Alimentary Pharmacology and Therapeutics

Systematic review with meta-analysis: the haemodynamic

effects of carvedilol compared with propranolol for portal
hypertension in cirrhosis
E. Sinagra,,1, G. Perricone,,1, M. DAmico, F. Tine* & G. DAmico*

*Gastroenterology Unit, A.O. Ospedali

Riuniti Villa Soa Cervello P.O.
Vincenzo Cervello, Palermo, Italy.

Internal Medicine Unit, A.O. Ospedali

Riuniti Villa Soa Cervello P.O.
Vincenzo Cervello, Palermo, Italy.

Hepatology and Gastroenterology

Unit, A.O. Ospedale Niguarda Ca
Granda, Piazza Ospedale Maggiore,
Milano, Italy.

Endoscopy and Gastroenterology

Unit, Fondazione Istituto San Raffaele
Giglio, Cefal
u, Italy.

Radiology Department, Universita di

Palermo, Palermo, Italy.

Corresponding author:
Dr G. DAmico, Gastroenterology Unit,
A.O. Ospedali Riuniti Villa Soa
Cervello P.O. Vincenzo Cervello, via
Trabucco 180, 90146 Palermo, Italy.
E-mail: gedamico@libero.it
These authors equally shared the rst
authorship.
1

Publication data
Submitted 23 November 2013
First decision 9 December 2013
Resubmitted 3 January 2014
Accepted 6 January 2014
EV Pub Online 26 January 2014
As part of AP&Ts peer-review process, a
technical check of this meta-analysis was
performed by Mr M. Siddiqui.

SUMMARY
Background
Propranolol is recommended for prophylaxis of variceal bleeding in cirrhosis. Carvedilol is a nonselective beta-blocker with a mild anti-alfa-1-adrenergic activity. Several studies have compared carvedilol and propranolol,
yielding inconsistent results.
Aim
To perform a systematic review and meta-analysis of the randomised clinical trials comparing carvedilol with propranolol for hepatic vein pressure
gradient reduction.
Methods
Studies were searched on the MEDLINE, EMBASE and Cochrane library
databases up to November 2013. The weighted mean difference in percent
hepatic vein pressure gradient reduction and the relative risk of failure to
achieve a hemodynamic response (reduction 20% of baseline or to
12 mmHg) with each drug were used as measures of treatment efcacy.
Results
Five studies (175 patients) were included. Indication to treatment was primary prophylaxis of variceal bleeding in 76% of patients. There were overall
three acute (6090 min after drug administration) and three long-term
(after 790 days of therapy) comparisons. The summary mean weighted
difference in % of reduction in hepatic vein pressure gradient was: acute
7.70 (CI 12.40, 3.00), long-term 6.81 (CI 11.35, 2.26), overall
7.24 (CI 10.50, 3.97), favouring carvedilol. The summary relative risk
of failure to achieve a hemodynamic response with carvedilol was 0.66 (CI
0.44, 1.00). Adverse events were nonsignicantly more frequent and serious
with carvedilol. However, quality of trials was mostly unsatisfactory.
Conclusions
Carvedilol reduces portal hypertension signicantly more than propranolol.
However, available data do not allow a satisfactory comparison of adverse
events. These results suggest a potential for a cautious clinical use.
Aliment Pharmacol Ther 2014; 39: 557568

2014 John Wiley & Sons Ltd

doi:10.1111/apt.12634

557

E. Sinagra et al.
INTRODUCTION
Portal hypertension is an almost unavoidable complication of cirrhosis1 and variceal haemorrhage is its most
dramatic consequence, bearing a mortality of 1015%
per episode.2 The hepatic venous pressure gradient
(HVPG) is signicantly associated with the risk of variceal bleeding, liver decompensation and hepatocellular
carcinoma (HCC).35 A reduction in HVPG by 20% of
baseline results in a signicant reduction in the bleeding
risk and a reduction to less than 12 mmHg virtually
abolishes the risk.3, 6 Propranolol, a nonselective betablocker (NSBB), signicantly reduces HVPG and is currently recommended for the prevention of primary and
secondary variceal bleeding. However, it achieves the target HVPG reduction only in approximately one-third of
patients, possibly because the increase in porto-collateral
resistance impairs the reduction in portal pressure.79
This effect may be reduced by adding a vasodilator such
as isosorbide mononitrate, which in fact rescues most of
nonresponders to propranolol, although at the expense
of increasing side effects.10
Carvedilol is a potent NSBB with a mild anti-alfa1
adrenergic activity, which confers to the drug a potential
for a higher portal pressure reduction compared with
other NSBB. Several studies have compared the acute or
long-term hemodynamic response of carvedilol and propranolol yielding inconsistent results.11
The aim of the present study was to assess the hemodynamic effects of carvedilol compared with propranolol
for portal hypertension. With this aim, we performed a
systematic review of randomised controlled trials (RCTs)
comparing the two drugs for their effect on hepatic vein
pressure gradient in cirrhosis.
METHODS
Study selection and participants
All the studies that met the following inclusion criteria
were included: (i) the study was an RCT comparing
carvedilol with propranolol for acute or long-term effect
on HVPG in cirrhotic patients; (ii) reduction in HVPG
under treatment was a measure of the treatment effect;
(iii) participants in the included studies were cirrhotic
patients with clinically signicant portal hypertension as
indicated by HVPG >10 mmHg and/or presence of
oesophageal varices, according to the Baveno III criteria.12 Randomised trials were included irrespective of
blinding, publication status or language. Trials using
quasi-randomisation, based on case record number, date
of birth, day of the week or similar, were excluded.
558

