Accepted Manuscript
Carvedilol versus Esophageal Variceal Band Ligation in the primary prophy-laxis of variceal hemorrhage: A multicentre randomized controlled trial
Hasnain Ali Shah, Zahid Azam, Javeria Rauf, Shahab Abid, Saeed Hamid,Wasim Jafri, Abdullah Khalid, Faisal Ismail, Om Parkash, Amna Subhan, SyedMohammad Munir
PII: S0168-8278(13)00820-9DOI: http://dx.doi.org/10.1016/j.jhep.2013.11.019Reference: JHEPAT 4945
To appear in: Journal of Hepatology
Received Date: 19 July 2013Revised Date: 19 November 2013Accepted Date: 20 November 2013
Please cite this article as: Ali Shah, H., Azam, Z., Rauf, J., Abid, S., Hamid, S., Jafri, W., Khalid, A., Ismail, F.,Parkash, O., Subhan, A., Mohammad Munir, S., Carvedilol versus Esophageal Variceal Band Ligation in the primaryprophylaxis of variceal hemorrhage: A multicentre randomized controlled trial, Journal of Hepatology (2013), doi:http://dx.doi.org/10.1016/j.jhep.2013.11.019
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1
Carvedilol versus Esophageal Variceal Band Ligation in the primary prophylaxis
of variceal hemorrhage: A multicentre randomized controlled trial
Hasnain Ali Shah1, Zahid Azam2, Javeria Rauf1, Shahab Abid1, Saeed Hamid1, Wasim
Jafri1, Abdullah Khalid2, Faisal Ismail1, Om Parkash1, Amna Subhan1, , Syed
Mohammad Munir3.
1Section of Gastroenterology, Aga Khan University, Karachi, Pakistan, 2National
Institute of Liver & GI Diseases, Dow University of Health Sciences, Karachi, Pakistan,
3Medical Unit VII, Jinnah Postgraduate Medical Centre, Karachi, Pakistan
(ClinicalTrials.gov identifier: NCT 01070641)
Corresponding author:
Prof. Hasnain Ali Shah
MD (Edin.); FRCP; FACG
Section of Gastroenterology, Department of Medicine, Aga Khan University, Karachi,
Pakistan.
Email: [email protected]
Tel no: +92-213-4864676 Fax no: +92-213-4934294
Number of figures: 3
Number of tables: 5
2
List of abbreviations:
EVL, Esophageal Variceal Ligation; EVB, Esophageal variceal bleed; HCV, Hepatitis C
Virus;HBV, Hepatitis B virus; HDV, Hepatitis Delta virus; PVT, Portal vein Thrombosis;
HCC, Hepatocellular Carcinoma; GCP, Good Clinical Practice; E.R, Emergency Room;
GV, Gastric varix; EV, Esophageal varix; EKG, Electrocardiogram; BCU, Bleeding Care
Unit; Hb, Hemoglobin; ITT, Intention to treat; CI, Confidence Interval; IHD, Ischemic
heart disease; HVPG, Hepatic venous pressure gradient; EGD, Esophago-gastro-
duodenoscopy; TIPS, Transjugular intrahepatic portosystemic shunt; PSE, Porto-
systemic encephalopathy.
CONFLICT OF INTEREST/STUDY SUPPORT:
Disclosures/Conflict of Interest:
• No author has to declare any conflict of interest in relation to this publication.
• The statistical analysis of the entire data sets pertaining to efficacy and safety have
been independently confirmed by a biostatistician who is not employed by the corporate
entity
• The corresponding author had full access to all of the data and takes full responsibility
for the veracity of the data and analysis.
Guarantor of the article: Ethics Review Committee and Professor Hasnain Ali Shah
(Corresponding author), Prof. of Medicine, Section of Gastroenterology, Aga Khan
University.
