Rifaximin for the prevention and treatment of hepatic encephalopathy: a systematic review and meta-analysis of randomized clinical trials
Harry Demetrios Zacharias et al.
SAT501 Rifaximin for the prevention and treatment of hepatic encephalopathy: a systematic review and meta-analysis of randomized clinical trials Harry D Zacharias1, Jaclyn Yizhen Tan1, Fady Kamel1, Nina Kimer2, Lise Lotte Gluud2, Marsha Morgan1. 1UCL Institute for Liver and Digestive Health, Division of Medicine, Royal Free Campus, University College London, London, London, United Kingdom; 2Gastrounit, Medical Division, Copenhagen University Hospital Hvidovre, Hvidovre, Denmark Email: marsha.morgan@ucl.ac.uk Background and aims: Rifaximin has been used for the treatment of hepatic encephalopathy (HE), in patients with cirrhosis, since the 1990s. However, whilst individual studies have shown benefit in acute/recurrent, chronic, and minimal HE, its main licensed indication remains the prevention of recurrent HE in combination with non-absorbable disaccharides (NAD). This systematic review and meta-analyses of randomised clinical trials (RCTs) for the prevention and treatment of HE, in patients with cirrhosis, compared (i) rifaximin vs. placebo/no intervention; (ii) rifaximin vs. NAD; and (iii) rifaximin co-administered with NAD vs. NAD alone. Method: Electronic/manual searches of the literature were undertaken; further information was obtained from authors/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/sensitivity analyses. Results: A total of 38 RCTs involving 4376 people were included; Individual patient data were available for 7 trials and additional information for a further 17; some trials included more than one comparison. Twelve studies compared rifaximin with placebo/no intervention minimal (n = 5) or chronic HE (n = 3) or for HE prevention (n = 4); meta-analysis showed no effects of rifaximin on mortality or serious adverse events (SAEs) but an overall beneficial effect on HE (RR = 0.58, 95% CI 0.56–0.91; NNTB = 5; participants = 969), confirmed in subgroup analyses in minimal HE but not in chronic HE or for HE prevention. Rifaximin was compared with NADs in 13 studies acute (n = 4), chronic (n = 4) and minimal HE (n = 2) and for HE prevention (n = 3); there were no effects of rifaximin on mortality, SAEs or HE. The effects of rifaximin plus lactulose against lactulose alone were compared in 16 trials in acute HE (n = 8) and for HE prevention (n = 8); rifaximin plus lactulose had a beneficial effect on mortality (RR 0.69, 0.55–0.86; NNTB = 20; participants = 1836), subgroup analyses confirmed mortality benefit in acute HE (RR 0.65, 0.46–0.92; NNTB = 13; participants = 692) but not in HE prevention. Co-administration of the two drugs also had a beneficial effect on HE (RR 0.58, 0.48 to 0.71; n = 2306), with a NNTB of 5. Subgroup analyses confirmed benefit in both the treatment of acute HE (RR 0.62, 0.45 to 0.87) and in HE prevention (RR 0.54, 0.42 to 0.69) (Figure 1); there was no overall effect on SAEs; the evidence was of low to very low quality. Figure: Random-effects meta-analysis of RCTs comparing the effect of rifaximin plus NAD vs. NAD alone Conclusion: Rifaximin monotherapy does not convey benefit compared to NADs. However, rifaximin combined with lactulose is a safe and effective intervention for people with cirrhosis and acute HE, and for the prevention of recurrent HE. However, further high quality studies are needed.