Compared treatments
Oral carvedilol was compared with either oral or i.v. propranolol for the acute hemodynamic effect, or oral carvedilol compared with oral propranolol for the long-term
effect. The assessment of the hemodynamic effect was
considered acute when performed during the same
hepatic veins catheterisation. When a second catheterisation was required (after days or months of treatment), it
was classied as assessment of long-term treatment
effect.
Treatment outcome
The primary measure of the treatment effect was the difference in % HVPG reduction achieved with each of the
two compared drugs. The proportion of patients failing
to achieve a hemodynamic response to the treatment
was considered a secondary outcome measure.
Hemodynamic responders were considered those
patients achieving a HVPG reduction 20% of baseline
value or in whom HVPG was lowered to
12 mmHg.3, 13, 14 The number and severity of adverse
events were also assessed as well as the difference in
mean arterial blood pressure reduction (MAP) with each
drug as an indicator of systemic treatment effect.
Search strategy
Medline, Embase, Cochrane Controlled Trial Registry
and The Cochrane Library were searched up to November 2013 to retrieve pertinent studies. Databases were
searched by the following search terms: carvedilol, propranolol, portal hypertension, randomised trial. A manual search of the reference lists of pertinent studies,
articles, reviews, editorials from the English language
medical literature was also performed. Proceedings of the
most relevant international congresses were handsearched.
Data collection and analysis
Decisions on which trials to include were taken independently by two of the authors (ES and GP), who were
unblinded with regard to the names of the authors,
investigators, institution, source, and results of the identied trials. Disagreements were resolved by discussion
with all the authors. Excluded trials were identied with
the reason for exclusion. Data were extracted by two
independent authors (ES and GP) and discrepancies
were solved by discussion. The following data were
extracted from each trial: (i) trial characteristics: time
interval between trial drug administration and hemodynamic effect assessment; denition of the outcome of
Aliment Pharmacol Ther 2014; 39: 557-568
2014 John Wiley & Sons Ltd

Systematic review with meta-analysis: carvedilol vs. propranolol for portal hypertension
interest; (ii) patients characteristics: number of patients,
mean age, sex, aetiology of cirrhosis, Child-Pugh score,
proportion of patients with previous variceal bleeding;
(iii) outcome: mean HVPG change under trial treatment;
number of patients achieving a hemodynamic response;
adverse events observed during the treatment period.

Assessment of study quality

Two of the authors (GP and ES) independently assessed
bias risk of the trials, without masking the trial names.
For this purpose, the risk of overestimation of intervention effects in randomised trials due to inadequate methodological quality was assessed using the following
domains.15, 16
Generation of the allocation sequence was dened adequate if sequences were generated by table of random
numbers or computer-generated random numbers or
similar; unclear if it was not described; inadequate if
sequences could be related to prognosis.
Allocation concealment was dened adequate when a
centralised randomisation or sequentially numbered,
sealed, opaque envelopes were used; unclear when studies
did not report any concealment approach; inadequate
when the following modalities were used: alternation, the
use of case record numbers, dates of birth or day of the
week, and any procedure that is entirely transparent before
allocation, such as an open list of random numbers.
Blinding was considered adequate when the study was
double-blind or single-blind (HVPG measurements were
blindly evaluated); unclear when no information was
reported; inadequate when an open design was used.
Handling of dropouts and withdrawals was considered
adequate when numbers of patients withdrawn or lost
and reasons were described; inadequate otherwise.
Intention-to-treat analysis was considered adequate
when all randomised patients were included in the analyses and inadequate otherwise.
Following the above denitions, an included trial was
judged as achieving inadequate or unclear control of bias
when the methodological quality was considered as inadequate or, respectively, unclear in at least 1 domain. If
the quality was judged adequate in all the domains, then
the control of bias was considered adequate.
Statistical methods
Trials and patient characteristics are reported as number
of observations, proportions or means  standard deviations. Where standard error of mean was reported in the
original article, the standard deviation was derived from
the standard error.
Aliment Pharmacol Ther 2014; 39: 557-568
2014 John Wiley & Sons Ltd