3
Specific author contributions: Hasnain Ali Shah and Zahid Azam contributed in terms
of original idea, study design, writing protocol, organizing logistics and funding, and
editing the article. Hasnain Ali Shah additionally contributed in statistical analysis and
review and submission of the final manuscript. Javeria Rauf contributed in CRF, data
entry and patient follow up. Shahab Abid, Wasim Jafri and Saeed Hamid contributed to
study design, logistics, caring for patients under study and editing the article. Faisal
Wasim, Amna Subhan and Om Parkash coordination between various departments,
literature search, writing of the article with 1st author. Abdullah Khalid and Syed
Muhammad Munir contributed in study design, care of study patients at their respective
centers and editing of the article.
Grant Support/Acknowledgements: The research team acknowledges the un-
conditional support of Ferozsons Laboratories (BF Bio-Sciences), Pakistan to support
this investigator initiated clinical trial in terms of bearing the cost of Carvedilol (Carvida),
clinical research associate honorarium and pharmacy charges for generation of
randomization sequence & dispensing of investigational products. The study was an
investigator initiated clinical trial and the protocol was written by the investigators and
the study was performed by the research team. The study sponsor (BF Biosciences/
Ferozsons Laboratories, Pakistan) had no role in the study design, in the collection,
analysis, and interpretation of date.
4
Writing Assistance:
The authors took no assistance of professional medical writers. The manuscript was
written and approved by all the authors and requirements for authorship were met, and
each author believes that the manuscript represents honest work.
5
Introduction:
Variceal bleed is a dreaded complication of portal hypertension and screening
endoscopy for varices is recommended in cirrhotic patients. Varices develop at the rate
of 5% per year and one third will bleed [1]. Nonselective ß-blockers (Propranolol or
Nadolol) reduce portal pressure by decreasing cardiac output (ß-1 effect) and, more
importantly, by producing splanchnic vasoconstriction (ß-2 effect), thereby reducing
portal blood flow. A decrease in Hepatic Venous Pressure Gradient (HVPG) < 12 mmHg
essentially eliminates the risk of hemorrhage and improves survival [2], while reductions
<20% from baseline [3] or even <10% from baseline [4] significantly decrease the risk of
first variceal hemorrhage. Endoscopic Variceal Band Ligation (EVL) is another modality
of treatment of esophageal varices and meta-analysis showed EVL to be associated
with significantly lower incidence of first variceal hemorrhage without differences in
mortality compared to β blockers [5]. Although the EVL group has a significantly lower
rate of adverse events, the EVL events are more severe and include bleeding from
ligation-induced esophageal ulcers [6].
Carvedilol possesses both non-selective β1/2-antagonist and α1-receptor antagonist
activity [7]. It has a greater potential for lowering portal pressure than propranolol due to
its dual action [8, 9]. A fall in both intrahepatic and porto-collateral resistance contributes
to the enhanced effects on portal pressure reduction through blockade of alpha-1
receptors as has been shown with Prazosin [10]. A reduction in HVPG of 8%-43% has
been observed with carvedilol in published hemodynamic studies [11-16]. Carvedilol
6
was also found to have a greater portal hypotensive effect than propranolol in
randomized controlled hemodynamic studies [11,12, 15,].
There is scanty data in the literature comparing carvedilol and EVL in the primary
prophylaxis of variceal hemorrhage [17]. Our study was aimed at comparing the efficacy
of carvedilol with EVL for primary prophylaxis of variceal bleed and mortality in patients
suffering from post-viral cirrhosis and portal hypertension.
Methods:
Study design and settings: This investigator initiated multicenter randomized
controlled trial was conducted in three tertiary care hospitals in Karachi, Pakistan
(Section of Gastroenterology, Department of Medicine, Aga Khan University; National
Institute of Liver & Gastrointestinal Diseases, Dow University of Health Sciences and
Medical ward VII of Jinnah Post Graduate Medical Center). Enrollment of patients into
the study was done between May 2007 and September 2011. Approval of the
Institutional Review Boards of each of the institution was taken prior to initiation of the
trial. Written informed consent from each subject was taken in accordance with the
Declaration of Helsinki. The study was conducted following the Good Clinical Practice
(GCP) guidelines. An independent data safety monitoring board monitored the trial and
had access to data. Study protocol was registered at www.clinicaltrials.gov
(ClinicalTrials.gov identifier: NCT 01070641).
