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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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: hasnain.alishah@aku.edu

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.

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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

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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).

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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.

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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).

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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.

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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

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(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,

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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

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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.

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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

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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

References:

[1] Merli M, Nicolini G, Angeloni S, Rinaldi V, De Santis A, Merkel C, et al. Incidence

and natural history of small esophageal varices in cirrhotic patients. J Hepatol. 2003

;38:266-72.

[2]. Groszmann RJ, Bosch J, Grace ND, Conn HO, Garcia-Tsao G, Navasa M, et al.

Hemodynamic events in a prospective randomized trial of propranolol versus placebo in

the prevention of a first variceal hemorrhage. Gastroenterology. 1990;99:1401-7.

[3]. Turnes J, Garcia-Pagan JC, Abraldes JG, Hernandez-Guerra M, Dell'Era A,

Bosch J. Pharmacological reduction of portal pressure and long-term risk of first variceal

bleeding in patients with cirrhosis. Am J Gastroenterol. 2006;101:506-12.

[4]. Villanueva C, Aracil C, Colomo A, Hernandez-Gea V, Lopez-Balaguer JM,

Alvarez-Urturi C, et al. Acute hemodynamic response to beta-blockers and prediction of

long-term outcome in primary prophylaxis of variceal bleeding. Gastroenterology.

2009;137:119-28.

[5]. Tripathi D, Graham C, Hayes PC. Variceal band ligation versus beta-blockers for

primary prevention of variceal bleeding: a meta-analysis. Eur J Gastroenterol Hepatol.

2007 ;19:835-45.

[6]. Funakoshi N, Duny Y, Valats JC, Segalas-Largey F, Flori N, Bismuth M, et al.

Meta-analysis: beta-blockers versus banding ligation for primary prophylaxis of

esophageal variceal bleeding. Ann Hepatol. 2012 ;11:369-83.

[7]. Bosch J. Carvedilol for portal hypertension in patients with cirrhosis. Hepatology.

2010 ;51:2214-8.

21

[8]. Hemstreet BA. Evaluation of carvedilol for the treatment of portal hypertension.

Pharmacotherapy. 2004 ;24:94-104.

[9]. Tsochatzis EA, Triantos CK, Burroughs AK. Gastrointestinal bleeding: Carvedilol-

the best beta-blocker for primary prophylaxis? Nat Rev Gastroenterol Hepatol.

2009;6:692-4.

[10]. Albillos A, Lledo JL, Banares R, Rossi I, Iborra J, Calleja JL, et al. Hemodynamic

effects of alpha-adrenergic blockade with prazosin in cirrhotic patients with portal

hypertension. Hepatology. 1994;20:611-7.

[11]. Banares R, Moitinho E, Piqueras B, Casado M, Garcia-Pagan JC, De Digego A,

et al. Carvedilol, a new beta-blocker with intrinsic anti-Alpha-adrenergic activity, has a

greater portal hypotensive effect than propranolol in patients with cirrhosis. Hepatology

1999;30:79-83.

Ref:12 Banares R, Moitinho E,Matilla A, Garcia-Pagan JC, Lampreave JL, Piera C, et

al. Randomized comparison of long term carvedilol and propranolol administration in the

treatment of portal hypertension I cirrhosis. Hepatology 2002;36:1367-1373

[13]. Tripathi D, Therapondos G, Lui HF, Stanley AJ, Hayes PC. Haemodynamic

effects of acute and chronic administration of low-dose carvedilol, a vasodilating beta-

blocker, in patients with cirrhosis and portal hypertension. Aliment Pharmacol Ther.

2002;16:373-80.

[14]. Stanley AJ, Therapondos G, Helmy A, Hayes PC. Acute and chronic

haemodynamic and renal effects of carvedilol in patients with cirrhosis. J Hepatol.

1999;30:479-84.

22

[15]. Lin HC, Yang YY, Hou MC, Huang YT, Lee FY, Lee SD. Acute administration of

carvedilol is more effective than propranolol plus isosorbide-5-mononitrate in the

reduction of portal pressure in patients with viral cirrhosis. Am J Gastroenterol.

2004;99:1953-8.

[16]. Forrest EH, Bouchier IA, Hayes PC. Acute haemodynamic changes after oral

carvedilol, a vasodilating beta-blocker, in patients with cirrhosis. J Hepatol.

1996;25:909-15.

[17]. Tripathi D, Ferguson JW, Kochar N, Leithead JA, Therapondos G, McAvoy NC,

et al. Randomized controlled trial of carvedilol versus variceal band ligation for the

prevention of the first variceal bleed. Hepatology. 2009;50:825-33.

[18]. de Franchis R. Revising consensus in portal hypertension: report of the Baveno

V consensus workshop on methodology of diagnosis and therapy in portal hypertension.

J Hepatol. 2010;53:762-8.

[19]. Reiberger T, Ulbrich G, Ferlitsch A, Payer BA, Schwabl P, Pinter M, et al.

Carvedilol for primary prophylaxis of variceal bleeding in cirrhotic patients with

haemodynamic non-response to propranolol. Gut. 2013 Nov;62(11):1634-41

[20]. Sarin SK, Lamba GS, Kumar M, Misra A, Murthy NS. Comparison of endoscopic

ligation and propranolol for the primary prevention of variceal bleeding. N Engl J Med.

1999;340:988-93.

[21]. Gluud LL, Krag A. Banding ligation versus beta-blockers for primary prevention in

oesophageal varices in adults. Cochrane Database Syst Rev. 2012;8:CD004544.

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

*Only Stage 1 Hepatic Encephalopathy was present as per West-Haven Criteria

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

Fig 1. Flow chart of study algorithm; enrolment, randomization and followup

Fig 2: Kaplan-Meier survival curve estimating time to variceal bleeding

Fig 3: Overall mortality by plan of treatment