Long-term Outcomes with Carvedilol versus Propranolol in Patients with Index Variceal Bleed: 6-year Follow-up Study

Abstract

Aims and background: There is limited information on comparison of clinical outcomes with carvedilol for secondary prophylaxis following acute variceal bleed (AVB) when compared with propranolol. We report long-term clinical and safety outcomes of a randomised controlled trial comparing carvedilol with propranolol with respect to reduction in hepatic venous pressure gradient (HVPG) in patients after AVB.

Methods: We conducted a post-hoc analysis of patients recruited in an open-label randomized controlled trial comparing carvedilol and propranolol following AVB, and estimated long-term rates of rebleed, survival, additional decompensation events and safety outcomes. Rebleed and other decompensations were compared using competing risks analysis, taking death as competing event, and survival was compared using Kaplan-Meier analysis.

Results: Forty-eight patients (25 taking carvedilol; 23 propranolol) were followed up for 6 years from randomization. More number of patients on carvedilol had HVPG response when compared with those taking propranolol (72%- carvedilol versus 47.8% propranolol, p = 0.047). Comparable 1-year and 3-year rates of rebleed (16.0% and 24.0% for carvedilol versus 8.9% and 36.7% for propranolol; p = 0.457) and survival (94.7% and 89.0% for carvedilol versus 100.0% and 79.8% for propranolol; p = 0.76) were obtained. New/worsening ascites was more common in those receiving propranolol (69.5% vs 40%; p = 0.04). Other clinical decompensations and complications of liver disease occurred at comparable rates between two groups. Drug-related adverse-events were similar in both groups.

Conclusion: Despite higher degree of HVPG response, long-term clinical, survival and safety outcomes in carvedilol are similar to those of propranolol in patients with decompensated cirrhosis after index variceal bleed with the exception of ascites that developed less frequently in patients with carvedilol.

Keywords: ACLF, acute on chronic liver failure; AFP, alpha fetoprotein; AVB, acute variceal bleed; CT, computer tomography; CTP, Child–Turcotte–Pugh; EASL-CLIF, European Association of Study of Liver Disease-Chronic Liver Failure Consortium; EBL, endoscopic band ligation; HE, hepatic encephalopathy; HRS, hepatorenal syndrome; HVPG, hepatic venous portal gradient; MELD score; MELD, model for end-stage liver disease; NSBB, non-selective beta blockers; SBP, spontaneous bacterial peritonitis; UGIE, upper gastrointestinal endoscopy; acute variceal bleed; ascites; carvedilol; hepatic venous pressure gradient; propranolol; secondary prophylaxis.

Figure 1

Competing risks plots showing cumulative rates of re-bleeding (green) and death (blue) across patients receiving carvedilol and propranolol in (A) the entire cohort and (B) the cohort of HVPG responders. The 1-year and 3-year cumulative re-bleeding rates were 8.9%, 36.7% and 16%, 24% for propranolol and carvedilol, respectively, (Gray's test; p = 0.457). Among HVPG responders, the 1-year and 3-year cumulative re-bleeding rates was 9.1%, 27.3% and 0%, 7.1% in propranolol and carvedilol group, respectively (Gray's test; p = 0.194).

Figure 2

Kaplan–Meier plots demonstrating overall survival rates in the whole cohort and in the subgroup of HVPG responders, with comparison across strata of the drug group, that is, carvedilol (red) or propranolol (blue), along with risk tables indicating number at risk of event in both groups. (A) The 1-year and 3-year survival in the propranolol and carvedilol group were 100%, 79% and 94.7%, 89% respectively (log-rank test; p = 0.76). (B) Among HVPG responders, the 1-year and 3 -year survival rates were 100%, 63.6% and 100%, 92.9% in propranolol and carvedilol groups, respectively (log-rank test; p = 0.27).

Figure 3

Competing risks plots representing cumulative rates of additional decompensation events that is, (A) new/worsening ascites, (B) spontaneous bacterial peritonitis, (C) hepatorenal syndrome, (D) overt hepatic encephalopathy, (E) acute on chronic liver failure and (F) hepatocellular carcinoma. Decompensation events were compared for both drugs, carvedilol and propranolol, and are represented in green, with death occurring before the respective event (blue) treated as competing risk.