7
Patient Selection: Patients with cirrhosis without history of variceal bleed, who were
booked for screening endoscopy for varices, were the study population. We included
male and female patients between 18- 75 years of age, who had medium or large sized
esophageal varices (Grade II-IV) [18] . The diagnosis of cirrhosis was made on the
basis of clinical, radiological, biochemical features and liver histology where available.
We excluded patients who were pregnant or lactating, had allergy to Carvedilol or
reactive airway disease, already on Beta adrenoceptor blocker treatment, presence of
any hepatic or other malignancy which could impair longevity of life or presence of
severe systemic illness which could impair the subject’s ability to participate in the trial,
psychiatric or mentally handicapped people that would prevent taking informed consent
and refusal to give consent. We also excluded patients who had gastric varices alone.
Randomization and study treatment:
Study subjects fulfilling the enrolment criteria after screening endoscopy for varices and
having signed the informed consent were randomized to receive either Carvedilol or
EVL. Randomization was done following screening endoscopy with 1:1 simple
randomization, centrally. Each of the three study sites were provided with the serially
labeled sealed opaque envelopes containing treatment assignment information. These
envelopes were opened in a consecutive manner to receive either Carvedilol or EVL
depending on the randomization assignment.
8
Patients who were randomized for EVL underwent the procedure within 48 hours of
randomization using Saeed Six Shooter Multi-Band Ligator® (Wilson-Cook Medical,
North Carolina, USA) attached to a video endoscope (Olympus GIF H-180, Tokyo,
Japan). Attending gastroenterologists with at least 5 years experience performed all
EVL procedures. This was subsequently repeated every three weeks until obliteration of
varices was achieved. Obliteration of varices was defined as no varices or only small
varices (varices which were small and flattened on air insufflations). Subsequent
endoscopy sessions were done at intervals of 6 months. If varices recurred on
surveillance Esophagogastroduodenoscopy (EGD), the protocol for eradication of
varices as described above was repeated.
Patients randomized to Carvedilol arm were given Carvedilol (Carvida®, manufactured
by Ferozsons laboratories, Pakistan) in an initial dose of 6.25 mg once a day which was
increased to 6.25 twice a day after an interval of 1 week. This dose is generally well
tolerated in cirrhotics and has been used in other studies [13]. Higher doses are likely to
produce symptomatic hypotension and thus impair tolerability. Side effects and adverse
reactions for each treatment arm were also recorded.
Follow up: The initial visit after introduction of carvedilol was at 2 weeks, followed by
one at 6 weeks and then at 3 monthly intervals in both arms of treatment. Clinical
examination was carried out at each visit. Hematological and biochemical parameters
were obtained on each visit. Abdominal ultrasound for hepatoma surveillance was done
at six months intervals. Compliance to carvedilol was confirmed by interviewing the
9
patient and the family. Blood pressure and peripheral pulse response also guided
towards patient compliance with carvedilol.
Patients were considered to have achieved end points on ITT if they bled, died, were
lost to follow up, underwent liver transplantation or transjugular intrahepatic
portosystemic shunt (TIPS) placement.
End Points and Outcomes: The primary end point was variceal bleed defined as overt
hemetemesis and/or melena with endoscopic evidence of variceal bleeding or signs of
recent bleed and at least 2 g/dl drop in hemoglobin within 24 hours of admission
Baveno IV [18]. Bleeding was managed by standard measures using transfusion of
blood/blood products, vasoactive drugs (Terlipressin/ Octreotide), antibiotics and
endoscopic means (EVL or sclerotherapy).
Secondary end-points included overall and bleed related mortality defined as death
within 6 weeks of index bleed [18].