Analyses were performed by STATA 10 (College Station, TX 77845 USA, 19842009) by a xed-effect
model if no statistically signicant heterogeneity was
found and by a random-effects model in case of signicant heterogeneity (P < 0.10). The treatment effect was
calculated as the weighted mean difference (WMD)
between the % HVPG reduction from baseline achieved
with propranolol and the % reduction achieved with
carvedilol. Data are expressed as % HVPG reduction
with propranolol minus % HVPG reduction with carvedilol. Therefore, negative values indicate a higher
HVPG reduction with carvedilol. The pooled WMD is
reported as the summary statistic of treatment effect
together with 95% condence interval (CI). The pooled
relative risk (RR) of failure to achieve a hemodynamic
response with either treatment was also assessed and
reported with 95% CI. Inter-trial heterogeneity was statistically assessed by a chi-square test and was expressed
using I2 values.17 If signicant heterogeneity was found,
potential reasons for heterogeneity were explored and
combinability of trials was reassessed accordingly. Analyses were performed using the intention-to-treat principle
including all patients randomised as they were reported
in each single study. Trials were rst combined independently of whether they assessed acute or long-term hemodynamic effect of the study treatment. However,
separate analyses according to the timing of assessment
were also performed.
To explore the robustness of estimates, the following
sensitivity analyses were performed: (i) random-effects
model; (ii) standardised mean difference (SMD) instead
of WMD to overcome potential measurement differences across trials; (iii) excluding trials with acute
assessment; (iv) excluding trials with long-term assessment; (v) excluding trials with inadequate control of
bias.
The weighted mean difference in arterial blood pressure with the two drugs was also assessed as a measure
of a major treatment side effect.

Study protocol
The full study protocol is available by contacting the corresponding author of this article.
RESULTS
Trial retrieval
Overall, 39 potentially eligible references were retrieved
in the literature search. Thirty references were excluded
by reading the title and abstract, because they did not
559

E. Sinagra et al.
38 references
identified through
database serching

One additional
reference identified
by handsearch

39 references
screened
30 excluded

9 references
assessed
for eligibility
7 references to 5
pertinent trials

2 RCTs exluded because did not include

hemodynamic assessment or -blocker control
group:
- one compared carvedilol with band ligation of
esophageal varices for primary prophylaxis
of variceal bleeding
- the other compared carvedilol with nadolol plus
isosorbide mononitrate for secondary prophylaxis
of variceal bleeding

5 RCTs included
In quantitative synthesis
(meta-analysis)

refer to randomised trials. The remaining 9 references

were fully assessed for inclusion in the study (Figure 1).
Among these, two referred to full articles and were
excluded for the following reasons: one was a randomised controlled trial of carvedilol vs. variceal band ligation for the prevention of the rst variceal bleed;18 the
other was a randomised controlled trial of carvedilol vs.
nadolol plus isosorbide mononitrate for the prevention
of variceal rebleeding, which did not include hemodynamic assessments.19 Seven references2026 to ve pertinent studies were eventually found: two of these referred
to the preliminary report20 or to a subgroup analysis25 of
a fully published study26 and were therefore excluded.
The remaining ve references2124, 26 referred to randomised controlled trials, which fullled our inclusion criteria and were included in the quantitative meta-analysis.

Description of included studies

The characteristics of the ve included studies are summarised in Tables 1 and 2. In two studies, the acute
hemodynamic effect was assessed 60 and 90 min after
trial drug administration21, 24 respectively. In two studies, the treatment effect was assessed after a mean of
11 weeks22 and 92.7 days.26 In one study,23 both acute
and long-term effects were assessed at 90 min and
1 week after initial trial drug administration, respectively.
Overall, therefore, there were three acute and three
long-term evaluations available for meta-analysis.
In the acute comparisons, all treated patients were
given a tablet of carvedilol 25 mg, while control patients
were given propranolol 0.15 mg/kg i.v. followed by a
continuous infusion of 0.2 mg/kg/h in one study,21
40 mg p.o.24 or 80 mg p.o.23 In one acute study,24
560

Figure 1 | Flow diagram of the

selection process of
randomised controlled trials
for inclusion in the metaanalysis. RCT, randomised
controlled trials.

propranolol was associated with isosorbide mononitrate

20 mg in the control group.
In the evaluation of the long-term hemodynamic
response, treated patients received a mean dose of 31 mg
of oral carvedilol and controls received a mean of 73 mg
of oral propranolol in one study;22 a xed oral dose of
12.5 mg of carvedilol was compared with a xed oral
dose of 80 mg of propranolol in another;23 and a mean
dose of 14 mg of carvedilol and 122 mg of propranolol
in the third.26
A second HVPG measurement was obtained in all the
included patients in three studies.21, 24, 26 In one study,22
discontinuation of treatment caused missing second
HVPG measurement in two patients in the carvedilol
group (heart failure one and pericardial effusion the
other) and in three in the propranolol group (portal systemic encephalopathy 1 and fatigue 2). In the other
study,23 discontinuation of treatment hampered a second
HVPG measurement in one patient in the carvedilol
group because of severe hypotension and in two patients
in the propranolol group because of bleeding.
Control of bias was adequate in one trial, unclear in
three and inadequate in one trial (Table 2). In the four
trials with inadequate or unclear control of bias, this was
mostly due to the generation of the allocation sequence
or to allocation concealment.
The characteristics of the 175 patients included in the
ve studies are summarised in Table 3. Males were 74%.
The number of patients with ascites was reported only in
two studies22, 23 and was 44 of 87 (51%); patients with a
previous bleeding episode were 42 of 153 (27%; information not reported in one study24). Mean age was 55 years
and aetiology was mostly viral or alcoholic in all the
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Systematic review with meta-analysis: carvedilol vs. propranolol for portal hypertension
Table 1 | Characteristics of included trials

