI) 28 24 1000 -850 [ -1667 -033 ]
Heterogeneity not applicable
Test for overall effect Z = 204 (P = 0041)
-100 -50 0 50 100
Favours bile acids Favours placebo
43Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 114 Comparison 1 Bile acids for liver-transplanted patients Outcome 14 Adverse events
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 14 Adverse events
Study or subgroup Bile acids Placebo Risk Ratio Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Angelico 1999 016 017 00 [ 00 00 ]
Barnes 1997 128 124 086 [ 006 1298 ]
Keiding 1997 554 548 089 [ 027 288 ]
Total (95 CI) 98 89 088 [ 030 260 ]
Total events 6 (Bile acids) 6 (Placebo)
Heterogeneity Chi2 = 000 df = 1 (P = 098) I2 =00
Test for overall effect Z = 022 (P = 082)
001 01 1 10 100
Favours bile acids Favours placebo
A P P E N D I C E S
Appendix 1 Search strategies
Data Base Date of Search Search Strategy
The Cochrane Hepato-Biliary Group Con-
trolled Trials Register
September 2009 1 rsquoliver transplantationrsquo and rsquochenodeoxy-
cholicrsquo
2 rsquoliver transplantationrsquo and rsquocholicrsquo
3 rsquoliver transplantationrsquo and rsquodeoxycholicrsquo
4 rsquoliver transplantationrsquo and rsquoglycochen-
odeoxycholicrsquo
5 rsquoliver transplantationrsquo and rsquoglycocholicrsquo
6 rsquoliver transplantationrsquo and rsquoglycodeoxy-
cholicrsquo
7 rsquoliver transplantationrsquo and rsquoglycolitho-
cholicrsquo
8 rsquoliver transplantationrsquo and rsquohyodeoxy-
cholicrsquo
9 rsquoliver transplantationrsquo and rsquolithocholicrsquo
10 rsquoliver transplantationrsquo and rsquotaurochen-
odeoxycholicrsquo
44Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
11 rsquoliver transplantationrsquo and rsquotauro-
cholicrsquo
12 rsquoliver transplantationrsquo and rsquotaurodehy-
drocholicrsquo
13 rsquoliver transplantationrsquo and rsquotau-
rodeoxycholicrsquo
14 rsquoliver transplantationrsquo and rsquotauroglyco-
cholicrsquo
15 rsquoliver transplantationrsquo and rsquotaurolitho-
cholicrsquo
16 rsquoliver transplantationrsquo and rsquotaurosel-
cholicrsquo
17 rsquoliver transplantationrsquo and rsquotaurourso-
cholicrsquo
18 rsquoliver transplantationrsquo and rsquotaurour-
sodeoxycholicrsquo
19 rsquoliver transplantationrsquo and rsquoursocholicrsquo
20 rsquoliver transplantationrsquo and rsquoursodeoxy-
cholicrsquo
The Cochrane Central Register of Con-
trolled Trials in The Cochrane Library
Issue 3 2009 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
6 3 or 4
7 5 and 6
MEDLINE September 2009 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
45Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
6 3 or 4
7 5 and 6
8 RANDOMIZED-CONTROLLED-
TRIAL ME
9 RANDOM
10 8 or 9
11 7 and 10
EMBASE September 2009 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
6 3 or 4
7 5 and 6
8 RANDOMIZED-CONTROLLED-
TRIAL ME
9 RANDOM
10 8 or 9
11 7 and 10
46Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
Science Citation Index Expanded September 2009 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
6 3 or 4
7 5 and 6
8 RANDOMIZED-CONTROLLED-
TRIAL ME
9 RANDOM
10 8 or 9
11 7 and 10
The Chinese Biomedical Database Searched from January 1980 to April 2002 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
47Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
6 3 or 4
7 5 and 6
8 RANDOMIZED-CONTROLLED-
TRIAL ME
9 RANDOM
10 8 or 9
11 7 and 10
W H A T rsquo S N E W
Last assessed as up-to-date 8 February 2010
18 September 2009 New citation required but conclusions have not
changed
This review is an updated version of a review that was
published for the first time in Issue 3 2005 of TheCochrane Library by Chen 2003b
18 September 2009 New search has been performed No new studies fulfilled the inclusion criteria
H I S T O R Y
Protocol first published Issue 3 2003
Review first published Issue 3 2005
C O N T R I B U T I O N S O F A U T H O R S
GP and VG independently performed searches of relevant databases GP validated the search selected trials for inclusion contacted
the authors of the trials performed data extraction and data analysis and drafted the systematic review VG revised the review update
CG and DS revised the review update solved discrepancies of data extraction validated data analyses and provided consultation
D E C L A R A T I O N S O F I N T E R E S T
None known
48Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
S O U R C E S O F S U P P O R T
Internal sources
bull Copenhagen Trial Unit Denmark
External sources
bull Danish Medical Research Councilrsquos Grant on Getting Research into Practice (GRIP) Denmark
D I F F E R E N C E S B E T W E E N P R O T O C O L A N D R E V I E W
We assessed the risk of bias in the included studies for another four domains that were added to the review protocol (incomplete
outcome data selective outcome reporting baseline imbalance and early stopping of trial) In general the text of the risk of bias
domains were updated following Higgins 2008 Trials were considered at low risk of bias when judged as adequate in all domains
Quasi-randomised studies observational and case-control studies were included for the report of adverse events
We performed trial sequential analysis for outcomes demonstrating a statistically significant result
I N D E X T E R M S
Medical Subject Headings (MeSH)
lowastLiver Transplantation Cholagogues and Choleretics [lowasttherapeutic use] Graft Rejection [lowastprevention amp control] Randomized Con-
trolled Trials as Topic Taurochenodeoxycholic Acid [lowasttherapeutic use] Ursodeoxycholic Acid [lowasttherapeutic use]
MeSH check words
Humans
49Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Total events 85 (Bile acids) 89 (Control)
Heterogeneity Chi2 = 387 df = 5 (P = 057) I2 =00
Test for overall effect Z = 120 (P = 023)
2 TUDCA versus no treatment
Angelico 1999 816 1017 95 085 [ 045 160 ]
Subtotal (95 CI) 16 17 95 085 [ 045 160 ]
Total events 8 (Bile acids) 10 (Control)
Heterogeneity not applicable
Test for overall effect Z = 050 (P = 061)
Total (95 CI) 174 165 1000 089 [ 074 106 ]
Total events 93 (Bile acids) 99 (Control)
Heterogeneity Chi2 = 392 df = 6 (P = 069) I2 =00
Test for overall effect Z = 130 (P = 019)
01 02 05 1 2 5 10
Favours bile acids Favours control
Analysis 18 Comparison 1 Bile acids for liver-transplanted patients Outcome 8 Subgroup analysis
number of patients with acute cellular rejection according to time of start of bile acid
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 8 Subgroup analysis number of patients with acute cellular rejection according to time of start of bile acid
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 Less than three days after transplantation
Keiding 1997 3554 3248 333 097 [ 073 129 ]
Koneru 1993 316 916 89 033 [ 011 101 ]
Subtotal (95 CI) 70 64 422 084 [ 063 111 ]
Total events 38 (Bile acids) 41 (Control)
Heterogeneity Chi2 = 374 df = 1 (P = 005) I2 =73
Test for overall effect Z = 124 (P = 022)
2 Three days or more after liver transplantation
Angelico 1999 816 1017 95 085 [ 045 160 ]
01 02 05 1 2 5 10
Favours bile acids Favours control
(Continued )
39Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Barnes 1997 1728 1724 180 086 [ 058 127 ]
Fleckenstein 1998 814 916 83 102 [ 054 190 ]
Pageaux 1995 926 924 92 092 [ 044 193 ]
Sama 1991 1320 1320 128 100 [ 063 158 ]
Subtotal (95 CI) 104 101 578 092 [ 072 117 ]
Total events 55 (Bile acids) 58 (Control)
Heterogeneity Chi2 = 041 df = 4 (P = 098) I2 =00
Test for overall effect Z = 067 (P = 050)
Total (95 CI) 174 165 1000 089 [ 074 106 ]
Total events 93 (Bile acids) 99 (Control)
Heterogeneity Chi2 = 392 df = 6 (P = 069) I2 =00
Test for overall effect Z = 130 (P = 019)
01 02 05 1 2 5 10
Favours bile acids Favours control
40Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 19 Comparison 1 Bile acids for liver-transplanted patients Outcome 9 Subgroup analysis
number of patients with acute cellular rejection according to treatment duration
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 9 Subgroup analysis number of patients with acute cellular rejection according to treatment duration
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 Less than six months
Barnes 1997 1728 1724 180 086 [ 058 127 ]
Fleckenstein 1998 814 916 83 102 [ 054 190 ]
Keiding 1997 3554 3248 333 097 [ 073 129 ]
Koneru 1993 316 916 89 033 [ 011 101 ]
Pageaux 1995 926 924 92 092 [ 044 193 ]
Subtotal (95 CI) 138 128 777 087 [ 071 107 ]
Total events 72 (Bile acids) 76 (Control)
Heterogeneity Chi2 = 374 df = 4 (P = 044) I2 =00
Test for overall effect Z = 129 (P = 020)
2 Six months or more
Angelico 1999 816 1017 95 085 [ 045 160 ]
Sama 1991 1320 1320 128 100 [ 063 158 ]
Subtotal (95 CI) 36 37 223 094 [ 065 136 ]
Total events 21 (Bile acids) 23 (Control)
Heterogeneity Chi2 = 017 df = 1 (P = 068) I2 =00
Test for overall effect Z = 035 (P = 073)
Total (95 CI) 174 165 1000 089 [ 074 106 ]