Statistical analysis: A total of 77 patients were required in each arm of the trial in order
to achieve 80% power at 5% level of significance. We assumed that carvedilol will be
more effective than EVL with a bleeding rate of 5% in the carvedilol group and 20% in
the EVL group at 24 months. The figure for EVL arm was derived from a published
study [20]. Sample size was inflated by 10% for dropout (lost to follow up) or consent
10
withdrawal. No interim analysis was planned or performed. Mean ±Standard Deviation
for age, child’s score and laboratory characteristics was used for the two study groups
and any differences in the groups were analyzed using an unpaired Student t test.
Frequencies (%) for gender, ultrasound characteristics and etiology of cirrhosis were
presented. Non-parametric data were analyzed using the chi-squared test. Cumulative
bleeding and survival were expressed using the Kaplan-Meier method and the
differences assessed using the log-rank test. Cox proportional hazard ratio was used to
assess variables predicting end points. Intension to analysis was used. Variables with
p< 0.05 following univariate analysis were entered into multivariate analysis. SPSS
(version 19, Chicago, IL) statistical package was used for analysis.
Results:
A total of 209 patients undergoing screening EGD for varices were evaluated and out of
them a total of 168 patients were enrolled into the study. Forty one patients were
excluded due to refusal to give consent or not meeting enrolment criteria. Following
endoscopy, 82 and 86 patients were randomized to receive either Carvedilol or EVL
respectively. The two arms of the study are elaborated in figure 1. The base line
characteristics were comparable in the two arms. Although there were more patients
randomized to EVL arm with large esophageal varices compared to carvedilol arm, this
difference was not statistically different. Ten patients (12.2% and 11.6% respectively) in
each arm of the study had history of Porto-systemic encephalopathy (PSE) stage I of
West Haven criteria in the past. However, they had no PSE at the time of enrolment.
(Table 1).
11
Etiology of viral cirrhosis was predominantly HCV related. However, 14 (17%) patients
in carvedilol arm and 11 (12.7%) in the EVL arm suffered from HBV related liver
disease, either alone or in combination with HCV or HDV infection . Ascites was present
in 33 (40.3%) in carvedilol and 32 (37.6%) patients in EVL arm (Table 1). This was
treated with Spironolactone (50-100 mg)/day with the addition of Frusemide as required.
On treatment, it was observed only in 5(6.1%) and 6(6.9%) patients in the two groups
respectively at six months of follow up. There was no significant net weight gain in
either group of patients on follow up. Carvedilol arm patients weighed 72.8 ±14.5 kg at
enrollment and 73.42±14.4 kg at 6 months (p=0.53), whereas EVL arm patients had a
mean weight of 70.9±15.9 kg which increased to 71.17±13.9 kg (p=0.77) at 6 months.
Moreover on comparison, a net weight gain difference between groups was also not
significant (p=0.76).
Compliance to carvedilol in our study patients was evidenced by lower pulse rates on
follow up compared to start of treatment at enrolment in the study (83.6± 10.01 beats/
min decreasing to 79.5± 8.95 at 6 weeks). There was also a significant drop in blood
pressure in the carvedilol group which was not the case in the banding patients. The
mean systolic blood pressure at baseline was 121.2 ± 14.2 mmHg in the carvedilol arm
which dropped to 110.5 ± 12.9mm Hg after 6 weeks of treatment (p<0.001). This was in
contrast to a mean systolic blood pressure of 118.2 ± 9.8mmHg in the EVL arm at
baseline which did not changed significantly (118 ± 9.5mm Hg) following 6 weeks of
follow up.
12
All patients randomized to EVL received the sessions as per protocol and none of the
patients withdrew consent or dropped out later. Varices were eradicated in 126 (75%)
patients after 2±1 mean number of sessions over 6-8 weeks. The time from
randomization to first EVL session was ≤48 hrs. No recurrence of varices was observed
in any patient following obliteration.
