Highlights
- •Carvedilol significantly decreases the risk of decompensation in patients with cirrhosis and CSPH, mainly by reducing risk of ascites.
- •Even more importantly, carvedilol significantly improves survival in compensated patients.
- •Early initiation of carvedilol could prevent disease progression in patients with compensated cirrhosis and CSPH.
- •Patients with compensated cirrhosis should be screened for CSPH, so that treatment can be started early.
Background & Aims
Whether non-selective β-blockers can prevent decompensation of cirrhosis warrants
clarification. Carvedilol might be particularly effective since its intrinsic vasodilatory
activity may ameliorate hepatic vascular resistance, a major mechanism of portal hypertension
in early cirrhosis. We assessed whether carvedilol may prevent decompensation and
improve survival in patients with compensated cirrhosis and clinically significant
portal hypertension (CSPH).
Methods
By systematic review we identified randomized-controlled trials (RCTs) comparing carvedilol
vs. control therapy (no-active treatment or endoscopic variceal ligation [EVL]) in patients
with cirrhosis and CSPH without previous bleeding. We performed a competing-risk time-to-event
meta-analysis using individual patient data (IPD) obtained from principal investigators
of RCTs. Only compensated patients were included. Primary outcomes were prevention
of decompensation (liver transplantation and death were competing events) and death
(liver transplantation was a competing event). Models were adjusted using propensity
scores for baseline covariates with the inverse probability of treatment weighting
(IPTW) approach.
Results
Among 125 full-text studies evaluated, 4 RCTs were eligible. The 4 provided IPD and
were included, comprising 352 patients with compensated cirrhosis, 181 treated with
carvedilol and 171 controls (79 received EVL and 92 placebo). Baseline characteristics
were similar between groups. Standardized differences were <10% by IPTW. The risk
of developing decompensation of cirrhosis was lower with carvedilol than in controls
(subdistribution hazard ratio [SHR] 0.506; 95% CI 0.289-0.887; p = 0.017; I2 = 0.0%, Q-statistic-p = 0.880), mainly due to a reduced risk of ascites (SHR 0.491; 95% CI 0.247-0.974; p = 0.042; I2 = 0.0%, Q-statistic-p = 0.384). The risk of death was also lower with carvedilol (SHR 0.417; 95% CI 0.194-0.896;
p = 0.025; I2 = 0.0%, Q-statistic-p = 0.989).
Conclusions
Long-term carvedilol therapy reduced decompensation of cirrhosis and significantly
improved survival in compensated patients with CSPH. This suggests that screening
patients with compensated cirrhosis for CSPH to enable the prompt initiation of carvedilol
could improve outcomes.
PROSPERO registration number
CRD42019144786.
Lay summary
The transition from compensated cirrhosis to decompensated cirrhosis is associated
with markedly reduced life expectancy. Therefore, preventing decompensation in patients
with compensated cirrhosis would be associated with greatly improved patient outcomes.
There has been controversy regarding the use of non-selective β-blockers (portal pressure-lowering
medications) in patients with cirrhosis and elevated portal blood pressure (portal
hypertension). Herein, using a competing-risk meta-analysis to optimize sample size
and properly investigate cirrhosis as a multistate disease and outcomes as time-dependent
events, we show that carvedilol (a non-selective β-blocker) is associated with a reduced
risk of decompensating events and improved survival in patients with cirrhosis and
portal hypertension.
Graphical abstract
Graphical Abstract
Keywords
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Article info
Publication history
Published online: May 31, 2022
Accepted:
May 9,
2022
Received in revised form:
April 25,
2022
Received:
December 17,
2021
Identification
Copyright
© 2022 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
