*Corresponding author:Achyut Bikram Hamal, Liver Unit, National Academy of Medical Sciences, Bir Hospital, Nepal
How to cite this article:Hamal AB, KC S, Thapa P, Sharma D, Karki N, et al. Carvedilol Versus Propranololol for Secondary Prophylaxis of Variceal
Hemorrhage in Patients with Liver Cirrhosis. Adv Res Gastroentero Hepatol, 2020;15(4): 555920. DOI: 10.19080/ARGH.2020.15.555920.
Introduction: Portal Hypertension in cirrhosis can have complication of variceal bleeding in 30-40 % of cases. The risk of index variceal bleeding is about 5-15 % per year. Prevention for index bleeding include non-selective beta blockers and endoscopic variceal ligation (EVL). Though propranolol is used as secondary prophylaxis in variceal bleeding, carvedilol is not commonly used. This study compares the efficacy of carvedilol and propranolol in preventing rebleed from esophageal varices in cirrhotic patients.
Methods: It is an open label prospective comparative study. Cirrhotic patients with index variceal bleeding were treated with EVL and Propranolol or Carvedilol. They were followed up and mean arterial pressure (MAP), Heart Rate (HR) and number of EVL sessions needed were analyzed in both the groups at 2, 6 and 12 weeks. The change in MAP and HR from the baseline was seen at 6 weeks. The adverse effect and overall mortality were seen in both the groups.
Results: There were 25 patients in propranolol group and 22 patients in carvedilol group. The decrease in MAP and HR at 2 weeks were higher in carvedilol than propranolol however not statistically significant. The decrease in HR at 6 weeks was significantly higher in carvedilol than propranolol group (p=0.036). The rebleeding at least once within 6 months was also higher in propranolol group than carvedilol group (32 vs 22.7%). The overall mortality in 6 months in carvedilol group was 18% which was higher than that in propranolol group (8%).
Conclusion:This shows that carvedilol was as efficacious as propranolol for secondary prophylaxis of variceal bleeding.
Abbreviations: EVL: Endoscopic Variceal Ligation; MAP: Mean Arterial Pressure; HR: Heart Rate; AASLD: American Association for the Study of Liver Diseases; HCV: Hepatitis C Virus; LEV: Large Esophageal Varices; NASH: Non- Alcoholic Steatohepatitis; PHG: Portal Hypertensive Gastropathy; SEV: Small Esophageal Varices; SI: Splenic Index
Bleeding occurs in 30% - 40% of cirrhotic patients once varices have formed . The incidence of first variceal bleeding in cirrhosis is about 5-15% per year  that occurs at a threshold of Hepatic venous pressure gradient (HVPG) > 12mm Hg  with mortality rate of 17-57 percent . Nonselective beta blocker is considered for secondary prophylaxis to further decrease rebleeding from 38% to 14% (P =.006) . Carvedilol, a nonselective beta and alpha-1 blocker decreases the intrahepatic resistance and is 2-4 times potent than propranolol . Three-fourth of patients in carvedilol and half of the patients in propranolol were HVPG responders (decrease in HVPG < 12 mm
Hg) when used for secondary prophylaxis in variceal bleeding and percentage of decrease in mean arterial pressure (MAP) is more in carvedilol than that in propranolol . We aimed to compare the efficacy of carvedilol and propranolol in secondary prophylaxis of variceal hemorrhage and identify the side effects of carvedilol and propranolol in cirrhotic patients.
This was a hospital based open label prospective comparative study carried out in the Liver Unit of Bir hospital from September 2019 to May 2020.
Consecutive patients of Child’s A and B liver cirrhosis
(LC) with index presentation of acute variceal bleeding either
esophageal or type 1 gastroesophageal varices (GOV)  were
included. Acute variceal bleeding was defined as hematemesis
within last 24 hours of presentation, and/or ongoing melena, with
last melanic stool within last 24 hours in a known or suspected
case of portal hypertension . Patients not giving consent, with
spontaneous bacterial peritonitis, hepatocellular carcinoma or
portal vein thrombosis and other comorbid illness such as acute
kidney injury, chronic kidney diseases, diagnosed coronary
artery disease (need for cardio selective beta blockers), bronchial
asthma, chronic obstructive pulmonary diseases, bradycardia,
hypotension, congestive heart failure or uncontrolled diabetes
The patients with first acute variceal bleeding were admitted
resuscitated and treated with somatostatin analogue (octreotide)
or terlipressin for 3 days along with endoscopic variceal ligation
(EVL). Variceal hemorrhage was confirmed by upper GI endoscopy
that was done within 12- 24 hours of admission. Esophageal
varices were categorized as large (> 5mm) or small (< 5mm) as
per American Association for the Study of Liver Diseases (AASLD)
2007 guidelines . EVL consists of the placement of rubber
rings on variceal columns which are sucked into a plastic hollow
cylinder attached to the tip of the endoscope. Nonselective beta
blocker was added after the stabilization of blood pressure on the
6th day of EVL.
