Background: Rifaximin 550 mg tablets is a nonsystemic antibiotic indicated for reducing the risk of overt hepatic encephalopathy (HE) recurrence in adults and may be used in combination with lactulose. Practice guidelines state that rifaximin is effective as add-on therapy to lactulose for preventing overt HE recurrence. This pooled analysis evaluated the efficacy and safety of rifaximin plus lactulose as prophylaxis in patients with a history of overt HE.
Methods: The analysis included 2 randomized trials (1 phase 3 double-blind; 1 phase 4 open-label) of adults with cirrhosis in remission (Conn score ≤1) after an overt HE episode during the past 6 months. Patients received rifaximin 550 twice daily (or placebo in phase 3) for up to 6 months. Lactulose use (titrated to produce 2-3 soft stools/d) was permitted (phase 3) or required (treatment arm of phase 4). The time to onset of an overt HE episode (Conn score ≥2; primary endpoint in each trial) and time to first HE-related hospitalization (secondary endpoint in each trial) were determined; a Cox proportional-hazards model was used with effect for treatment.
Results: A total of 381 patients were treated with rifaximin + lactulose (n=236) or lactulose (+ placebo) alone (n=145). The mean age in the rifaximin + lactulose and lactulose alone groups was 56.9 vs 56.6 years, respectively; 58.9% vs 68.3% of patients were male, mean Model for End-Stage Liver Disease score was 12.5 vs 12.9, and 67.4% vs 67.6% of patients had a baseline Conn score of 0. Breakthrough HE was reported in significantly fewer patients treated with rifaximin + lactulose (19.1%) vs lactulose alone (49.0%; P<0.0001). Patients receiving rifaximin + lactulose had a 67.8% reduction in the risk of a breakthrough HE event during 6 months of treatment vs lactulose alone (hazard ratio [HR], 0.32; 95% confidence interval [CI]: 0.22 to 0.47). HE-related hospitalizations were observed in 11.9% of patients treated with rifaximin + lactulose vs 23.4% of patients treated with placebo during 6 months of treatment, with a 59.2% reduction in risk (HR=0.41; 95% CI: 0.25 to 0.67; P=0.0003). The mortality rate during the studies was similar in the rifaximin + lactulose (5.1%) and lactulose alone (6.9%) groups. The most common AEs in the rifaximin + lactulose vs lactulose alone groups were peripheral edema (14.8% vs 9.0%), HE (13.6% vs 31.0%), nausea (13.1% vs 14.5%), ascites (12.3% vs 10.3%), diarrhea (11.9% vs 14.5%), fatigue (11.0% vs 12.4%), and insomnia (10.2% vs 7.6%).
Conclusions: Rifaximin + lactulose therapy was efficacious in reducing the risk of overt HE recurrence and HE-related hospitalization during a 6-month period in patients with cirrhosis and a history of overt HE. Rifaximin + lactulose prophylaxis should be considered for any patient with a history of or hospitalized due to an episode of overt HE.Support provided by Salix Pharmaceuticals.