Total events 93 (Bile acids) 99 (Control)
Heterogeneity Chi2 = 392 df = 6 (P = 069) I2 =00
Test for overall effect Z = 130 (P = 019)
01 02 05 1 2 5 10
Favours bile acids Favours control
41Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 110 Comparison 1 Bile acids for liver-transplanted patients Outcome 10 Number of patients
with chronic rejection at maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 10 Number of patients with chronic rejection at maximum follow-up
Study or subgroup Bile acids Placebo Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Barnes 1997 128 624 611 014 [ 002 110 ]
Fleckenstein 1998 114 116 88 114 [ 008 1663 ]
Keiding 1997 154 348 300 030 [ 003 275 ]
Total (95 CI) 96 88 1000 028 [ 008 095 ]
Total events 3 (Bile acids) 10 (Placebo)
Heterogeneity Chi2 = 148 df = 2 (P = 048) I2 =00
Test for overall effect Z = 204 (P = 0041)
0001 001 01 1 10 100 1000
Favours bile acids Favours placebo
Analysis 111 Comparison 1 Bile acids for liver-transplanted patients Outcome 11 Number of patients
with steroid-resistant rejection at maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 11 Number of patients with steroid-resistant rejection at maximum follow-up
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Barnes 1997 328 724 277 037 [ 011 127 ]
Fleckenstein 1998 314 316 103 114 [ 027 478 ]
Keiding 1997 1454 1548 583 083 [ 045 154 ]
Pageaux 1995 226 124 38 185 [ 018 1908 ]
Total (95 CI) 122 112 1000 077 [ 047 127 ]
Total events 22 (Bile acids) 26 (Control)
Heterogeneity Chi2 = 226 df = 3 (P = 052) I2 =00
Test for overall effect Z = 102 (P = 031)
001 01 1 10 100
Favours bile acids Favours placebo
42Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 112 Comparison 1 Bile acids for liver-transplanted patients Outcome 12 Serum bilirubin (mgdl)
at the end of treatment
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 12 Serum bilirubin (mgdl) at the end of treatment
Study or subgroup Bile acids Placebo Mean Difference Weight Mean Difference
N Mean(SD) N Mean(SD) IVFixed95 CI IVFixed95 CI
Fleckenstein 1998 14 319 (68) 16 059 (022) 1000 260 [ -096 616 ]
Total (95 CI) 14 16 1000 260 [ -096 616 ]
Heterogeneity not applicable
Test for overall effect Z = 143 (P = 015)
-10 -5 0 5 10
Favours bile acids Favours placebo
Analysis 113 Comparison 1 Bile acids for liver-transplanted patients Outcome 13 Number of days of
hospitalisation after liver transplantation
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 13 Number of days of hospitalisation after liver transplantation
Study or subgroup Bile acids Placebo Mean Difference Weight Mean Difference
N Mean(SD) N Mean(SD) IVFixed95 CI IVFixed95 CI
Barnes 1997 28 25 (17) 24 335 (13) 1000 -850 [ -1667 -033 ]
Total (95 CI) 28 24 1000 -850 [ -1667 -033 ]
Heterogeneity not applicable
Test for overall effect Z = 204 (P = 0041)
-100 -50 0 50 100
Favours bile acids Favours placebo
43Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 114 Comparison 1 Bile acids for liver-transplanted patients Outcome 14 Adverse events
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 14 Adverse events
Study or subgroup Bile acids Placebo Risk Ratio Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Angelico 1999 016 017 00 [ 00 00 ]
Barnes 1997 128 124 086 [ 006 1298 ]
Keiding 1997 554 548 089 [ 027 288 ]
Total (95 CI) 98 89 088 [ 030 260 ]
Total events 6 (Bile acids) 6 (Placebo)
Heterogeneity Chi2 = 000 df = 1 (P = 098) I2 =00
Test for overall effect Z = 022 (P = 082)
001 01 1 10 100
Favours bile acids Favours placebo
A P P E N D I C E S
Appendix 1 Search strategies
Data Base Date of Search Search Strategy
The Cochrane Hepato-Biliary Group Con-
trolled Trials Register
September 2009 1 rsquoliver transplantationrsquo and rsquochenodeoxy-
cholicrsquo
2 rsquoliver transplantationrsquo and rsquocholicrsquo
3 rsquoliver transplantationrsquo and rsquodeoxycholicrsquo
4 rsquoliver transplantationrsquo and rsquoglycochen-
odeoxycholicrsquo
5 rsquoliver transplantationrsquo and rsquoglycocholicrsquo
6 rsquoliver transplantationrsquo and rsquoglycodeoxy-
cholicrsquo
7 rsquoliver transplantationrsquo and rsquoglycolitho-
cholicrsquo
8 rsquoliver transplantationrsquo and rsquohyodeoxy-
cholicrsquo
9 rsquoliver transplantationrsquo and rsquolithocholicrsquo
10 rsquoliver transplantationrsquo and rsquotaurochen-
odeoxycholicrsquo
44Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
11 rsquoliver transplantationrsquo and rsquotauro-
cholicrsquo
12 rsquoliver transplantationrsquo and rsquotaurodehy-
drocholicrsquo
13 rsquoliver transplantationrsquo and rsquotau-
rodeoxycholicrsquo
14 rsquoliver transplantationrsquo and rsquotauroglyco-
cholicrsquo
15 rsquoliver transplantationrsquo and rsquotaurolitho-
cholicrsquo
16 rsquoliver transplantationrsquo and rsquotaurosel-
cholicrsquo
17 rsquoliver transplantationrsquo and rsquotaurourso-
cholicrsquo
18 rsquoliver transplantationrsquo and rsquotaurour-
sodeoxycholicrsquo
19 rsquoliver transplantationrsquo and rsquoursocholicrsquo
20 rsquoliver transplantationrsquo and rsquoursodeoxy-
cholicrsquo
The Cochrane Central Register of Con-
trolled Trials in The Cochrane Library
Issue 3 2009 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
6 3 or 4
7 5 and 6
MEDLINE September 2009 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
45Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
6 3 or 4
7 5 and 6
8 RANDOMIZED-CONTROLLED-
TRIAL ME
9 RANDOM
10 8 or 9
11 7 and 10
EMBASE September 2009 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
6 3 or 4
7 5 and 6
8 RANDOMIZED-CONTROLLED-
TRIAL ME
9 RANDOM
10 8 or 9
11 7 and 10
46Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
Science Citation Index Expanded September 2009 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
6 3 or 4
7 5 and 6
8 RANDOMIZED-CONTROLLED-
TRIAL ME
9 RANDOM
10 8 or 9
11 7 and 10
The Chinese Biomedical Database Searched from January 1980 to April 2002 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
47Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
6 3 or 4
7 5 and 6
8 RANDOMIZED-CONTROLLED-
TRIAL ME
9 RANDOM
10 8 or 9
11 7 and 10
W H A T rsquo S N E W
Last assessed as up-to-date 8 February 2010
18 September 2009 New citation required but conclusions have not
changed
This review is an updated version of a review that was
published for the first time in Issue 3 2005 of TheCochrane Library by Chen 2003b
18 September 2009 New search has been performed No new studies fulfilled the inclusion criteria
H I S T O R Y
Protocol first published Issue 3 2003
Review first published Issue 3 2005
C O N T R I B U T I O N S O F A U T H O R S
GP and VG independently performed searches of relevant databases GP validated the search selected trials for inclusion contacted
the authors of the trials performed data extraction and data analysis and drafted the systematic review VG revised the review update
CG and DS revised the review update solved discrepancies of data extraction validated data analyses and provided consultation
D E C L A R A T I O N S O F I N T E R E S T
None known
48Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
S O U R C E S O F S U P P O R T
Internal sources
bull Copenhagen Trial Unit Denmark
External sources
bull Danish Medical Research Councilrsquos Grant on Getting Research into Practice (GRIP) Denmark
D I F F E R E N C E S B E T W E E N P R O T O C O L A N D R E V I E W
We assessed the risk of bias in the included studies for another four domains that were added to the review protocol (incomplete
outcome data selective outcome reporting baseline imbalance and early stopping of trial) In general the text of the risk of bias
domains were updated following Higgins 2008 Trials were considered at low risk of bias when judged as adequate in all domains
Quasi-randomised studies observational and case-control studies were included for the report of adverse events
We performed trial sequential analysis for outcomes demonstrating a statistically significant result
I N D E X T E R M S
Medical Subject Headings (MeSH)
lowastLiver Transplantation Cholagogues and Choleretics [lowasttherapeutic use] Graft Rejection [lowastprevention amp control] Randomized Con-
trolled Trials as Topic Taurochenodeoxycholic Acid [lowasttherapeutic use] Ursodeoxycholic Acid [lowasttherapeutic use]
MeSH check words
Humans
49Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
( Continued)Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Barnes 1997 1728 1724 180 086 [ 058 127 ]
Fleckenstein 1998 814 916 83 102 [ 054 190 ]
Pageaux 1995 926 924 92 092 [ 044 193 ]
Sama 1991 1320 1320 128 100 [ 063 158 ]
Subtotal (95 CI) 104 101 578 092 [ 072 117 ]
Total events 55 (Bile acids) 58 (Control)
Heterogeneity Chi2 = 041 df = 4 (P = 098) I2 =00
Test for overall effect Z = 067 (P = 050)
Total (95 CI) 174 165 1000 089 [ 074 106 ]
Total events 93 (Bile acids) 99 (Control)