The dose of propranolol for secondary prophylaxis was started
as 20 mg twice daily with increment as needed up to maximum
of 160mg and carvedilol was started with 3.125mg twice daily
with increment of 3.125mg every 3rd day to achieve the target
heart rate between 55 and 60 beats/min or decrease in the heart
rate by 25% from the baseline or intolerance to the b blockers
whichever happened earlier. The maximum dose of 160 mg daily
for propranolol and 25 mg daily for carvedilol was planned. These
drugs were continued until there were any serious side effects.
MAP and Heart Rate (HR) of the patients with the lab parameters
were studied in follow up at second, sixth and twelfth weeks.
The patients were followed up every month till the eradication
of the varices during which the liver function tests were done.
Any variceal rebleeding was assessed with the help of history
of hematemesis or melena along with fall in hemoglobin and
clinical examination. The patients were followed up for 6 months
and mortality was noted in both the groups. The data from the
proforma was entered in Microsoft excel software. The data was
cleaned, and coding was done. The data was then exported to SPSS
version 20 software for analysis.
Descriptive analysis consisted for presenting the continuous
data in mean and standard deviation, while frequency and
percentages were mere mentioned for categorical data. Inferential
statistics consisted of comparing the groups using chi-square
test or Fischer exact test for categorical data; and unpaired
t-test or Mann-Whitney test for continuous data. For statistical
significance, p value of <0.05 was considered.
The total number of patients with index acute variceal bleeding
was sixty-one. Out of 61, forty-nine patients were eligible for the
enrollment. Two patients of hepatocellular carcinoma (HCC), one
patient of Carcinoma of lung, 3 patients of extrahepatic portal
vein obstruction (EHPVO), 2 patients of chronic kidney disease
(CKD), 2 patients who left against medical advice (LAMA), one
patient of Hepatorenal syndrome (HRS) and one patient expired,
were excluded. Among them, 24 patients received carvedilol and
25 of them received propranolol by simple random sampling. Two
patients in the carvedilol group lost in follow up. The study design
of the patients is shown in Figure 1.
There was no difference in baseline characteristics except age of the patients in the two groups (Table 1).
The MAP and HR in the two study groups were not significant
at baseline and subsequently at 2 weeks and 6 weeks (Table 2).
The maximum dose used for carvedilol was 12.5mg/day and
it was 60mg/day for propranolol to achieve a decrease of heart
rate of by 25% from the baseline or heart rate of 60/min or
titrated as per tolerability of the patients and lab parameters The
median dose of propranolol was 40mg/day (40-60mg) and that of
carvedilol was 6.25mg/day (6.25-12.5mg).
The mean decrease in MAP and HR at 2 weeks were higher
in carvedilol than propranolol group however not significant.
Similarly, the decrease in MAP at 3 months was comparable in both
the groups. The mean decrease in HR at 3 months was significantly
higher in carvedilol group than that in the propranolol group
(p=0.036) Table 2.
The percentage of change in MAP and HR at 6 weeks in both
the groups in overall were not significant. The total frequency
of EVL to eradicate the varices was higher in propanolol group
than that of carvedilol group though not significant (1.4 vs 1.2).
The rebleeding at least once within 6 months was also higher
in propranolol group than carvedilol group (32 vs 22.7%). The
overall mortality in 6 months in carvedilol group was 18% which
was higher than that in propranolol group (8%) But on further
analysis, it was found that the deaths were not due to complications
of re-bleeding and were mostly due to other complications of liver
cirrhosis (Table 3).
The mean change in MAP in non-bleeders was higher in
carvedilol than propranolol (10 vs 5.47 %) at 2 weeks. Similarly,
the change in MAP in rebleeder was low in both the two groups.
