Systematic Review With Meta-analysis

The Effects of Rifaximin in Hepatic Encephalopathy

N. Kimer; A. Krag; S. Møller; F. Bendtsen; L. L. Gluud


Aliment Pharmacol Ther. 2014;40(2):123-132. 

In This Article

Abstract and Introduction


Background Rifaximin is recommended for prevention of hepatic encephalopathy (HE). The effects of rifaximin on overt and minimal HE are debated.

Aim To perform a systematic review and meta-analysis of randomised controlled trials (RCTs) on rifaximin for HE.

Methods We performed electronic and manual searches, gathered information from the U.S. Food and Drug Administration Home Page, and obtained unpublished information on trial design and outcome measures from authors and pharmaceutical companies. Meta-analyses were performed and results presented as risk ratios (RR) with 95% confidence intervals (CI) and the number needed to treat. Subgroup, sensitivity, regression and sequential analyses were performed to evaluate the risk of bias and sources of heterogeneity.

Results We included 19 RCTs with 1370 patients. Outcomes were recalculated based on unpublished information of 11 trials. Overall, rifaximin had a beneficial effect on secondary prevention of HE (RR: 1.32; 95% CI 1.06–1.65), but not in a sensitivity analysis on rifaximin after TIPSS (RR: 1.27; 95% CI 1.00–1.53). Rifaximin increased the proportion of patients who recovered from HE (RR: 0.59; 95% CI: 0.46–0.76) and reduced mortality (RR: 0.68, 95% CI 0.48–0.97). The results were robust to adjustments for bias control. No small study effects were identified. The sequential analyses only confirmed the results of the analysis on HE recovery.

Conclusions Rifaximin has a beneficial effect on hepatic encephalopathy and may reduce mortality. The combined evidence suggests that rifaximin may be considered in the evidence-based management of hepatic encephalopathy.


Hepatic encephalopathy (HE) is a neuropsychiatric syndrome seen in patients with advanced liver disease. The symptoms include neurological impairment, ranging from minor defaults in orientation and coordination to deep coma.[1] Hospitalisations are common and the impact on the quality of life among out-patients is significant and 1-year survival rates are below 50%.[2] The type of HE can be divided into clinically overt and minimal, which requires neurological and functional testing.[3,4] The development of HE involves ammonia, inflammation and nitrosative stress.[1,5] Current treatment regimens aim to reduce the production or increase the elimination of ammonia.[1,6–11] Several trials have evaluated the effects of branched-chain amino acids and rifaximin.[12,13] A meta-analysis of randomised controlled trials (RCTs) on branched-chain amino acids found a beneficial effect on manifestations of HE, but no effect on mortality.[14] A large RCT found that rifaximin prevents HE episodes.[15] The results of RCTs on rifaximin for minimal or overt HE are equivocal and none provides firm evidence to allow for clinical recommendations. Meta-analyses on rifaximin for patients with HE have also generated inconsistent results. One meta-analysis including seven RCTs found that rifaximin had a beneficial effect on HE compared to non-absorbable disaccharides.[16] A subsequent meta-analysis including eight controlled trials concluded that the effect of rifaximin and non-absorbable disaccharides on HE was similar.[17] A larger meta-analysis on 12 RCTs also found that the effect of rifaximin was similar to conventional treatments.[12] The combined evidence therefore remains inconclusive. Accordingly, we performed a systematic review with meta-analyses of RCTs on rifaximin vs. placebo, disaccharides or other antibiotics for overt, minimal and recurrent HE.