Heterogeneity Chi2 = 392 df = 6 (P = 069) I2 =00
Test for overall effect Z = 130 (P = 019)
01 02 05 1 2 5 10
Favours bile acids Favours control
40Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 19 Comparison 1 Bile acids for liver-transplanted patients Outcome 9 Subgroup analysis
number of patients with acute cellular rejection according to treatment duration
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 9 Subgroup analysis number of patients with acute cellular rejection according to treatment duration
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 Less than six months
Barnes 1997 1728 1724 180 086 [ 058 127 ]
Fleckenstein 1998 814 916 83 102 [ 054 190 ]
Keiding 1997 3554 3248 333 097 [ 073 129 ]
Koneru 1993 316 916 89 033 [ 011 101 ]
Pageaux 1995 926 924 92 092 [ 044 193 ]
Subtotal (95 CI) 138 128 777 087 [ 071 107 ]
Total events 72 (Bile acids) 76 (Control)
Heterogeneity Chi2 = 374 df = 4 (P = 044) I2 =00
Test for overall effect Z = 129 (P = 020)
2 Six months or more
Angelico 1999 816 1017 95 085 [ 045 160 ]
Sama 1991 1320 1320 128 100 [ 063 158 ]
Subtotal (95 CI) 36 37 223 094 [ 065 136 ]
Total events 21 (Bile acids) 23 (Control)
Heterogeneity Chi2 = 017 df = 1 (P = 068) I2 =00
Test for overall effect Z = 035 (P = 073)
Total (95 CI) 174 165 1000 089 [ 074 106 ]
Total events 93 (Bile acids) 99 (Control)
Heterogeneity Chi2 = 392 df = 6 (P = 069) I2 =00
Test for overall effect Z = 130 (P = 019)
01 02 05 1 2 5 10
Favours bile acids Favours control
41Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 110 Comparison 1 Bile acids for liver-transplanted patients Outcome 10 Number of patients
with chronic rejection at maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 10 Number of patients with chronic rejection at maximum follow-up
Study or subgroup Bile acids Placebo Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Barnes 1997 128 624 611 014 [ 002 110 ]
Fleckenstein 1998 114 116 88 114 [ 008 1663 ]
Keiding 1997 154 348 300 030 [ 003 275 ]
Total (95 CI) 96 88 1000 028 [ 008 095 ]
Total events 3 (Bile acids) 10 (Placebo)
Heterogeneity Chi2 = 148 df = 2 (P = 048) I2 =00
Test for overall effect Z = 204 (P = 0041)
0001 001 01 1 10 100 1000
Favours bile acids Favours placebo
Analysis 111 Comparison 1 Bile acids for liver-transplanted patients Outcome 11 Number of patients
with steroid-resistant rejection at maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 11 Number of patients with steroid-resistant rejection at maximum follow-up
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Barnes 1997 328 724 277 037 [ 011 127 ]
Fleckenstein 1998 314 316 103 114 [ 027 478 ]
Keiding 1997 1454 1548 583 083 [ 045 154 ]
Pageaux 1995 226 124 38 185 [ 018 1908 ]
Total (95 CI) 122 112 1000 077 [ 047 127 ]
Total events 22 (Bile acids) 26 (Control)
Heterogeneity Chi2 = 226 df = 3 (P = 052) I2 =00
Test for overall effect Z = 102 (P = 031)
001 01 1 10 100
Favours bile acids Favours placebo
42Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 112 Comparison 1 Bile acids for liver-transplanted patients Outcome 12 Serum bilirubin (mgdl)
at the end of treatment
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 12 Serum bilirubin (mgdl) at the end of treatment
Study or subgroup Bile acids Placebo Mean Difference Weight Mean Difference
N Mean(SD) N Mean(SD) IVFixed95 CI IVFixed95 CI
Fleckenstein 1998 14 319 (68) 16 059 (022) 1000 260 [ -096 616 ]
Total (95 CI) 14 16 1000 260 [ -096 616 ]
Heterogeneity not applicable
Test for overall effect Z = 143 (P = 015)
-10 -5 0 5 10
Favours bile acids Favours placebo
Analysis 113 Comparison 1 Bile acids for liver-transplanted patients Outcome 13 Number of days of
hospitalisation after liver transplantation
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 13 Number of days of hospitalisation after liver transplantation
Study or subgroup Bile acids Placebo Mean Difference Weight Mean Difference
N Mean(SD) N Mean(SD) IVFixed95 CI IVFixed95 CI
Barnes 1997 28 25 (17) 24 335 (13) 1000 -850 [ -1667 -033 ]
Total (95 CI) 28 24 1000 -850 [ -1667 -033 ]
Heterogeneity not applicable
Test for overall effect Z = 204 (P = 0041)
-100 -50 0 50 100
Favours bile acids Favours placebo
43Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 114 Comparison 1 Bile acids for liver-transplanted patients Outcome 14 Adverse events
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 14 Adverse events
Study or subgroup Bile acids Placebo Risk Ratio Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Angelico 1999 016 017 00 [ 00 00 ]
Barnes 1997 128 124 086 [ 006 1298 ]
Keiding 1997 554 548 089 [ 027 288 ]
Total (95 CI) 98 89 088 [ 030 260 ]
Total events 6 (Bile acids) 6 (Placebo)
Heterogeneity Chi2 = 000 df = 1 (P = 098) I2 =00
Test for overall effect Z = 022 (P = 082)
001 01 1 10 100
Favours bile acids Favours placebo
A P P E N D I C E S
Appendix 1 Search strategies
Data Base Date of Search Search Strategy
The Cochrane Hepato-Biliary Group Con-
trolled Trials Register
September 2009 1 rsquoliver transplantationrsquo and rsquochenodeoxy-
cholicrsquo
2 rsquoliver transplantationrsquo and rsquocholicrsquo
3 rsquoliver transplantationrsquo and rsquodeoxycholicrsquo
4 rsquoliver transplantationrsquo and rsquoglycochen-
odeoxycholicrsquo
5 rsquoliver transplantationrsquo and rsquoglycocholicrsquo
6 rsquoliver transplantationrsquo and rsquoglycodeoxy-
cholicrsquo
7 rsquoliver transplantationrsquo and rsquoglycolitho-
cholicrsquo
8 rsquoliver transplantationrsquo and rsquohyodeoxy-
cholicrsquo
9 rsquoliver transplantationrsquo and rsquolithocholicrsquo
10 rsquoliver transplantationrsquo and rsquotaurochen-
odeoxycholicrsquo
44Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
11 rsquoliver transplantationrsquo and rsquotauro-
cholicrsquo
12 rsquoliver transplantationrsquo and rsquotaurodehy-
drocholicrsquo
13 rsquoliver transplantationrsquo and rsquotau-
rodeoxycholicrsquo
14 rsquoliver transplantationrsquo and rsquotauroglyco-
cholicrsquo
15 rsquoliver transplantationrsquo and rsquotaurolitho-
cholicrsquo
16 rsquoliver transplantationrsquo and rsquotaurosel-
cholicrsquo
17 rsquoliver transplantationrsquo and rsquotaurourso-
cholicrsquo
18 rsquoliver transplantationrsquo and rsquotaurour-
sodeoxycholicrsquo
19 rsquoliver transplantationrsquo and rsquoursocholicrsquo
20 rsquoliver transplantationrsquo and rsquoursodeoxy-
cholicrsquo
The Cochrane Central Register of Con-
trolled Trials in The Cochrane Library
Issue 3 2009 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
6 3 or 4
7 5 and 6
MEDLINE September 2009 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
45Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
6 3 or 4
7 5 and 6
8 RANDOMIZED-CONTROLLED-
TRIAL ME
9 RANDOM
10 8 or 9
11 7 and 10
EMBASE September 2009 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
6 3 or 4
7 5 and 6
8 RANDOMIZED-CONTROLLED-
TRIAL ME
9 RANDOM
10 8 or 9
11 7 and 10
46Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
Science Citation Index Expanded September 2009 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
6 3 or 4
7 5 and 6
8 RANDOMIZED-CONTROLLED-
TRIAL ME
9 RANDOM
10 8 or 9
11 7 and 10
The Chinese Biomedical Database Searched from January 1980 to April 2002 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
47Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
6 3 or 4
7 5 and 6
8 RANDOMIZED-CONTROLLED-
TRIAL ME
9 RANDOM
10 8 or 9
11 7 and 10
W H A T rsquo S N E W
Last assessed as up-to-date 8 February 2010
18 September 2009 New citation required but conclusions have not
changed
This review is an updated version of a review that was
published for the first time in Issue 3 2005 of TheCochrane Library by Chen 2003b
18 September 2009 New search has been performed No new studies fulfilled the inclusion criteria
H I S T O R Y
Protocol first published Issue 3 2003
Review first published Issue 3 2005
C O N T R I B U T I O N S O F A U T H O R S
GP and VG independently performed searches of relevant databases GP validated the search selected trials for inclusion contacted
the authors of the trials performed data extraction and data analysis and drafted the systematic review VG revised the review update
CG and DS revised the review update solved discrepancies of data extraction validated data analyses and provided consultation
D E C L A R A T I O N S O F I N T E R E S T
None known
48Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
S O U R C E S O F S U P P O R T
Internal sources
bull Copenhagen Trial Unit Denmark
External sources
bull Danish Medical Research Councilrsquos Grant on Getting Research into Practice (GRIP) Denmark
D I F F E R E N C E S B E T W E E N P R O T O C O L A N D R E V I E W
We assessed the risk of bias in the included studies for another four domains that were added to the review protocol (incomplete