Outcomes:
Variceal bleed and Mortality: A total of 7 (8.5%) patients bled in the Carvedilol
compared to 6 (6.9%) in the EVL treated group including one patient who bled from
banding related esophageal ulcer. This patient was included in the ITT analysis. The
difference in variceal bleed was not statistically different (p=0.61). A subgroup analysis
of HCV cirrhotics (n=60 and 66 in carvedilol and EVL groups respectively) excluding
HBV related cirrhosis revealed no difference in variceal bleed and overall mortality
between groups. Similarly, a subgroup analysis of HBV cirrhotics vs. the rest of the
patients was also carried out. One patient (4%) in the HBV cirrhosis group had variceal
bleed on follow up compared to 4 (2.8%) in the rest (p=0.75). Eight (32%) patients in the
HBV subgroup died compared to 19 (13.5%) in the rest of patients (p=0.02). This points
towards the fact that patients with HBV related liver disease did not have a better
outcome (bleed and mortality) compared to non-B virus related cirrhosis.
The all cause mortality was 16 (19.51%) and 11 (12.79%) in carvedilol and EVL groups
respectively (p=0.23). (Table 2) Four patients died due to variceal bleed in each group
13
(4.8% and 4.6% respectively). The causes of death are summarized in Table 4. Cardiac
causes (Ischemia, arrhythmias and infarction leading to death) were secondary to
sepsis and metabolic derangements due to liver failure in 4 patients in carvedilol and 2
in the EVL group who were classified as having died of cardiac causes on death
certificates issued by the treating physicians.
We applied the crude hazard ratio to test for different variables as predictors of
outcome in our study population. Keeping EVL, age >45 years, male gender, viral
etiology, gastric varices and medium sized varices as reference, a number of variables
were tested. We found no significant difference on univariate analysis, except for
gender and serum albumin in overall mortality which did not lose its significance on
multivariate analysis (Table 3).
Side effects on follow up:
Carvedilol arm: Patients tolerated the drug well except for 2 patients who developed
symptomatic hypotension and were subsequently offered band ligation. These were
considered serious adverse events. Side effects such as transient dyspnea (n=30) and
nausea in (n=18) were not severe enough for patients to require specific therapy or
discontinue treatment.
EVL arm: None of the patients bled from gastric varices but 1 patient bled from banding
induced esophageal ulcer which was not fatal. This was treated with Terlipressin,
14
Omeprazole and Sucralfate. This patient was considered treatment failure on ITT and
the complication was classified as serious adverse event. Non-significant transient post
EVL dysphagia was experienced in n=58 (68%). Mild chest pain was reported after
banding in n=17(20%) of patients but resolved with Sucralfate and Acetaminophen
syrup (Calpol 6-Plus, manufactured by GSK, Pakistan). This was also categorized as a
serious adverse event. The adverse events are presented in Table 5.
Discussion:
The present prospective randomized controlled study presents a comparison of
Carvedilol (a pharmacological therapeutic agent, which has non-selective beta- and
alpha-1 adrenoceptor blocking actions) and EVL in the primary prevention of portal
hypertensive esophageal variceal bleed. We have found carvedilol to be as effective as
EVL for the prevention of first variceal bleed in cirrhotic patients with no difference in
mortality between groups. A meta-analysis of 19 trials comparing propranolol as the
beta blocker showed greater efficacy of EVL in the primary prophylaxis of esophageal
variceal bleed [21]. Carvedilol has been shown from published hemodynamic data to
have a greater portal pressure lowering effect than propranolol [19]. We therefore tested
carvedilol in a clinical study to determine its role in primary prophylaxis of portal
hypertensive variceal bleed. Target dose of 12.5 mg/day was used based on previous
studies [7, 13] and tolerability data from our patient population. The most recent study
by Reiberger et al [19] has shown that increasing the dose above 12.5 mg/day may not
further decrease portal pressure while increasing the risk of arterial hypotension and
15
bradycardia. This study also highlights the facts that carvedilol is effective in a
substantial number of patients who did not achieve a hemodynamic response to
propranolol and that the mean decrease of portal pressure is significantly more
pronounced under carvedilol (19%) than with propranolol (12%).
