Efficacy and Safety of Rifaximin Versus Placebo or Other Active Drugs in Critical ill Patients With Hepatic Encephalopathy

Abstract

Objective: Rifaximin has been approved for use as a first-line therapy for secondary prophylaxis of hepatic encephalopathy (HE). This article is to update existing evidence on efficacy and safety of rifaximin treatment and prevention for HE. Methods: We systematically searched multiple databases until January 31 2021. The studies compared rifaximin vs. placebo or other active drugs (i.e., nonabsorbable disaccharides, other antibiotics, L-ornithine-L-aspartate (LOLA), and probiotics) for patients with overt HE (OHE), minimal HE (MHE), and recurrent HE. Results: Twenty-eight randomized controlled trials with a total of 2979 patients were included. Compared with the controls, rifaximin significantly reduced HE grade (OHE: RR = 1.11, 95% CI = 1.02-1.21), improved the cognitive impairments (MHE: RR = 1.82, 95% CI = 1.12-2.93) and prevented the risk of HE recurrent episodes (RR = 1.33, 95% CI = 1.18-1.49). No statistical difference was observed in mortality between rifaximin and their controls (RR = 0.82, 95% CI = 0.54-1.24). The incidence of total adverse events in rifaximin-treated groups was significantly lower than that in the controls during the treatment period (RR = 0.73, 95% CI = 0.54-0.98). In addition, rifaximin treatment was better than other active drugs in improving psychometric indicators (mental state, flapping tremor and portosystemic encephalopathy (PSE) index) and reducing the risk of rehospitalization in HE patients. Conclusion: Rifaximin therapy is effective and well-tolerated in different types of HE, which might be recommended as an alternative to conventional oral drugs in clinical settings.

Keywords: efficacy; hepatic encephalopathy; meta-analysis; rifaximin; safety.

FIGURE 1

Flowchart of study screen in this meta-analysis.

FIGURE 2

Risk of bias graph: reviewers’ judgments about each risk of bias item presented as percentages across all included studies (A). Risk of bias summary: reviewers’ judgments about each risk of bias item for each included study according to the Cochrane Collaboration’s “Risk of Bias” tool, the green circle with “plus” sign representing low risk of bias, the yellow circle with “question mark” sign representing unclear risk of bias and the red circle with “minus” sign representing high risk of bias (B).

FIGURE 3

Funnel plots evaluating publication bias for different outcomes: (A) OHE improvement, (B) prevention of recurrent HE, (C) blood ammonia level, (D) mortality, (E) total adverse events, (F) abdominal pain, and (G) diarrhea.

FIGURE 4

Forest plot of randomized controlled trials on rifaximin vs. placebo or other active drugs on the OHE improvement (A), MHE reversal (B), and prevention of recurrent HE (C).

FIGURE 5

Forest plot of randomized controlled trials on rifaximin treatment for HE. The outcome measure was mortality. The control groups received placebo or other active drugs.

FIGURE 6

Forest plot of randomized controlled trials on the safety of rifaximin treatment for HE. The outcome measures included total adverse events, abdominal pain, diarrhea, nausea, vomiting and fatigue. The control groups received placebo or other active drugs. (A) Total adverse events; (B) Abdominal pain; (C) Diarrhea; (D) Nausea; (E) Vomiting; (F) Fatigue.