Author,
year

Participants

N of randomised
patients C/P

Interventions
C; P*
C: Carvedilol
25 mg p.o.
P: Propranolol
(0.15 mg/kg
i.v. followed by
a continuous
infusion of
0.2 mg/kg/h)
C: Carvedilol
31  4 mg/day
p.o.(range, 12.550)*
P: Propranolol
73  10 mg/day
p.o. (range, 10160)*
Acute:
C: Carvedilol
25 mg p.o.;
P: Propranolol
80 mg p.o.
Maintenance:
C: carvedilol
6.25 mg p.o.
twice daily
P: propranolol
40 mg p.o.
twice daily
C: Carvedilol
25 mg p.o.
P: propranolol
40 mg p.o +
isosorbide
5-mononitrate
20 mg p.o.
C: Carvedilol
14  7 mg*
P: Propranolol
122  64 mg*

Banares, 1999

Cirrhotic patients
with oesophageal
varices, with or
without previous
variceal bleeding

14/14
7 more patients
were randomised
to placebo

Banares,2002

Cirrhotic patients
with oesophageal
varices, no previous
bleeding, and
HVPG >12 mmHg

26/25

De, 2002

Cirrhotic patients
with oesophageal
varices, with or
without previous
variceal bleeding

18/18

Lin, 2004

Cirrhotic patients
with HVPG 12 with
or without previous
variceal bleeding

11/11

Hobolth, 2012

Cirrhotic patients with

HVPG12 mmHg,
independent of varices
or previous bleeding

21/17

Time of
outcome
assessment

N of patients with 1st/2nd

HVPG measurement
Carvedilol

Propranolol

60 min

14/14

14/14

11  4.1 weeks

26/24

25/22

Acute: 90 min
Long-term: 1 week

Acute: 18/18
Long-term 18/17

Acute: 18/18
Long-term 18/16

90 min

11/11

11/11

92.7  13.6 days

21/21

17/17

C, Carvedilol group; P, Propranolol group; p.o., orally; i.v., intravenously.

* Mean dose  standard deviation.
Interval between baseline and second HVPG measurement, mean  s.d.

studies but one where only patients with cirrhosis from

HBV and/or HCV were included.24 Child-Pugh class C
patients were overall 31 of 153 (20%) in four studies and
the mean Child-Pugh score was eight in the fth.24 No
appreciable differences in major patient characteristics
were observed between the two study groups across the
ve studies (Table 3).

Outcome evaluation
HVPG reduction. Mean baseline HVPG was 18.3 mmHg
(median 18, range 16.620.4) in propranolol-treated
patients and 18.8 mmHg (median 19, range 17.619.5)
Aliment Pharmacol Ther 2014; 39: 557-568
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in the carvedilol-treated patients. The mean % HVPG

reduction under treatment was 15.6 (median 12.6, range
10.123.2) with propranolol and 22.2 (median 19.8,
range 18.627.7) with carvedilol (crude mean difference
6.61%).
The pooled WMD between % HVPG reductions with
the two drugs was 7.24 ( 10.50, 3.97; xed-effect
model) indicating a signicantly higher HVPG reduction
with carvedilol than propranolol. No heterogeneity was
found (P = 0.99; I2 = 0.0) (Figure 2). A sensitivity analysis performed by using the standardised mean difference
between the % HVPG reductions with the two drugs
561

E. Sinagra et al.
Table 2 | Methodological quality assessment of included trials*

Author, year

Generation
of the allocation
sequence

Allocation
concealment

Blinding

Dropouts
and withdrawals

Intention-totreat analysis

Overall risk
of bias

Banares, 1999
Banares, 2002
De, 2002
Lin, 2004
Hobolth, 2012

Unclear
Adequate
Unclear
Adequate
Unclear

Unclear
Adequate
Inadequate
Unclear
Adequate

Adequate
Adequate
Adequate
Unclear
Adequate

Adequate
Adequate
Adequate
Adequate
Adequate

Adequate
Adequate
Adequate
Adequate
Adequate

Unclear
Adequate
Inadequate
Unclear
Unclear

* Denition used for rating of each quality item are reported in the method section.
Blinded reading of HVPG measurements.
Double-blind.