The results of our study are different from a recently published study from Scotland [17]
in that the rates of variceal bleeding in the carvedilol and EVL groups are similar as
opposed to lower bleeding rates in the carvedilol treated group in the Scottish study.
This could be because of higher variceal eradication rate (75%) in our study compared
to the study by Tripathi et al. The higher variceal eradication rate in the banding arm
may also explain the lower variceal bleeding rates on follow up as compared to that
study. Moreover, contrary to the recent study by Reidberger et al (19), our study
population included more patients with advanced liver disease and ascites. This could
have influenced the difference in results between the two studies.
Two patients on Carvedilol complained of dizziness due to hypotension. These patients
were subsequently offered band ligation and considered failure of treatment.
Unexpectedly, our study has shown a drop in mean systolic blood pressure of the group
treated with Carvedilol without an appreciable decrease in heart rate. We are unable to
explain the lack of correlation between the heart rate and blood pressure response on
Carvedilol treatment in this study EVL group manifested transient dysphagia and chest
pain following the procedure in a proportion of patients. This resolved with Sucralfate
and acid suppressant treatment and did not lead to any drop outs. One patient bled
16
from banding induced ulcer which was not fatal. This was treated with Terlipressin,
Omeprazole and Sucralfate. These can be classified as serious adverse events. The
baseline data of our study population has shown a lower mean platelet count in the EVL
group compared to the carvedilol treated patients. This was however statistically not
significantly different and was unlikely to have affected the bleeding rates. Similarly,
there were a greater proportion of patients with large varices in the banding arm but the
difference did not achieve statistical significance (Table 1).
A total of 6 (6.9%) patients bled in the EVL treated group, out of which 2 patients
(2.32%) bled within six months of enrolment. One patient in the banding arm bled within
one week of the procedure. This bleed was found at endoscopy to be from an ulcer
consequent to banding. (This patient was included in the ITT analysis). This is in
contrast to previous studies where a higher rate of early variceal bleed has been
observed in the EVL group with some being fatal [17]. Variceal bleeding events (fatal
and non-fatal) in our study occurred within the first 12 months of follow up in our
patients. (Table 2, Fig. 2 and 3). In this respect, our data is in agreement with that of
previously published data by Sarin et al [20] and Tripathi et al [17] who compared β-
blocker (propranolol) and carvedilol therapy respectively with EVL in primary
prophylaxis of variceal bleed in high risk varices. The reason for paucity of further
bleeding events after the first 12 months of follow up in our study is better Child Pugh
grade in survivors beyond 12 months who had low risk of bleeding and mortality.
17
HBV related cirrhosis was present in 14(17.1%) patients in Carvedilol group and 11
(12.8%) patients in EVL group. This is a relatively small number of patients compared to
the total number of patients and also comparable in the two groups. We do not have
information regarding treatment of HBV infection in these patients which, if successful
could have lowered the portal pressure. This could be considered as a potential
limitation of the study, however considering the comparable and relatively small number
in the two subgroups of patients, this is unlikely to have affected the results comparing
treatment outcomes. We have also carried out subgroup analysis of HCV related
cirrhosis patients and found that variceal bleed and mortality are comparable (p=0.50
and 0.33 respectively) for these two outcomes. Similarly, analysis of outcomes between
HBV and non-HBV related cirrhosis did not reveal difference in variceal bleed but worse
outcome in mortality in the former group on follow up.
The vast majority of our patients (n=126; 75%) have HCV disease. They presented late
in the course of illness, (n=94; 56%) with Child’s grade B/C and a significant number
had ascites. Anti-viral treatment for HCV disease is contra-indicated in these patients.
Hence, the results of our study cannot be extrapolated to situations where patients
present early in the course of their illness and anti-viral therapy is likely to influence
portal pressures.
