Carvedilol reduces the risk of decompensation and mortality in patients with compensated cirrhosis in a competing-risk meta-analysis.

Whether non-selective β-blockers can prevent decompensation of cirrhosis needs 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 compensated cirrhosis with clinically significant portal hypertension (CSPH).

METHODS

By systematic review we identified RCTs comparing carvedilol vs control therapy (no-active treatment or 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 (OLT and death were competing-events) and death (OLT, competing-event). Models were adjusted using propensity score for baseline covariates with the IPTW approach.

RESULTS

Among 125 full-text studies evaluated, 4 RCTs were eligible. The four 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 (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 start therapy with carvedilol can improve outcomes.

LAY SUMMARY

Portal hypertension is a main determinant of the progression of cirrhosis from compensated to decompensation with the consequent increase in morbidity and worsening of life expectancy. It has been suggested that NSBBs can prevent decompensation, but this has not been clarified. Carvedilol might be particularly useful since its intrinsic vasodilatory activity may ameliorate hepatic vascular resistance, which is a major mechanism of portal hypertension in compensated cirrhosis. We aimed to investigate such possibility using an individual participant data with competing-risk meta-analysis, to optimize sample size and properly investigate cirrhosis as a multistate disease and outcomes as time-dependent events. The study shows that carvedilol significantly decreases the risk of decompensation in patients with compensated cirrhosis and CSPH, mainly by reducing the risk of developing ascites. Even more importantly, carvedilol improved survival in these patients. The findings suggest that screening patients with compensated cirrhosis for CSPH to start therapy with carvedilol, can prevent the progression of compensated cirrhosis to decompensation improving survival.

PROSPERO REGISTRATION NUMBER

CRD42019144786.