Rifaximin for the Prevention and Treatment of Hepatic Encephalopathy: A Systematic Review With Meta-Analyses of Randomised Controlled Trials

Abstract

Background: The main licensed indication for rifaximin is the prevention of recurrent hepatic encephalopathy (HE) after an index event although many early trials showed it was an efficacious treatment for both acute and chronic HE. The aim of this study was to assess the efficacy and safety of rifaximin in patients with cirrhosis by undertaking meta-analyses of RCTs comparing rifaximin vs. placebo/no intervention or vs. non-absorbable disaccharides (NADs). Methods: Electronic and manual searches of the literature were undertaken; further information was obtained from trialists and pharmaceutical companies. Meta-analyses were conducted and results presented as relative risks (RR) and 95% confidence intervals (CI). Sources of heterogeneity and the influence of random and systematic errors were evaluated in subgroup and trial sequential analyses. Results: A total of 21 RCTs involving 2258 patients were included. Individual patient data were obtained from five trials and unpublished information from 10 trials. Rifaximin showed a beneficial effect on mortality compared with placebo/no intervention when including all 11 RCTs (RR 0.58, 0.44–0.77; participants = 1129). Subgroup analyses showed that rifaximin reduced mortality in overt HE (0.50, 0.36–0.71), but not in minimal HE (0.50, 0.20–1.22), or in the prevention trials (1.01, 0.54–1.88) or when excluding the five RCTs in which NADs were used as co-intervention (0.74, 0.31–1.77) (Figure 1). Additional analyses showed a beneficial effect of rifaximin on overt HE (0.62, 0.41–0.93) and minimal HE (0.43, 0.30–0.62), but not in the prevention of HE (0.80, 0.45–1.42) or in an analysis that excluded RCTs in which NADs were used as co-invention (0.64, 0.39–1.04). Rifaximin reduced the risk of serious adverse events (SAE) (0.65, 0.51–0.84) and had a potential beneficial effect on Quality of Life (MD −2.05, −2.78 to −1.32). In meta-analyses of six RCTs comparing rifaximin vs. NADs, it had no effect on mortality (0.86, 0.42–1.77; participants = 447); it had a beneficial effect on overt HE (0.64, 0.43–0.93), but not minimal HE (0.85, 0.47–1.53) or in the prevention trials (0.89, 0.51–1.57); it did not reduce the risk of SAEs (RR 0.89, 0.56–1.42). Conclusion: There is moderate to low quality evidence that rifaximin combined with NADs is a safe and effective intervention for patients with cirrhosis and overt or minimal HE and for the prevention of recurrent HE after an index event. Disclosures/Financial Association: Nina Kimer has received rifaximin and placebo tablets, and an unrestricted grant from Norgine for a clinical trial. The authors have none to declare.