Both the drugs were not free from side effects. Patients
treated with Propranolol and carvedilol had hypotension though
only one patient had bradycardia in carvedilol group. Fatigue,
hepatic encephalopathy, and increased creatinine were higher in
carvedilol group than propranolol group though not significant.
(Table 4). The need for drug withdrawal was also comparable
between the two groups (Table 5).
Although both the drugs have been used for primary
prophylaxis, carvedilol is less commonly used than propranolol for
secondary prophylaxis of variceal bleeding. Propranolol reduces
the portal pressure by lowering the portal blood flow through
decreased cardiac output and decreased azygous blood flow as a
result of ß-1 receptor blockade and vasoconstriction because of
unopposed alpha vasoconstriction effect which leads to arteriolar
splanchnic vasoconstriction (beta 2 blockade) but it is not always
enough for preventing rebleeding . The inability of propanolol
to prevent rebleeding may be attributed to the fact that it has
no action that decreases the intrahepatic resistance, which is
raised in cirrhosis of liver. However, carvedilol decreases the
intrahepatic resistance and thus has a greater portal hypotensive
effect than propranolol5. It can have more reduction in MAP and be
more potent than propranolol. The use of carvedilol for primary
prophylaxis was found to achieve a hemodynamic response with
improved outcome in terms of prevention of variceal bleeding,
hepatic decompensation, and mortality in 56% of propranolol
non-responders . Moreover, it is rapidly absorbed orally with
absolute bioavailability of around 25 %. It has a rapid onset of
action of 1–2 hours and an elimination half-life of 6–10 hours.
It is excreted mainly through bile and does not require dose
adjustment in renal failure . Carvedilol which decreases
significant portal pressure and intrahepatic resistance suggests
a greater therapeutic potential though it is less commonly used
for secondary prophylaxis. Therefore, based on this benefit of
carvedilol which was used for secondary prophylaxis of variceal
bleeding in our study, has shown an effective comparable benefit
using carvedilol though it is not superior to propranolol.
In our study, carvedilol or propranolol decreased HR and
MAP at 6 weeks and 3 months that is similar to the results of
the study done by Gupta V et al . The mean decrease in HR in
carvedilol group was higher than that in propranolol group (22 +
11 vs 15 + 11) with significant p value 0.034 and this was higher
as compared to other studies [14,15]. The mean reduction of MAP
in the non bleeders was higher than that of re-bleeders. Among
the nonbleeders the mean decrease in MAP at 2 weeks higher in
carvedilol than propranolol group (10 vs 5.47%).
Fatigue and hepatic encephalopathy were the common side
effects associated with use of both the drugs. There was 10
percent lower rate of rebleed in patients with carvedilol group as
compared to propranolol group though not significant. Rebleeding
within 6 months was more in propranolol than in carvedilol group
(32 vs 22.7%). This is comparable to the rebleeding rate i.e. 61%
(37 out of 61) in carvedilol after a median follow up of 30 months
done by Lo GH et al. . Another study done by Faust Feu et al, 25
out of 69 patients (36%) treated with propranolol had rebleeding
at least once during follow up period of 28 months . The need
for transient withdrawal of drug for few days was comparable
between the two groups.
The overall mortality was higher in carvedilol as compared to
propranolol group though not significant. This was attributed to
other complications of cirrhosis but not due to rebleeding or side
effects of carvedilol. Our study has few limitations. The change in
HVPG which could have added the beneficial role in comparison
of efficacy of both the drugs, could not be done because of
unavailability of this facility at our center. The decrease in the
MAP and HR in both the groups may not be translated into the
significant clinical outcomes of decreased rebleeding. Moreover,
active alcoholism in the two groups were not considered into
Our study shows that carvedilol was equally efficacious if not
superior to the propranolol in preventing the rebleed. The MAP
reduction in nonbleeders was higher in carvedilol group than that
in the rebleeders. This shows that future larger studies may be
needed to conclude whether carvedilol is superior to propranolol
or not. Nevertheless, carvedilol may be preferred over propranolol
due to lower rate of rebleeding than the latter. The rate of side
effects was seen more in carvedilol group than that of propranolol
group without statistical significance. The side effects seen in the
carvedilol group were attributed to the complications of cirrhosis
itself rather than the direct effects of carvedilol.