Table 3 | Characteristics of participants in the included studies

Banares, 1999
Banares, 2002
De, 2002
Lin, 2004
Hobolth, 2012

Treatment
group

Patients
N

Age,
mean  s.d.

C
P
C
P
C
P
C
P
C
P

14
14
26
25
18
18
11
11
21
17

54.6
51.4
57.9
58.4
42.3
47.3
59
61
58.2
56.2












8.8
8.5
7.6
11
11.9
12.9
13.3
13.3
6.8
6.1

Males
N

Alcoholic/
viral
aetiology N

Child-Pugh
class A/B/
C, N

Oesophageal
varices large/
small, N

Ascites
N

Previous
variceal
bleeding, N

NR
NR
19
15
15
17
8
9
12
12

8/NR
8/NR
6/18
9/16
5/9
10/5
0/11
0/11
18/2
12/1

8/4/2
5/6/3
13/10/3
15/6/4
5/9/4
0/13/5
8.7  3.0
7.3  2.7
8/7/6
6/6/4

NR
NR
10/16
14/11
NR
NR
NR
NR
4/10
1/11

7*
7*
10
6
12
16
NR
NR
NR
NR

9
9
0
0
7
7
NR
NR
5
5

C, Carvedilol; P, Propranolol.
* Previous ascites.
Child-Pugh score, mean  standard deviation (derived from the standard error reported in the article).

conrmed the principal analysis: pooled SMD 0.50 (CI

0.78, 0.23; xed-effect model) without signicant heterogeneity (P = 0.5; I2 = 0.0). The other sensitivity
analyses conrmed that either the acute or the long-term
% HVPG reduction is signicantly higher with carvedilol
than with propranolol (Figure 2) and superiority of carvedilol held true also by excluding the study with inadequate control of bias22 (WMD 7.41, CI 10.79, 4.03;
data not shown).
The mean % HVPG reduction was 20% in 2 of 6
comparisons with propranolol and in 3 of 6 with carvedilol. Overall, a reduction in HVPG of 20% or to
12 mmHg was achieved with propranolol in 33 of 87
evaluable patients as compared to 57 of 94 with carvedilol (including patients with both acute and chronic
assessments; P = 0.003, Fishers exact test) (Table 4).
562

The pooled relative risk of failure to achieve a hemodynamic response with carvedilol was 0.66 (CI 0.441.00)
(Figure 3).

Adverse events. Mean arterial blood pressure (MAP)

was reduced more by carvedilol (WMD 10.40; 95% CI:
13.90, 6.90; I2 = 0.0%, P = 0.477) than by propranolol (WMD 6.35; 95% CI 9.86, 2.83; I2 = 0.0%,
P = 0.936) (Figure 4). The lack of complete information
on the difference in MAP reduction between the two
drugs hampered obtaining a summary statistics. However, as the CI of MAP reduction achieved with each
drug largely overlapped, it may be concluded that the
difference in MAP reduction between the two drugs was
not signicantly different (Figure 4). On the other hand,
even if not statistically signicant, this difference was
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Systematic review with meta-analysis: carvedilol vs. propranolol for portal hypertension

Acute assessment
Banares (1999)

7.70 (13.24, 2.16)

34.70

De (2002)

4.69 (23.94, 14.56)

2.88

Lin (2004)

8.50 (18.48, 1.48)

10.71

Subtotal
(I 2 = 0.0%, P = 0.942)

7.70 (12.40, 3.00)

48.29

Banares (2002)

7.00 (12.26, 1.74)

38.48

De(2002)

4.72 (21.99, 12.55)

3.58

Hobolth (2012)

6.80 (17.31, 3.71)

9.66

Subtotal
(I 2 = 0.0%, P = 0.970)

6.81 (11.35, 2.26)

51.71

7.24 (10.50, 3.97)

100.00

Long-term assessment

Heterogeneity between groups: P = 0.789

Overall
(I 2 = 0.0%, P = 0.998)

20
10
Better carvedilol

10
20
Better propranolol

Weighted Mean Difference: fixed effects

Figure 2 | Weighted mean difference (WMD) (xed-effect model) of the % hepatic vein pressure gradient (HVPG)
reduction between propranolol and carvedilol in the subsets of RCTs assessing the acute and, respectively, the longterm treatment effect together with the overall estimation of the whole set of studies. Each study is identied by the
name of the rst author and year of publication (references in the text). Squares indicate the WMD per each trial and
the size of the squares is proportional to the weight of trials. The horizontal bars denote the 95% condence intervals
of WMD. The vertical solid line is the equivalence line, where WMD is equal to 0. Differences are given as values in
the propranolol group minus values in the carvedilol group. Therefore, negative values (WMDs on the left of the
equivalence line) denote superiority, whereas those on the right denote inferiority of carvedilol. The diamonds
represent 95% CI of the WMDs per each subset and in whole set of RCTs. The vertical dashed line represents the
pooled WMD of the whole set of trials. The study by De (2002) provided estimation of either acute or long-term
treatment effect.