There are reports in the literature of weight gain and worsening ascites due to sodium
retention on carvedilol treatment. However, our patients failed to show either of these on
18
follow up. This is similar to the findings of Tripathi et al (17). There was also no
significant difference in mean weight change between groups on follow up, in our
patients which signifies lack of negative effect on sodium retention by carvedilol
treatment.
Lack of invasive haemodynamic data like HVPG measurements could be considered as
another potential limitation of our study. However, since carvedilol has been shown in
previous studies [11] to have a significantly more pronounced effect in lowering HVPG
compared to the established ß blocker (propranolol), it could be argued that it was not
necessary in a clinical study like ours to measure HVPG and other hemodynamics
invasively which is not possible in the vast majority of medical centers in
underdeveloped countries like Pakistan.
The sample size calculation was based on a relative difference in variceal bleed rate.
We assumed that carvedilol will be more effective than EVL with a bleeding rate of 5%
in the carvedilol group and 20% in the EVL group at 24 months. The figure for EVL arm
was derived from a published study on this subject [20]. Another paper published
recently [17] showed this difference as 13%. Our study failed to show any significant
difference in outcomes between groups and hence on post hoc analysis it can be
considered under powered to detect difference in variceal bleed over a 2 year period.
The cost of one year treatment with carvedilol amounts to Pak Rs. 3832/= (US$ 36.50)
compared to Pak Rs. 50000/= approx. (US$ 476/=) for 2 sessions of EVL in Pakistan.
This is a huge difference in cost of treatment and although the outcomes by variceal
19
bleed and bleed related mortality are similar in the two groups, this along with
convenience of administration makes carvedilol the favored modality of treatment from
patients’ perspective.
In conclusion, although our study is underpowered, the findings suggest that carvedilol
is probably not superior to EVL in preventing first variceal bleed in cirrhosis. Given the
safe side effect profile of the medication and the convenience of oral administration
compared to EVL, carvedilol is likely to establish itself more widely as a treatment
modality in primary prophylaxis of variceal bleed in cirrhosis.
20
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Table 1: Baseline characteristics of study population
Characteristics Carvedilol (n=82) EVL (n=86)
Age (years) 48.3± 11.3 47.2 ± 13.2
Male Gender n (%) 59 (72%) 63 (73.3%)
Presence of Ascites n (%) 33 (40.7%) 32 (37.6%)
History of Hepatic encephalopathy* n (%) 10(12.2%) 10(11.6%)
Esophageal varices Size
Medium sized varices n (%)
Large sized varices n (%)
49 (59.8%)
33 (40.2%)
42 (48.8%)
44 (51.2%)
Concomitant Gastric varices n (%) 16 (29.1%) 21 (33.9%)
Portal gastropathy n (%) 50 (86.2%) 56 (78.9%)
Child score 7.4±1.6 7.2±1.5
Child Class
Class A
Class B
Class C
37 (45.1%)
35 (42.7%)
10 (12.2%)