outcome data selective outcome reporting baseline imbalance and early stopping of trial) In general the text of the risk of bias
domains were updated following Higgins 2008 Trials were considered at low risk of bias when judged as adequate in all domains
Quasi-randomised studies observational and case-control studies were included for the report of adverse events
We performed trial sequential analysis for outcomes demonstrating a statistically significant result
I N D E X T E R M S
Medical Subject Headings (MeSH)
lowastLiver Transplantation Cholagogues and Choleretics [lowasttherapeutic use] Graft Rejection [lowastprevention amp control] Randomized Con-
trolled Trials as Topic Taurochenodeoxycholic Acid [lowasttherapeutic use] Ursodeoxycholic Acid [lowasttherapeutic use]
MeSH check words
Humans
49Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 19 Comparison 1 Bile acids for liver-transplanted patients Outcome 9 Subgroup analysis
number of patients with acute cellular rejection according to treatment duration
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 9 Subgroup analysis number of patients with acute cellular rejection according to treatment duration
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
1 Less than six months
Barnes 1997 1728 1724 180 086 [ 058 127 ]
Fleckenstein 1998 814 916 83 102 [ 054 190 ]
Keiding 1997 3554 3248 333 097 [ 073 129 ]
Koneru 1993 316 916 89 033 [ 011 101 ]
Pageaux 1995 926 924 92 092 [ 044 193 ]
Subtotal (95 CI) 138 128 777 087 [ 071 107 ]
Total events 72 (Bile acids) 76 (Control)
Heterogeneity Chi2 = 374 df = 4 (P = 044) I2 =00
Test for overall effect Z = 129 (P = 020)
2 Six months or more
Angelico 1999 816 1017 95 085 [ 045 160 ]
Sama 1991 1320 1320 128 100 [ 063 158 ]
Subtotal (95 CI) 36 37 223 094 [ 065 136 ]
Total events 21 (Bile acids) 23 (Control)
Heterogeneity Chi2 = 017 df = 1 (P = 068) I2 =00
Test for overall effect Z = 035 (P = 073)
Total (95 CI) 174 165 1000 089 [ 074 106 ]
Total events 93 (Bile acids) 99 (Control)
Heterogeneity Chi2 = 392 df = 6 (P = 069) I2 =00
Test for overall effect Z = 130 (P = 019)
01 02 05 1 2 5 10
Favours bile acids Favours control
41Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 110 Comparison 1 Bile acids for liver-transplanted patients Outcome 10 Number of patients
with chronic rejection at maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 10 Number of patients with chronic rejection at maximum follow-up
Study or subgroup Bile acids Placebo Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Barnes 1997 128 624 611 014 [ 002 110 ]
Fleckenstein 1998 114 116 88 114 [ 008 1663 ]
Keiding 1997 154 348 300 030 [ 003 275 ]
Total (95 CI) 96 88 1000 028 [ 008 095 ]
Total events 3 (Bile acids) 10 (Placebo)
Heterogeneity Chi2 = 148 df = 2 (P = 048) I2 =00
Test for overall effect Z = 204 (P = 0041)
0001 001 01 1 10 100 1000
Favours bile acids Favours placebo
Analysis 111 Comparison 1 Bile acids for liver-transplanted patients Outcome 11 Number of patients
with steroid-resistant rejection at maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 11 Number of patients with steroid-resistant rejection at maximum follow-up
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Barnes 1997 328 724 277 037 [ 011 127 ]
Fleckenstein 1998 314 316 103 114 [ 027 478 ]
Keiding 1997 1454 1548 583 083 [ 045 154 ]
Pageaux 1995 226 124 38 185 [ 018 1908 ]
Total (95 CI) 122 112 1000 077 [ 047 127 ]
Total events 22 (Bile acids) 26 (Control)
Heterogeneity Chi2 = 226 df = 3 (P = 052) I2 =00
Test for overall effect Z = 102 (P = 031)
001 01 1 10 100
Favours bile acids Favours placebo
42Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 112 Comparison 1 Bile acids for liver-transplanted patients Outcome 12 Serum bilirubin (mgdl)
at the end of treatment
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 12 Serum bilirubin (mgdl) at the end of treatment
Study or subgroup Bile acids Placebo Mean Difference Weight Mean Difference
N Mean(SD) N Mean(SD) IVFixed95 CI IVFixed95 CI
Fleckenstein 1998 14 319 (68) 16 059 (022) 1000 260 [ -096 616 ]
Total (95 CI) 14 16 1000 260 [ -096 616 ]
Heterogeneity not applicable
Test for overall effect Z = 143 (P = 015)
-10 -5 0 5 10
Favours bile acids Favours placebo
Analysis 113 Comparison 1 Bile acids for liver-transplanted patients Outcome 13 Number of days of
hospitalisation after liver transplantation
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 13 Number of days of hospitalisation after liver transplantation
Study or subgroup Bile acids Placebo Mean Difference Weight Mean Difference
N Mean(SD) N Mean(SD) IVFixed95 CI IVFixed95 CI
Barnes 1997 28 25 (17) 24 335 (13) 1000 -850 [ -1667 -033 ]
Total (95 CI) 28 24 1000 -850 [ -1667 -033 ]
Heterogeneity not applicable
Test for overall effect Z = 204 (P = 0041)
-100 -50 0 50 100
Favours bile acids Favours placebo
43Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 114 Comparison 1 Bile acids for liver-transplanted patients Outcome 14 Adverse events
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 14 Adverse events
Study or subgroup Bile acids Placebo Risk Ratio Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Angelico 1999 016 017 00 [ 00 00 ]
Barnes 1997 128 124 086 [ 006 1298 ]
Keiding 1997 554 548 089 [ 027 288 ]
Total (95 CI) 98 89 088 [ 030 260 ]
Total events 6 (Bile acids) 6 (Placebo)
Heterogeneity Chi2 = 000 df = 1 (P = 098) I2 =00
Test for overall effect Z = 022 (P = 082)
001 01 1 10 100
Favours bile acids Favours placebo
A P P E N D I C E S
Appendix 1 Search strategies
Data Base Date of Search Search Strategy
The Cochrane Hepato-Biliary Group Con-
trolled Trials Register
September 2009 1 rsquoliver transplantationrsquo and rsquochenodeoxy-
cholicrsquo
2 rsquoliver transplantationrsquo and rsquocholicrsquo
3 rsquoliver transplantationrsquo and rsquodeoxycholicrsquo
4 rsquoliver transplantationrsquo and rsquoglycochen-
odeoxycholicrsquo
5 rsquoliver transplantationrsquo and rsquoglycocholicrsquo
6 rsquoliver transplantationrsquo and rsquoglycodeoxy-
cholicrsquo
7 rsquoliver transplantationrsquo and rsquoglycolitho-
cholicrsquo
8 rsquoliver transplantationrsquo and rsquohyodeoxy-
cholicrsquo
9 rsquoliver transplantationrsquo and rsquolithocholicrsquo
10 rsquoliver transplantationrsquo and rsquotaurochen-
odeoxycholicrsquo
44Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
11 rsquoliver transplantationrsquo and rsquotauro-
cholicrsquo
12 rsquoliver transplantationrsquo and rsquotaurodehy-
drocholicrsquo
13 rsquoliver transplantationrsquo and rsquotau-
rodeoxycholicrsquo
14 rsquoliver transplantationrsquo and rsquotauroglyco-
cholicrsquo
15 rsquoliver transplantationrsquo and rsquotaurolitho-
cholicrsquo
16 rsquoliver transplantationrsquo and rsquotaurosel-
cholicrsquo
17 rsquoliver transplantationrsquo and rsquotaurourso-
cholicrsquo
18 rsquoliver transplantationrsquo and rsquotaurour-
sodeoxycholicrsquo
19 rsquoliver transplantationrsquo and rsquoursocholicrsquo
20 rsquoliver transplantationrsquo and rsquoursodeoxy-
cholicrsquo
The Cochrane Central Register of Con-
trolled Trials in The Cochrane Library
Issue 3 2009 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
6 3 or 4
7 5 and 6
MEDLINE September 2009 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
45Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
6 3 or 4
7 5 and 6
8 RANDOMIZED-CONTROLLED-
TRIAL ME
9 RANDOM
10 8 or 9
11 7 and 10
EMBASE September 2009 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
6 3 or 4
7 5 and 6
8 RANDOMIZED-CONTROLLED-
TRIAL ME
9 RANDOM
10 8 or 9
11 7 and 10
46Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
Science Citation Index Expanded September 2009 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
6 3 or 4
7 5 and 6
8 RANDOMIZED-CONTROLLED-
TRIAL ME
9 RANDOM
10 8 or 9
11 7 and 10
The Chinese Biomedical Database Searched from January 1980 to April 2002 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
47Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
6 3 or 4
7 5 and 6
8 RANDOMIZED-CONTROLLED-
TRIAL ME
9 RANDOM
10 8 or 9
11 7 and 10
W H A T rsquo S N E W
Last assessed as up-to-date 8 February 2010
18 September 2009 New citation required but conclusions have not
changed
This review is an updated version of a review that was
published for the first time in Issue 3 2005 of TheCochrane Library by Chen 2003b
18 September 2009 New search has been performed No new studies fulfilled the inclusion criteria
H I S T O R Y
Protocol first published Issue 3 2003
Review first published Issue 3 2005
C O N T R I B U T I O N S O F A U T H O R S
GP and VG independently performed searches of relevant databases GP validated the search selected trials for inclusion contacted
the authors of the trials performed data extraction and data analysis and drafted the systematic review VG revised the review update
CG and DS revised the review update solved discrepancies of data extraction validated data analyses and provided consultation
