Flumazenil vs. placebo in hepatic encephalopathy in patients with cirrhosis: a meta-analysis

Background: Randomized controlled trials testing flumazenil in hepatic encephalopathy have shown conflicting results. Aim: To compare flumazenil and placebo in hepatic encephalopathy in patients with cirrhosis. Methods: An overview of randomized controlled trials comparing flumazenil and placebo in hepatic encephalopathy in patients with cirrhosis was performed. For each end-point, heterogeneity and treatment efficacy were assessed by Peto and Der Simonian methods. As most trials were crossover in nature, a sensitivity analysis was performed including the two treatment periods. Results: Six double-blind randomized controlled trials, including 641 patients (326 treated with flumazenil and 315 with placebo), were identified. The treatment duration ranged from 5 min to 3 days. Heterogeneity tests between control groups were not significant. The mean percentages of patients with clinical improvement (five trials) were 27% in treated groups and 3% in placebo groups. This difference was significant by both methods (Peto: odds ratio == 6.15: 95% confidence interval, 4.0-9.5: P<0.001: Der Simonian: mean rate difference, 29%: 95% confidence interval. 17-41; P<0.001). The mean percentages of patients with electroencephalographic improvement were 19% in treated groups and 2% in placebo groups. This difference was significant only with the Peto method (odds ratio = 5.8; 95% confidence interval, 3.4-9.7; P<0.001). The sensitivity analysis showed similar results. Conclusions: This, meta-analysis shows that flumazenil induces clinical and electroencephalographic improvement of hepatic encephalopathy in patients with cirrhosis.