Stratified efficacy of first -line therapy to prevent first variceal bleeding according to previous decompensation of cirrhosis. A competing-risk meta-analyses of individual participant data

Abstract

Background and aims: Non-selective β-blockers (NSBB) and endoscopic variceal ligation (EVL) are indicated to prevent first variceal bleeding in cirrhosis. However, compensated and decompensated cirrhosis differ in pathophysiology, prognosis and response to NSBB. Moreover, recent data show that NSBB may prevent ascites in compensated patients. We aimed to assess the efficacy of NSBB vs EVL in patients with high-risk varices treated to prevent first bleeding, stratifying risk according compensation/decompensation of cirrhosis.

Method: A systematic review was performed to identify RCTs comparing NSBBs vs EVL, either in monotherapy or combined, for 1ry prevention of bleeding in cirrhosis. We performed a competing-risk time-to-event meta-analysis using individual patient data (IPD) obtained from principal investigators of RCTs, using an Inverse Probability of the Treatment Weights (IPTW) approach. Analyses were stratified according to present or previous decompensation (bleeding, ascites or encephalopathy). Outcomes included death, prevention of bleeding and prevention of ascites. OLT and death were competing-events.

Results: Among 25 RCTs eligible, 11 providing IPD were included. Overall, 1400 patients were included (656 compensated), 625 treated with NSBB, 546 with EVL and 229 with NSBB+EVL. There were no differences in baseline characteristics between groups. Over 19 months of follow-up, bleeding occurred in 16% compensated vs 16% decompensated (SHR = 1.09, 95% CI = 0.83–1.44, P = 0.537), and death in 15% vs 28% respectively (SHR = 2.58, 95% CI = 1.02–3.28, P < 0.0001). Overall, risk of death was similar with EVL vs NSBB (SHR = 1.04, 95% CI = 0.71–1.52, P = 0.848) and with EVL+NSBB vs either alone, with heterogeneity (I2 = 77%). In compensated patients, mortality risk was lower with NSBB vs EVL (SHR = 0.57, 95% CI = 0.36–0.90; P = 0.016) and was similar with NSBB+EVL vs NSBB ( p = 0.104), without heterogeneity (I2 = 0.0%). In decompensated patients, mortality risk was similar with EVL vs NSBB (SHR = 0.81, 95% CI = 0.52–1.26, P = 0.350) and with NSBB+EVL vs NSBB ( p = 0.469) and vs EVL ( p = 0.357), without heterogeneity (I2 = 34%). The risk of first bleeding was similar with EVL vs NSBB in compensated ( p = 0.85) and decompensated patients ( p = 0.64). The risk of ascites was higher with EVL vs NSBB (SHR = 2.66, 95% CI = 1.36–5.19, P = 0.004) in compensated patients and was similar in decompensated ( p = 0.316).

Conclusion: In patients with compensated cirrhosis and high-risk varices treated to prevent bleeding, NSBB achieved better survival than EVL, without additional benefit by adding EVL to NSBB. The risk of bleeding was similar with both therapies but risk of developing ascites was lower with NSBB. In decompensated patients, survival was similar using NSBB or EVL or combining both. The NSBB may be preferable in compensated patients for prevention of bleeding, while either NSBB or EVL can be used in decompensated.