D E C L A R A T I O N S O F I N T E R E S T
None known
48Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
S O U R C E S O F S U P P O R T
Internal sources
bull Copenhagen Trial Unit Denmark
External sources
bull Danish Medical Research Councilrsquos Grant on Getting Research into Practice (GRIP) Denmark
D I F F E R E N C E S B E T W E E N P R O T O C O L A N D R E V I E W
We assessed the risk of bias in the included studies for another four domains that were added to the review protocol (incomplete
outcome data selective outcome reporting baseline imbalance and early stopping of trial) In general the text of the risk of bias
domains were updated following Higgins 2008 Trials were considered at low risk of bias when judged as adequate in all domains
Quasi-randomised studies observational and case-control studies were included for the report of adverse events
We performed trial sequential analysis for outcomes demonstrating a statistically significant result
I N D E X T E R M S
Medical Subject Headings (MeSH)
lowastLiver Transplantation Cholagogues and Choleretics [lowasttherapeutic use] Graft Rejection [lowastprevention amp control] Randomized Con-
trolled Trials as Topic Taurochenodeoxycholic Acid [lowasttherapeutic use] Ursodeoxycholic Acid [lowasttherapeutic use]
MeSH check words
Humans
49Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 110 Comparison 1 Bile acids for liver-transplanted patients Outcome 10 Number of patients
with chronic rejection at maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 10 Number of patients with chronic rejection at maximum follow-up
Study or subgroup Bile acids Placebo Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Barnes 1997 128 624 611 014 [ 002 110 ]
Fleckenstein 1998 114 116 88 114 [ 008 1663 ]
Keiding 1997 154 348 300 030 [ 003 275 ]
Total (95 CI) 96 88 1000 028 [ 008 095 ]
Total events 3 (Bile acids) 10 (Placebo)
Heterogeneity Chi2 = 148 df = 2 (P = 048) I2 =00
Test for overall effect Z = 204 (P = 0041)
0001 001 01 1 10 100 1000
Favours bile acids Favours placebo
Analysis 111 Comparison 1 Bile acids for liver-transplanted patients Outcome 11 Number of patients
with steroid-resistant rejection at maximum follow-up
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 11 Number of patients with steroid-resistant rejection at maximum follow-up
Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Barnes 1997 328 724 277 037 [ 011 127 ]
Fleckenstein 1998 314 316 103 114 [ 027 478 ]
Keiding 1997 1454 1548 583 083 [ 045 154 ]
Pageaux 1995 226 124 38 185 [ 018 1908 ]
Total (95 CI) 122 112 1000 077 [ 047 127 ]
Total events 22 (Bile acids) 26 (Control)
Heterogeneity Chi2 = 226 df = 3 (P = 052) I2 =00
Test for overall effect Z = 102 (P = 031)
001 01 1 10 100
Favours bile acids Favours placebo
42Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 112 Comparison 1 Bile acids for liver-transplanted patients Outcome 12 Serum bilirubin (mgdl)
at the end of treatment
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 12 Serum bilirubin (mgdl) at the end of treatment
Study or subgroup Bile acids Placebo Mean Difference Weight Mean Difference
N Mean(SD) N Mean(SD) IVFixed95 CI IVFixed95 CI
Fleckenstein 1998 14 319 (68) 16 059 (022) 1000 260 [ -096 616 ]
Total (95 CI) 14 16 1000 260 [ -096 616 ]
Heterogeneity not applicable
Test for overall effect Z = 143 (P = 015)
-10 -5 0 5 10
Favours bile acids Favours placebo
Analysis 113 Comparison 1 Bile acids for liver-transplanted patients Outcome 13 Number of days of
hospitalisation after liver transplantation
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 13 Number of days of hospitalisation after liver transplantation
Study or subgroup Bile acids Placebo Mean Difference Weight Mean Difference
N Mean(SD) N Mean(SD) IVFixed95 CI IVFixed95 CI
Barnes 1997 28 25 (17) 24 335 (13) 1000 -850 [ -1667 -033 ]
Total (95 CI) 28 24 1000 -850 [ -1667 -033 ]
Heterogeneity not applicable
Test for overall effect Z = 204 (P = 0041)
-100 -50 0 50 100
Favours bile acids Favours placebo
43Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 114 Comparison 1 Bile acids for liver-transplanted patients Outcome 14 Adverse events
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 14 Adverse events
Study or subgroup Bile acids Placebo Risk Ratio Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Angelico 1999 016 017 00 [ 00 00 ]
Barnes 1997 128 124 086 [ 006 1298 ]
Keiding 1997 554 548 089 [ 027 288 ]
Total (95 CI) 98 89 088 [ 030 260 ]
Total events 6 (Bile acids) 6 (Placebo)
Heterogeneity Chi2 = 000 df = 1 (P = 098) I2 =00
Test for overall effect Z = 022 (P = 082)
001 01 1 10 100
Favours bile acids Favours placebo
A P P E N D I C E S
Appendix 1 Search strategies
Data Base Date of Search Search Strategy
The Cochrane Hepato-Biliary Group Con-
trolled Trials Register
September 2009 1 rsquoliver transplantationrsquo and rsquochenodeoxy-
cholicrsquo
2 rsquoliver transplantationrsquo and rsquocholicrsquo
3 rsquoliver transplantationrsquo and rsquodeoxycholicrsquo
4 rsquoliver transplantationrsquo and rsquoglycochen-
odeoxycholicrsquo
5 rsquoliver transplantationrsquo and rsquoglycocholicrsquo
6 rsquoliver transplantationrsquo and rsquoglycodeoxy-
cholicrsquo
7 rsquoliver transplantationrsquo and rsquoglycolitho-
cholicrsquo
8 rsquoliver transplantationrsquo and rsquohyodeoxy-
cholicrsquo
9 rsquoliver transplantationrsquo and rsquolithocholicrsquo
10 rsquoliver transplantationrsquo and rsquotaurochen-
odeoxycholicrsquo
44Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
11 rsquoliver transplantationrsquo and rsquotauro-
cholicrsquo
12 rsquoliver transplantationrsquo and rsquotaurodehy-
drocholicrsquo
13 rsquoliver transplantationrsquo and rsquotau-
rodeoxycholicrsquo
14 rsquoliver transplantationrsquo and rsquotauroglyco-
cholicrsquo
15 rsquoliver transplantationrsquo and rsquotaurolitho-
cholicrsquo
16 rsquoliver transplantationrsquo and rsquotaurosel-
cholicrsquo
17 rsquoliver transplantationrsquo and rsquotaurourso-
cholicrsquo
18 rsquoliver transplantationrsquo and rsquotaurour-
sodeoxycholicrsquo
19 rsquoliver transplantationrsquo and rsquoursocholicrsquo
20 rsquoliver transplantationrsquo and rsquoursodeoxy-
cholicrsquo
The Cochrane Central Register of Con-
trolled Trials in The Cochrane Library
Issue 3 2009 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
6 3 or 4
7 5 and 6
MEDLINE September 2009 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
45Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
6 3 or 4
7 5 and 6
8 RANDOMIZED-CONTROLLED-
TRIAL ME
9 RANDOM
10 8 or 9
11 7 and 10
EMBASE September 2009 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
6 3 or 4
7 5 and 6
8 RANDOMIZED-CONTROLLED-
TRIAL ME
9 RANDOM
10 8 or 9
11 7 and 10
46Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
Science Citation Index Expanded September 2009 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
6 3 or 4
7 5 and 6
8 RANDOMIZED-CONTROLLED-
TRIAL ME
9 RANDOM
10 8 or 9
11 7 and 10
The Chinese Biomedical Database Searched from January 1980 to April 2002 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
47Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
6 3 or 4
7 5 and 6
8 RANDOMIZED-CONTROLLED-
TRIAL ME
9 RANDOM
10 8 or 9
11 7 and 10
W H A T rsquo S N E W
Last assessed as up-to-date 8 February 2010
18 September 2009 New citation required but conclusions have not
changed
This review is an updated version of a review that was
published for the first time in Issue 3 2005 of TheCochrane Library by Chen 2003b
18 September 2009 New search has been performed No new studies fulfilled the inclusion criteria
H I S T O R Y
Protocol first published Issue 3 2003
Review first published Issue 3 2005
C O N T R I B U T I O N S O F A U T H O R S
GP and VG independently performed searches of relevant databases GP validated the search selected trials for inclusion contacted
the authors of the trials performed data extraction and data analysis and drafted the systematic review VG revised the review update
CG and DS revised the review update solved discrepancies of data extraction validated data analyses and provided consultation
D E C L A R A T I O N S O F I N T E R E S T
None known
48Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
S O U R C E S O F S U P P O R T
Internal sources
bull Copenhagen Trial Unit Denmark
External sources
bull Danish Medical Research Councilrsquos Grant on Getting Research into Practice (GRIP) Denmark
D I F F E R E N C E S B E T W E E N P R O T O C O L A N D R E V I E W
We assessed the risk of bias in the included studies for another four domains that were added to the review protocol (incomplete
outcome data selective outcome reporting baseline imbalance and early stopping of trial) In general the text of the risk of bias