37 (43%)
37 (43%)
12 (14%)
Etiology n (%)
Viral etiology
HCV
HBV
HBV+HCV
HBV+HDV
Alcoholic etiology
Others (cryptogenic + autoimmune)
74(90.2%)
60(73.1%)
8(9.8%)
4(4.9%)
2(2.4%)
0
8(9.8%)
77(89.5%)
66(76.2%)
7 (8.1%) 1 (1.2%) 3 (3.5%) 3(3.5%) 6(7.0%)
Hemoglobin (g/dl) 11.5±2.3 11.43±1.9
Platelets (10x6) 112.3±60.9 96.2±66.9
WBC 9.6±33.1 8.35±14.1
PT (seconds) 19.8±22.9 18.1±17.5
ALT (IU/L) 65.8±49.4 62.9±68.1
BUN ( mg/dl) 16.5±7.6 19.4±16.9
Creatinine (mg/dl) 0.9±.3 1.0±1.0
Albumin (g/dl) 2.9±.79 2.9±.80
Total bilirubin (mg/dl) 2.2±2.6 1.9±1.8
Follow up (months) 13.2±11.7 13.4±12.4
Table 2: Summary of outcomes by study time
Upto 6
months
Upto 12
months
Upto 18
months
Upto 24
months Total
p-
value
Variceal bleed
Carvedilol n (%) 3 (3.6%) 7 (8.5%) 7 (8.5%) 7 (8.5%) 7 (8.5%)
0.61
EVL n (%) 5 (5.8%) 6 (6.9%) 6 (6.9%) 6 (6.9%) 6 (6.9%)
All cause Mortality
Carvedilol n (%) 9 (10.9%) 14 (17.1%) 14 (17.1%) 16 (19.51%) 16 (19.5%)
0.23
EVL n (%) 4 (4.6%) 9 (10.5%) 10 (11.5%) 11 (12.8%) 11 (12.8%)
Table 3: Cox Regression Analysis
First variceal bleed
Variable
Univariate analysis Multivariate analysis
Relative Hazard (95%
Confidence Interval) p-value
Relative Hazard (95% Confidence
Interval) p-value
*First variceal bleed
Treatment (carvedilol) 1.61 (0.27 – 9.69) 0.59 - -
Age (<45 years) 6.03 (0.67 – 54.27) 0.10 - -
Sex (Female) 1.58 (0.26 – 9.52) 0.61 - -
Viral etiology 1.96 (0.21 – 17.56) 0.54 - -
Gastric varices 37.84 (0.00 – 1.50) 0.68 - -
Large sized varices 5.46(0.60-49.13) 0.12 - -
Child score 0.71 (0.37 – 1.34) 0.29 - -
Haemoglobin 0.80 (0.54 – 1.20) 0.29 - -
Platelets 0.99 (0.97 – 1.01) 0.43 - -
PT 0.99 (0.95 – 1.04) 0.85 - -
Creatinine 1.10 (0.40 – 3.04) 0.84 - -
Albumin 2.25 (0.68 – 7.42) 0.18 - -
*Mortality
Treatment (carvedilol) 1.53 (0.71-3.30) 0.27 - -
Age (<45 years) 0.95 (0.43-2.10) 0.90 - -
Sex (Female) 0.28 (0.08-0.93) 0.03 0.18 (0.05 – 0.63) 0.007
Viral etiology 0.04 (0.00-8.57) 0.24 - -
Gastric varices 0.47 (0.19-1.17) 0.11 - -
Large sized varices 0.93 (0.43-2.02) 0.87 - -
Child score 1.23 (0.96 – 1.57) 0.09 - -
Haemoglobin 0.86 (0.72 – 1.02) 0.09 - -
Platelets 1.003 (0.99 – 1.008) 0.29 - -
PT 1.00 (0.98 – 1.02) 0.87 - -
Creatinine 0.86 (0.42 – 1.77) 0.68 - -
Albumin 0.43 (0.23 – 0.79) 0.007 0.31 (0.16 – 0.63) 0.001
~p values were insignificant in all variables except sex and serum albumin in mortality which did not lose their significance on
multivariate analysis.
Reference: We kept EVL, age >45 years, male, viral etiology, gastric varices and grade varices as reference
Table 4: Causes of Death
Cause of death Carvedilol (n) EVL (n)
1 Variceal bleed 4 4
2 Infection 3 4
3 Liver failure 5 4
4 Respiratory cause 1 0
5 Cardiac cause 7 4
TABLE 5: Adverse Events of Treatment in the two arms.
Serious Adverse Events Carvedilol
(n=82)
EVL
(n=86) p value
Hypotension requiring withdrawal of Carvedilol
GI Bleed from post-banding ulcer
Chest pain requiring medication
2
0
0
0
1
17
0.14
0.99
<0.001
Non-serious Adverse Events
Dyspnea
Nausea
Transient dysphagia
30
18
0
0
0
58
<0.001
<0.001
<0.001
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