clinically relevant, with at least one symptomatic episode

of hypotension reported with carvedilol and a total of 14
patients with orthostatic hypotension out of 65 patients
treated with carvedilol, compared to 9/60 with propranolol (P = 0.37) in three of the ve studies.22, 23, 26
Other adverse events, even if not fully reported in all
the studies, were the following: need for increasing
diuretics in 14/47 patients treated with carvedilol and in
6/42 with propranol;22, 26 shortness of breath in 12/47
and 7/42;22, 26 portosystemic encephalopathy in 3/26 and
4/2522 respectively. Overall carvedilol was withdrawn in
6/65 and propranolol in 8/60 treated patients22, 23, 26
because of adverse events. None of these differences was
statistically signicant.
Aliment Pharmacol Ther 2014; 39: 557-568
2014 John Wiley & Sons Ltd

DISCUSSION
The present meta-analysis shows that, in the available
RCTs comparing propranolol and carvedilol for portal
hypertension, carvedilol reduces HVPG signicantly
more than propranolol. Superiority of carvedilol is consistent across all the trials, regardless of acute or longterm assessment. The summary weighed mean difference
between the percent HVPG reduction achieved with propranolol and carvedilol is 7.24 (CI 10.50 to 3.97) in
favour of carvedilol. No heterogeneity was found and all
the sensitivity analyses conrmed the principal result.
Patients in the two treatment groups were fairly comparable across the included studies, regarding demography, aetiology, indicators of disease severity, baseline
563

E. Sinagra et al.
Table 4 | Main results of the included studies
Carvedilol

Author, year

Baseline
HVPG, mmHg
mean  s.d.*

Acute assessment
Banares, 1999
19.5
De, 2002
19.0
Lin, 2004
18.9
Subtotal

Long-term assessment
Banares, 2002
19.1
De, 2002
19.0
Hobolth, 2012
17.6
Subtotal

Total

 4.9
 3.8
 6.0

Propranolol

% HVPG
reduction,
mean  s.d.*

Hemo-dynamic
responders
n/N (%)

20.4  7.5
27.7  31.5
18.6  11.9

9/14 (64)
11/18 (61)
NR

20.4  4.1
16.60  3.9
17.6  4.0

19  9.8
27.7  31.5
19.3  16.1

13/24 (54)
11/17 (65)
13/21 (62)

20.3  4.2
16.6  4.0
18.4  3.6

12  9.4
22.98  20.1
12.5  16.7

 5.4
 3.8
 4.2

Baseline HVPG,
mean  s.d.*

Weighed
Mean Difference
in % HVPG
reduction (CI)

% HVPG
reduction,
mean  s.d.*

Hemo-dynamic
responders
n/N (%)

12.7  7.48
22.9  27.4
10.1  11.9

2/14 (14)
9/18 (50)

7.70
4.69
8.50
7.70

5/22 (23)
10/16 (62)
7/17 (41)

7.00 (
4.72 (
6.80 (
6.81
( 11.35,
7.24 (

NR

(
(
(
(

13.24, 2.16)
23.94, 14.56)
18.48, 1.48)
12.4, 3.00)
12.26, 1.74)
21.99, 12.55)
17.31, 3.71)
2.26)
10.50,

3.97)

* s.d., standard deviation of mean. In the studies by Banares 1999 and 2002 and by Lin 2004, the standard deviation of the mean
was calculated from the standard error of the mean reported in the original articles.
Patients achieving a HVPG reduction 20% or HVPG 12 mmHg.
Hemodynamic response was dened as a reduction in HVPG of 20% of baseline in the Des study.
n, number of responders; N, total number of evaluable patients.
The difference is calculated as % HVPG reduction with propranolol
carvedilol.

HVPG and history of previous bleeding. A second measurement of HVPG was available in all the included
patients, but three in the Des study23 and ve in the
long-term study by Banares.22 Only two of the missing
second HVPG measurements were due to bleeding (both
in proporanolol-treated patients), while the others were
caused by adverse events requiring treatment withdrawal.
Control of bias was considered inadequate in only one
trial and the benecial effect of carvedilol over propranolol was conrmed also when excluding this study. On
the other hand, control of bias was adequate in only one
study: this nding calls for caution when interpreting the
present results.
The number of patients achieving a reduction in
HVPG to 20% or to 12 mmHg was reported in 4 of
the 5 studies and was also markedly higher with carvedilol (57/94 vs. 33/87). However, the reduction in the
pooled relative risk of failure to achieve a hemodynamic
response failed to reach statistical signicance with carvedilol (0.67, CI 0.441.01), conceivably because of a type
II error. It may also be worth noting that in the only
study assessing both acute and long-term effects,23 the
number of patients with acute hemodynamic response
was almost identical to the number of patients with
response after 7 days: respectively 11/18 and 11/17 with
564

% HVPG reduction with carvedilol: negative values favour

carvedilol and 9/18 and 10/16 with propranolol.