domains were updated following Higgins 2008 Trials were considered at low risk of bias when judged as adequate in all domains
Quasi-randomised studies observational and case-control studies were included for the report of adverse events
We performed trial sequential analysis for outcomes demonstrating a statistically significant result
I N D E X T E R M S
Medical Subject Headings (MeSH)
lowastLiver Transplantation Cholagogues and Choleretics [lowasttherapeutic use] Graft Rejection [lowastprevention amp control] Randomized Con-
trolled Trials as Topic Taurochenodeoxycholic Acid [lowasttherapeutic use] Ursodeoxycholic Acid [lowasttherapeutic use]
MeSH check words
Humans
49Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 112 Comparison 1 Bile acids for liver-transplanted patients Outcome 12 Serum bilirubin (mgdl)
at the end of treatment
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 12 Serum bilirubin (mgdl) at the end of treatment
Study or subgroup Bile acids Placebo Mean Difference Weight Mean Difference
N Mean(SD) N Mean(SD) IVFixed95 CI IVFixed95 CI
Fleckenstein 1998 14 319 (68) 16 059 (022) 1000 260 [ -096 616 ]
Total (95 CI) 14 16 1000 260 [ -096 616 ]
Heterogeneity not applicable
Test for overall effect Z = 143 (P = 015)
-10 -5 0 5 10
Favours bile acids Favours placebo
Analysis 113 Comparison 1 Bile acids for liver-transplanted patients Outcome 13 Number of days of
hospitalisation after liver transplantation
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 13 Number of days of hospitalisation after liver transplantation
Study or subgroup Bile acids Placebo Mean Difference Weight Mean Difference
N Mean(SD) N Mean(SD) IVFixed95 CI IVFixed95 CI
Barnes 1997 28 25 (17) 24 335 (13) 1000 -850 [ -1667 -033 ]
Total (95 CI) 28 24 1000 -850 [ -1667 -033 ]
Heterogeneity not applicable
Test for overall effect Z = 204 (P = 0041)
-100 -50 0 50 100
Favours bile acids Favours placebo
43Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 114 Comparison 1 Bile acids for liver-transplanted patients Outcome 14 Adverse events
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 14 Adverse events
Study or subgroup Bile acids Placebo Risk Ratio Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Angelico 1999 016 017 00 [ 00 00 ]
Barnes 1997 128 124 086 [ 006 1298 ]
Keiding 1997 554 548 089 [ 027 288 ]
Total (95 CI) 98 89 088 [ 030 260 ]
Total events 6 (Bile acids) 6 (Placebo)
Heterogeneity Chi2 = 000 df = 1 (P = 098) I2 =00
Test for overall effect Z = 022 (P = 082)
001 01 1 10 100
Favours bile acids Favours placebo
A P P E N D I C E S
Appendix 1 Search strategies
Data Base Date of Search Search Strategy
The Cochrane Hepato-Biliary Group Con-
trolled Trials Register
September 2009 1 rsquoliver transplantationrsquo and rsquochenodeoxy-
cholicrsquo
2 rsquoliver transplantationrsquo and rsquocholicrsquo
3 rsquoliver transplantationrsquo and rsquodeoxycholicrsquo
4 rsquoliver transplantationrsquo and rsquoglycochen-
odeoxycholicrsquo
5 rsquoliver transplantationrsquo and rsquoglycocholicrsquo
6 rsquoliver transplantationrsquo and rsquoglycodeoxy-
cholicrsquo
7 rsquoliver transplantationrsquo and rsquoglycolitho-
cholicrsquo
8 rsquoliver transplantationrsquo and rsquohyodeoxy-
cholicrsquo
9 rsquoliver transplantationrsquo and rsquolithocholicrsquo
10 rsquoliver transplantationrsquo and rsquotaurochen-
odeoxycholicrsquo
44Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
11 rsquoliver transplantationrsquo and rsquotauro-
cholicrsquo
12 rsquoliver transplantationrsquo and rsquotaurodehy-
drocholicrsquo
13 rsquoliver transplantationrsquo and rsquotau-
rodeoxycholicrsquo
14 rsquoliver transplantationrsquo and rsquotauroglyco-
cholicrsquo
15 rsquoliver transplantationrsquo and rsquotaurolitho-
cholicrsquo
16 rsquoliver transplantationrsquo and rsquotaurosel-
cholicrsquo
17 rsquoliver transplantationrsquo and rsquotaurourso-
cholicrsquo
18 rsquoliver transplantationrsquo and rsquotaurour-
sodeoxycholicrsquo
19 rsquoliver transplantationrsquo and rsquoursocholicrsquo
20 rsquoliver transplantationrsquo and rsquoursodeoxy-
cholicrsquo
The Cochrane Central Register of Con-
trolled Trials in The Cochrane Library
Issue 3 2009 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
6 3 or 4
7 5 and 6
MEDLINE September 2009 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
45Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
6 3 or 4
7 5 and 6
8 RANDOMIZED-CONTROLLED-
TRIAL ME
9 RANDOM
10 8 or 9
11 7 and 10
EMBASE September 2009 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
6 3 or 4
7 5 and 6
8 RANDOMIZED-CONTROLLED-
TRIAL ME
9 RANDOM
10 8 or 9
11 7 and 10
46Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
Science Citation Index Expanded September 2009 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
6 3 or 4
7 5 and 6
8 RANDOMIZED-CONTROLLED-
TRIAL ME
9 RANDOM
10 8 or 9
11 7 and 10
The Chinese Biomedical Database Searched from January 1980 to April 2002 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
47Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
6 3 or 4
7 5 and 6
8 RANDOMIZED-CONTROLLED-
TRIAL ME
9 RANDOM
10 8 or 9
11 7 and 10
W H A T rsquo S N E W
Last assessed as up-to-date 8 February 2010
18 September 2009 New citation required but conclusions have not
changed
This review is an updated version of a review that was
published for the first time in Issue 3 2005 of TheCochrane Library by Chen 2003b
18 September 2009 New search has been performed No new studies fulfilled the inclusion criteria
H I S T O R Y
Protocol first published Issue 3 2003
Review first published Issue 3 2005
C O N T R I B U T I O N S O F A U T H O R S
GP and VG independently performed searches of relevant databases GP validated the search selected trials for inclusion contacted
the authors of the trials performed data extraction and data analysis and drafted the systematic review VG revised the review update
CG and DS revised the review update solved discrepancies of data extraction validated data analyses and provided consultation
D E C L A R A T I O N S O F I N T E R E S T
None known
48Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
S O U R C E S O F S U P P O R T
Internal sources
bull Copenhagen Trial Unit Denmark
External sources
bull Danish Medical Research Councilrsquos Grant on Getting Research into Practice (GRIP) Denmark
D I F F E R E N C E S B E T W E E N P R O T O C O L A N D R E V I E W
We assessed the risk of bias in the included studies for another four domains that were added to the review protocol (incomplete
outcome data selective outcome reporting baseline imbalance and early stopping of trial) In general the text of the risk of bias
domains were updated following Higgins 2008 Trials were considered at low risk of bias when judged as adequate in all domains
Quasi-randomised studies observational and case-control studies were included for the report of adverse events
We performed trial sequential analysis for outcomes demonstrating a statistically significant result
I N D E X T E R M S
Medical Subject Headings (MeSH)
lowastLiver Transplantation Cholagogues and Choleretics [lowasttherapeutic use] Graft Rejection [lowastprevention amp control] Randomized Con-
trolled Trials as Topic Taurochenodeoxycholic Acid [lowasttherapeutic use] Ursodeoxycholic Acid [lowasttherapeutic use]
MeSH check words
Humans
49Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
Analysis 114 Comparison 1 Bile acids for liver-transplanted patients Outcome 14 Adverse events
Review Bile acids for liver-transplanted patients
Comparison 1 Bile acids for liver-transplanted patients
Outcome 14 Adverse events
Study or subgroup Bile acids Placebo Risk Ratio Risk Ratio
nN nN M-HFixed95 CI M-HFixed95 CI
Angelico 1999 016 017 00 [ 00 00 ]
Barnes 1997 128 124 086 [ 006 1298 ]
Keiding 1997 554 548 089 [ 027 288 ]
Total (95 CI) 98 89 088 [ 030 260 ]
Total events 6 (Bile acids) 6 (Placebo)
Heterogeneity Chi2 = 000 df = 1 (P = 098) I2 =00
Test for overall effect Z = 022 (P = 082)
001 01 1 10 100
Favours bile acids Favours placebo
A P P E N D I C E S
Appendix 1 Search strategies
Data Base Date of Search Search Strategy
The Cochrane Hepato-Biliary Group Con-
trolled Trials Register
September 2009 1 rsquoliver transplantationrsquo and rsquochenodeoxy-
cholicrsquo
2 rsquoliver transplantationrsquo and rsquocholicrsquo
3 rsquoliver transplantationrsquo and rsquodeoxycholicrsquo
4 rsquoliver transplantationrsquo and rsquoglycochen-
odeoxycholicrsquo
5 rsquoliver transplantationrsquo and rsquoglycocholicrsquo
6 rsquoliver transplantationrsquo and rsquoglycodeoxy-
cholicrsquo
7 rsquoliver transplantationrsquo and rsquoglycolitho-
cholicrsquo
8 rsquoliver transplantationrsquo and rsquohyodeoxy-
cholicrsquo
9 rsquoliver transplantationrsquo and rsquolithocholicrsquo
10 rsquoliver transplantationrsquo and rsquotaurochen-
odeoxycholicrsquo
44Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
11 rsquoliver transplantationrsquo and rsquotauro-
cholicrsquo
12 rsquoliver transplantationrsquo and rsquotaurodehy-
drocholicrsquo
13 rsquoliver transplantationrsquo and rsquotau-
rodeoxycholicrsquo
14 rsquoliver transplantationrsquo and rsquotauroglyco-
cholicrsquo
15 rsquoliver transplantationrsquo and rsquotaurolitho-
cholicrsquo
16 rsquoliver transplantationrsquo and rsquotaurosel-
cholicrsquo
17 rsquoliver transplantationrsquo and rsquotaurourso-
cholicrsquo
18 rsquoliver transplantationrsquo and rsquotaurour-
sodeoxycholicrsquo
19 rsquoliver transplantationrsquo and rsquoursocholicrsquo
20 rsquoliver transplantationrsquo and rsquoursodeoxy-
cholicrsquo
The Cochrane Central Register of Con-
trolled Trials in The Cochrane Library
Issue 3 2009 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
6 3 or 4
7 5 and 6
MEDLINE September 2009 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
45Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
6 3 or 4
7 5 and 6
8 RANDOMIZED-CONTROLLED-
TRIAL ME
9 RANDOM
10 8 or 9
11 7 and 10
EMBASE September 2009 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
6 3 or 4
7 5 and 6
8 RANDOMIZED-CONTROLLED-
TRIAL ME
9 RANDOM
10 8 or 9
11 7 and 10
46Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
Science Citation Index Expanded September 2009 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
6 3 or 4
7 5 and 6
8 RANDOMIZED-CONTROLLED-
TRIAL ME
9 RANDOM
10 8 or 9
11 7 and 10
The Chinese Biomedical Database Searched from January 1980 to April 2002 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
47Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
6 3 or 4
7 5 and 6
8 RANDOMIZED-CONTROLLED-
TRIAL ME
9 RANDOM
10 8 or 9
11 7 and 10
W H A T rsquo S N E W
Last assessed as up-to-date 8 February 2010
18 September 2009 New citation required but conclusions have not
changed
This review is an updated version of a review that was
published for the first time in Issue 3 2005 of TheCochrane Library by Chen 2003b
18 September 2009 New search has been performed No new studies fulfilled the inclusion criteria
H I S T O R Y
Protocol first published Issue 3 2003
Review first published Issue 3 2005
C O N T R I B U T I O N S O F A U T H O R S
GP and VG independently performed searches of relevant databases GP validated the search selected trials for inclusion contacted
the authors of the trials performed data extraction and data analysis and drafted the systematic review VG revised the review update
CG and DS revised the review update solved discrepancies of data extraction validated data analyses and provided consultation
D E C L A R A T I O N S O F I N T E R E S T
None known
48Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
S O U R C E S O F S U P P O R T
Internal sources
bull Copenhagen Trial Unit Denmark
External sources
bull Danish Medical Research Councilrsquos Grant on Getting Research into Practice (GRIP) Denmark
D I F F E R E N C E S B E T W E E N P R O T O C O L A N D R E V I E W
We assessed the risk of bias in the included studies for another four domains that were added to the review protocol (incomplete
outcome data selective outcome reporting baseline imbalance and early stopping of trial) In general the text of the risk of bias
domains were updated following Higgins 2008 Trials were considered at low risk of bias when judged as adequate in all domains
Quasi-randomised studies observational and case-control studies were included for the report of adverse events
We performed trial sequential analysis for outcomes demonstrating a statistically significant result
I N D E X T E R M S
Medical Subject Headings (MeSH)
lowastLiver Transplantation Cholagogues and Choleretics [lowasttherapeutic use] Graft Rejection [lowastprevention amp control] Randomized Con-
trolled Trials as Topic Taurochenodeoxycholic Acid [lowasttherapeutic use] Ursodeoxycholic Acid [lowasttherapeutic use]
MeSH check words
Humans
49Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
11 rsquoliver transplantationrsquo and rsquotauro-
cholicrsquo
12 rsquoliver transplantationrsquo and rsquotaurodehy-
drocholicrsquo
13 rsquoliver transplantationrsquo and rsquotau-
rodeoxycholicrsquo
14 rsquoliver transplantationrsquo and rsquotauroglyco-
cholicrsquo
15 rsquoliver transplantationrsquo and rsquotaurolitho-
cholicrsquo
16 rsquoliver transplantationrsquo and rsquotaurosel-
cholicrsquo
17 rsquoliver transplantationrsquo and rsquotaurourso-
cholicrsquo
18 rsquoliver transplantationrsquo and rsquotaurour-
sodeoxycholicrsquo
19 rsquoliver transplantationrsquo and rsquoursocholicrsquo
20 rsquoliver transplantationrsquo and rsquoursodeoxy-
cholicrsquo
The Cochrane Central Register of Con-
trolled Trials in The Cochrane Library
Issue 3 2009 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
6 3 or 4
7 5 and 6
MEDLINE September 2009 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
45Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
6 3 or 4
7 5 and 6
8 RANDOMIZED-CONTROLLED-
TRIAL ME
9 RANDOM
10 8 or 9
11 7 and 10
EMBASE September 2009 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
6 3 or 4
7 5 and 6
8 RANDOMIZED-CONTROLLED-
TRIAL ME
9 RANDOM
10 8 or 9
11 7 and 10
46Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
Science Citation Index Expanded September 2009 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
6 3 or 4
7 5 and 6
8 RANDOMIZED-CONTROLLED-
TRIAL ME
9 RANDOM
10 8 or 9
11 7 and 10
The Chinese Biomedical Database Searched from January 1980 to April 2002 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
47Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
6 3 or 4
7 5 and 6
8 RANDOMIZED-CONTROLLED-
TRIAL ME
9 RANDOM
10 8 or 9
11 7 and 10
W H A T rsquo S N E W
Last assessed as up-to-date 8 February 2010
18 September 2009 New citation required but conclusions have not
changed
This review is an updated version of a review that was
published for the first time in Issue 3 2005 of TheCochrane Library by Chen 2003b
18 September 2009 New search has been performed No new studies fulfilled the inclusion criteria
H I S T O R Y
Protocol first published Issue 3 2003
Review first published Issue 3 2005
C O N T R I B U T I O N S O F A U T H O R S
GP and VG independently performed searches of relevant databases GP validated the search selected trials for inclusion contacted
the authors of the trials performed data extraction and data analysis and drafted the systematic review VG revised the review update
CG and DS revised the review update solved discrepancies of data extraction validated data analyses and provided consultation
D E C L A R A T I O N S O F I N T E R E S T
None known
48Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
S O U R C E S O F S U P P O R T
Internal sources
bull Copenhagen Trial Unit Denmark
External sources
bull Danish Medical Research Councilrsquos Grant on Getting Research into Practice (GRIP) Denmark
D I F F E R E N C E S B E T W E E N P R O T O C O L A N D R E V I E W
We assessed the risk of bias in the included studies for another four domains that were added to the review protocol (incomplete
outcome data selective outcome reporting baseline imbalance and early stopping of trial) In general the text of the risk of bias
domains were updated following Higgins 2008 Trials were considered at low risk of bias when judged as adequate in all domains
Quasi-randomised studies observational and case-control studies were included for the report of adverse events
We performed trial sequential analysis for outcomes demonstrating a statistically significant result
I N D E X T E R M S
Medical Subject Headings (MeSH)
lowastLiver Transplantation Cholagogues and Choleretics [lowasttherapeutic use] Graft Rejection [lowastprevention amp control] Randomized Con-
trolled Trials as Topic Taurochenodeoxycholic Acid [lowasttherapeutic use] Ursodeoxycholic Acid [lowasttherapeutic use]
MeSH check words
Humans
49Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
6 3 or 4
7 5 and 6
8 RANDOMIZED-CONTROLLED-
TRIAL ME
9 RANDOM
10 8 or 9
11 7 and 10
EMBASE September 2009 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
6 3 or 4
7 5 and 6
8 RANDOMIZED-CONTROLLED-
TRIAL ME
9 RANDOM
10 8 or 9
11 7 and 10
46Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
Science Citation Index Expanded September 2009 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
6 3 or 4
7 5 and 6
8 RANDOMIZED-CONTROLLED-
TRIAL ME
9 RANDOM
10 8 or 9
11 7 and 10
The Chinese Biomedical Database Searched from January 1980 to April 2002 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
47Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
6 3 or 4
7 5 and 6
8 RANDOMIZED-CONTROLLED-
TRIAL ME
9 RANDOM
10 8 or 9
11 7 and 10
W H A T rsquo S N E W
Last assessed as up-to-date 8 February 2010
18 September 2009 New citation required but conclusions have not
changed
This review is an updated version of a review that was