Although no individual patient data are reported in the
article,23 it may be assumed that the acute hemodynamic
response tends to be maintained.
Superiority of carvedilol over propranolol in reducing
HVPG is accredited to be a consequence of the alfa-1
blocking effect reducing intra-hepatic resistance. In this
respect it remains unclear the better (although not statistically signicant) effect of carvedilol in the trial by
Lin,24 comparing carvedilol with propranolol plus isosorbide mononitrate. The authors adduce viral aetiology or
the known hyper-responsiveness to alfa-1 blockers in cirrhosis as potential explanations, although equivalence of
drug doses with respect to the expected hemodynamic
effect should also be accounted for. On the other hand,
the only RCT comparing the clinical efcacy of carvedilol with nadolol plus isosorbide mononitrate showed that
the two treatments did not differ in the prevention of
variceal rebleeding after a median follow-up of
30 months.19
Adverse events were satisfactorily reported in only one
study.21 The most serious reported adverse event was
orthostatic hypotension (14/65 carvedilol- and 9/60 propranolol-treated patients). Although not statistically signicant, the higher incidence of this serious adverse
Aliment Pharmacol Ther 2014; 39: 557-568
2014 John Wiley & Sons Ltd

Systematic review with meta-analysis: carvedilol vs. propranolol for portal hypertension
RR (95% CI)

%Weight

Banares (1999)

0.22 (0.06, 0.85)

8.00

De (2002)

0.82 (0.45, 1.48)

25.10

Subtotal
(I 2 = 71.3%, P = 0.062)

0.48 (0.13, 1.85)

33.10

Banares (2002)

0.42 (0.18, 0.99)

16.09

De (2002)

0.97 (0.58, 1.62)

28.55

Hobolth (2012)

0.67 (0.34, 1.29)

22.27

Subtotal
(I 2 = 35.1%, P = 0.214)

0.71 (0.44, 1.13)

66.90

Overall (I 2 = 39.9%, P = 0.155)

0.66 (0.44, 1.00)

100.00

Acute assessment

Long-term assessment

.2
.5
1
5
10
Better carvedilol
Better propranolol
Relative risk: random effects

Figure 3 | Summary relative risk (RR) of treatment nonresponse (reduction in HVPG of 20% of baseline or to
<12 mmHg not achieved) with carvedilol compared with propranolol (random-effects model) in the subsets of RCTs
assessing the acute and, respectively, the long-term treatment effect together with the overall estimation of the whole
set of studies. Each study is identied by the name of the rst author and year of publication (references in the text).
Squares indicate the RR per each trial and the size of the squares is proportional to the weight of trials. The
horizontal bars denote the 95% condence intervals of RR. The vertical solid line is the equivalence line, where RR is
equal to 1. RRs on the left of the equivalence line denote superiority, whereas those on the right denote inferiority of
Carvedilol. The diamonds represent 95% CI of the RRs per each subset and in whole set of RCTs. The vertical dashed
line represents the summary RR of the whole set of trials. The study by De (2002) provided estimation of either
acute or long-term treatment effect.

event calls for caution in clinical practice when using

carvedilol. Moreover, the overall mean weighed reduction
in the mean arterial pressure was 6.66 mmHg (CI
10.17 to 3.15) with propranolol and 10.40 (CI
13.9 to 6.9) with carvedilol. Thus, the mean arterial
pressure was signicantly reduced by both treatments
and the reduction was in the order of one-third more
with carvedilol than with propranolol. The difference in
arterial pressure reduction between the two drugs was
not statistically signicant as shown by the overlapping
95% condence boundaries of the reduction with each of
the two drugs, although it is clearly clinically signicant.
Of note, in at least one carvedilol patient (with ascites),
orthostatic hypotension was symptomatic and followed
Aliment Pharmacol Ther 2014; 39: 557-568
2014 John Wiley & Sons Ltd

by oliguria requiring treatment withdrawal and active

intervention for recovering.23 Importantly, the hypotensive effect of carvedilol was markedly reduced by starting
with a very low dose and careful titration by stepwise
increases every 47 days.22, 26
In the study assessing the 11-week effect of the
drugs,22 a signicant increase in plasma volume and
body weigh was noted with carvedilol, but not with propranolol, and an increase in diuretics dosage was needed
in seven carvedilol compared with two propranolol
patients because of new onset or worsening ascites or
ankle oedema. This effect, similar to that observed with
propranolol combined with prazosin,27 has been
attributed to a possible increase in sodium retention,22
565

E. Sinagra et al.
Propranolol

WMD (95% CI)

Weight

Banares (1999)

4.00 (12.32, 4.32)

17.87

De, acute (2002)

3.60 (14.41, 7.21)

10.57

Banares (2002)

4.80 (15.51, 5.91)

10.77

De, chronic (2002)

5.70 (15.32, 3.92)

13.35

Lin (2004)

9.00 (17.32, 0.68)

17.87

Hobolth (2012)

8.00 (14.47, 1.53)

29.56

Overall

6.35 (9.86, 2.83)

100.00

(I 2 = 0.0%, P = 0.936)
20

10

10

Carvedilol

Banares (1999)

20
WMD (95% CI)

Weight

16.00 (25.80, 6.20)

12.75

De, acute (2002)

10.50 (18.26, 2.74)

20.36

Banares (2002)

10.20 (17.56, 2.84)

22.62

De, chronic (2002)

15.10 (24.12, 6.08)

15.05

Lin (2004)

8.00 (22.13, 6.13)

6.13

Hobolth (2012)

5.00 (12.28, 2.28)

23.09

10.40 (13.90, 6.90)

100.00

Overall
(I 2 = 0.0%, P = 0.477)
20

10

0
MABP reduction, mmHg

10

20

Figure 4 | Weighted mean difference (WMD) of arterial pressure from before to after treatment. Data are expressed
as baseline minus post-treatment value. The top section of the gure represents the arterial pressure changes with
propranolol and the bottom section changes with carvedilol. Each study is identied by the name of the rst author
and year of publication (references in the text). Squares indicate the WMD per each trial and the size of the squares
is proportional to the weight of trials. The horizontal bars denote the 95% condence intervals of WMD. The vertical
solid line is the equivalence line, where WMD is equal to 0. WMDs on the left of the equivalence line denote
reduction in arterial blood pressure after treatment, whereas those on the right denote increase. The vertical dashed
line represents the pooled WMD of the whole set of studies in the arms of propranolol (top) and, respectively,
carvedilol (bottom). The diamonds represent 95% CI of the WMDs.

and might require some weeks to present, as it was not

noted after 1 week.21 It is, however, worth noting that in
two randomised clinical trials of carvedilol, one for
primary11 and the other for secondary19 prevention of
variceal bleeding, no difference was noted in the new
onset or worsening of ascites between the study groups.
The carvedilol dose in these studies was 12.5 mg/day
suggesting that worsening of sodium and water retention
may be not relevant for relatively low carvedilol doses,
which, on the other hand, may be effective in clinical
practice. However, in a more recent study of primary
566

prophylaxis of variceal bleeding,28 where carvedilol

was used as a rescue treatment for propranolol hemodynamic nonresponders, no increase in new ascites
development was reported under carvedilol, although 27
of 67 patients given carvedilol received a dose 25 mg/
day.
A nal consideration is with regard to publication
bias. We may not exclude that some negative trial has
been performed and not published. On the other hand,
the low number of available studies with low and similar
numbers of patients included hampers achieving a
Aliment Pharmacol Ther 2014; 39: 557-568
2014 John Wiley & Sons Ltd

Systematic review with meta-analysis: carvedilol vs. propranolol for portal hypertension
reliable estimation by Funnel plot asymmetry tests29,
which, in such a situation, have unsatisfactory power.
In conclusion, this meta-analysis shows that carvedilol
reduces HVPG signicantly more than propranolol either
after one single administration or in a more long-term up
to 1 week to 3 months. This effect is achieved at the
expense of marked reduction in arterial pressure, which
becomes symptomatic in an appreciable proportion of
patients. Yet, worsening of water retention is to be
expected in several patients, although the lack of randomised trials comparing the clinical effects of carvedilol
with propranolol hampers drawing conclusions for clinical
practice on this potentially harmful effect. Moreover, the
two recent RCTs showing that carvedilol is as effective as
banding ligation for primary prevention of variceal bleeding (and even superior in the intention-to-treat analysis)18
and as effective as nadolol plus isosorbide mononitrate for
secondary prevention19 support a potential for a clinical
benet from carvedilol. This consideration is much
strengthened by a recent study showing that carvedilol
may achieve a hemodynamic response in 56% of patients
failing to respond to propranolol,28 although further RCTs
should be encouraged.
Available data suggest that carvedilol may be considered for portal hypertension at least in patients failing to
reach a hemodynamic response to propranolol28 or for

concomitant presence of portal and arterial hypertension,

while liver decompensation and serum creatinine above
the upper normal limit should be considered at least relative contraindications. If a decision is made to use carvedilol, the starting dose should be very low with stepwise
titration up to 12.5 (or 25 if tolerated) mg/day, preferably in two daily doses. The dose may be lower in decompensated patients in whom a better hemodynamic effect
may be expected. Side effects should be strictly monitored, particularly hypotension, and worsening of sodium
and water retention and renal function.

AUTHORSHIP
Guarantor of the article: G.DAmico
Author contributions: E. Sinagra: study design, data collection, results interpretation, rst draft of the article. G.
Perricone: study design, data collection, results interpretation, correction of draft article and tables. M DAmico:
data checking, results interpretation, draft article correction. F Tine: checking statistical analysis, results interpretation. G DAmico: research idea, study design, statistical
analysis, results interpretation, nal article writing. All
authors approved the nal version of the manuscript.
ACKNOWLEDGEMENT
Declaration of personal and funding interests: None.

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