published for the first time in Issue 3 2005 of TheCochrane Library by Chen 2003b
18 September 2009 New search has been performed No new studies fulfilled the inclusion criteria
H I S T O R Y
Protocol first published Issue 3 2003
Review first published Issue 3 2005
C O N T R I B U T I O N S O F A U T H O R S
GP and VG independently performed searches of relevant databases GP validated the search selected trials for inclusion contacted
the authors of the trials performed data extraction and data analysis and drafted the systematic review VG revised the review update
CG and DS revised the review update solved discrepancies of data extraction validated data analyses and provided consultation
D E C L A R A T I O N S O F I N T E R E S T
None known
48Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
S O U R C E S O F S U P P O R T
Internal sources
bull Copenhagen Trial Unit Denmark
External sources
bull Danish Medical Research Councilrsquos Grant on Getting Research into Practice (GRIP) Denmark
D I F F E R E N C E S B E T W E E N P R O T O C O L A N D R E V I E W
We assessed the risk of bias in the included studies for another four domains that were added to the review protocol (incomplete
outcome data selective outcome reporting baseline imbalance and early stopping of trial) In general the text of the risk of bias
domains were updated following Higgins 2008 Trials were considered at low risk of bias when judged as adequate in all domains
Quasi-randomised studies observational and case-control studies were included for the report of adverse events
We performed trial sequential analysis for outcomes demonstrating a statistically significant result
I N D E X T E R M S
Medical Subject Headings (MeSH)
lowastLiver Transplantation Cholagogues and Choleretics [lowasttherapeutic use] Graft Rejection [lowastprevention amp control] Randomized Con-
trolled Trials as Topic Taurochenodeoxycholic Acid [lowasttherapeutic use] Ursodeoxycholic Acid [lowasttherapeutic use]
MeSH check words
Humans
49Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
Science Citation Index Expanded September 2009 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
6 3 or 4
7 5 and 6
8 RANDOMIZED-CONTROLLED-
TRIAL ME
9 RANDOM
10 8 or 9
11 7 and 10
The Chinese Biomedical Database Searched from January 1980 to April 2002 1 LIVER-TRANSPLANTATION
ME
2 LIVER AND TRANSPLANTATION
3 BILE ACID ME
4
CHENODEOXYCHOLIC or CHOLIC
or DEOXYCHOLIC or GLYCOCHEN-
ODEOXYCHOLIC or GLYCOCHOLIC
or GLYCODEOXYCHOLIC or GLY-
COLITHOCHOLIC or HYODEOXY-
CHOLIC or LITHOCHOLIC or TAU-
ROCHENODEOXYCHOLIC or TAU-
ROCHOLIC or TAURODEHYDRO-
CHOLIC or TAURODEOXYCHOLIC
or TAUROGLYCOCHOLIC or TAU-
ROLITHOCHOLIC or TAUROSEL-
CHOLIC or TAUROURSOCHOLIC or
TAUROURSODEOXYCHOLIC or UR-
SOCHOLIC or URSODEOXYCHOLIC
5 1 or 2
47Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
6 3 or 4
7 5 and 6
8 RANDOMIZED-CONTROLLED-
TRIAL ME
9 RANDOM
10 8 or 9
11 7 and 10
W H A T rsquo S N E W
Last assessed as up-to-date 8 February 2010
18 September 2009 New citation required but conclusions have not
changed
This review is an updated version of a review that was
published for the first time in Issue 3 2005 of TheCochrane Library by Chen 2003b
18 September 2009 New search has been performed No new studies fulfilled the inclusion criteria
H I S T O R Y
Protocol first published Issue 3 2003
Review first published Issue 3 2005
C O N T R I B U T I O N S O F A U T H O R S
GP and VG independently performed searches of relevant databases GP validated the search selected trials for inclusion contacted
the authors of the trials performed data extraction and data analysis and drafted the systematic review VG revised the review update
CG and DS revised the review update solved discrepancies of data extraction validated data analyses and provided consultation
D E C L A R A T I O N S O F I N T E R E S T
None known
48Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
S O U R C E S O F S U P P O R T
Internal sources
bull Copenhagen Trial Unit Denmark
External sources
bull Danish Medical Research Councilrsquos Grant on Getting Research into Practice (GRIP) Denmark
D I F F E R E N C E S B E T W E E N P R O T O C O L A N D R E V I E W
We assessed the risk of bias in the included studies for another four domains that were added to the review protocol (incomplete
outcome data selective outcome reporting baseline imbalance and early stopping of trial) In general the text of the risk of bias
domains were updated following Higgins 2008 Trials were considered at low risk of bias when judged as adequate in all domains
Quasi-randomised studies observational and case-control studies were included for the report of adverse events
We performed trial sequential analysis for outcomes demonstrating a statistically significant result
I N D E X T E R M S
Medical Subject Headings (MeSH)
lowastLiver Transplantation Cholagogues and Choleretics [lowasttherapeutic use] Graft Rejection [lowastprevention amp control] Randomized Con-
trolled Trials as Topic Taurochenodeoxycholic Acid [lowasttherapeutic use] Ursodeoxycholic Acid [lowasttherapeutic use]
MeSH check words
Humans
49Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
(Continued)
6 3 or 4
7 5 and 6
8 RANDOMIZED-CONTROLLED-
TRIAL ME
9 RANDOM
10 8 or 9
11 7 and 10
W H A T rsquo S N E W
Last assessed as up-to-date 8 February 2010
18 September 2009 New citation required but conclusions have not
changed
This review is an updated version of a review that was
published for the first time in Issue 3 2005 of TheCochrane Library by Chen 2003b
18 September 2009 New search has been performed No new studies fulfilled the inclusion criteria
H I S T O R Y
Protocol first published Issue 3 2003
Review first published Issue 3 2005
C O N T R I B U T I O N S O F A U T H O R S
GP and VG independently performed searches of relevant databases GP validated the search selected trials for inclusion contacted
the authors of the trials performed data extraction and data analysis and drafted the systematic review VG revised the review update
CG and DS revised the review update solved discrepancies of data extraction validated data analyses and provided consultation
D E C L A R A T I O N S O F I N T E R E S T
None known
48Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
S O U R C E S O F S U P P O R T
Internal sources
bull Copenhagen Trial Unit Denmark
External sources
bull Danish Medical Research Councilrsquos Grant on Getting Research into Practice (GRIP) Denmark
D I F F E R E N C E S B E T W E E N P R O T O C O L A N D R E V I E W
We assessed the risk of bias in the included studies for another four domains that were added to the review protocol (incomplete
outcome data selective outcome reporting baseline imbalance and early stopping of trial) In general the text of the risk of bias
domains were updated following Higgins 2008 Trials were considered at low risk of bias when judged as adequate in all domains
Quasi-randomised studies observational and case-control studies were included for the report of adverse events
We performed trial sequential analysis for outcomes demonstrating a statistically significant result
I N D E X T E R M S
Medical Subject Headings (MeSH)
lowastLiver Transplantation Cholagogues and Choleretics [lowasttherapeutic use] Graft Rejection [lowastprevention amp control] Randomized Con-
trolled Trials as Topic Taurochenodeoxycholic Acid [lowasttherapeutic use] Ursodeoxycholic Acid [lowasttherapeutic use]
MeSH check words
Humans
49Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd
S O U R C E S O F S U P P O R T
Internal sources
bull Copenhagen Trial Unit Denmark
External sources
bull Danish Medical Research Councilrsquos Grant on Getting Research into Practice (GRIP) Denmark
D I F F E R E N C E S B E T W E E N P R O T O C O L A N D R E V I E W
We assessed the risk of bias in the included studies for another four domains that were added to the review protocol (incomplete
outcome data selective outcome reporting baseline imbalance and early stopping of trial) In general the text of the risk of bias
domains were updated following Higgins 2008 Trials were considered at low risk of bias when judged as adequate in all domains
Quasi-randomised studies observational and case-control studies were included for the report of adverse events
We performed trial sequential analysis for outcomes demonstrating a statistically significant result
I N D E X T E R M S
Medical Subject Headings (MeSH)
lowastLiver Transplantation Cholagogues and Choleretics [lowasttherapeutic use] Graft Rejection [lowastprevention amp control] Randomized Con-
trolled Trials as Topic Taurochenodeoxycholic Acid [lowasttherapeutic use] Ursodeoxycholic Acid [lowasttherapeutic use]
MeSH check words
Humans
49Bile acids for liver-transplanted patients (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd