Background: Cirrhosis-related complications and resulting decompensation are associated with poor prognosis. Reducing the risk of cirrhosis-related complications is an important goal when managing patients with cirrhosis. Bacterial-derived endotoxins are hypothesized to be a major contributor to the development of many of these complications. Rifaximin, a nonsystemic antibiotic, is currently indicated as secondary prophylaxis for reducing the risk of overt hepatic encephalopathy (HE) in adults. This post hoc analysis evaluated rifaximin for reducing the risk of cirrhosis-related complications versus placebo (PBO).

Methods: In a randomized, PBO-controlled, phase 3 trial, adults with cirrhosis and a history of ≥2 HE episodes, currently in remission, were randomly assigned to rifaximin 550 mg or PBO twice daily for 6 months. Clinic visits occurred on days 7 and 14, and every 2 weeks thereafter through to day 168 (end of treatment), with optional visits on days 42, 70, 98, 126, and 154. Time to first complication of cirrhosis (ie, overt HE, acute kidney injury/hepatorenal syndrome, variceal bleeding, and spontaneous bacterial peritonitis) was determined in subgroups. Subgroups were categorized by select baseline disease characteristics: Model of End-Stage Liver Disease (MELD) score and international normalized ratio (INR) value (MELD ≥12 and INR ≥1.2 vs MELD <12 and INR <1.2), and presence/absence of ascites.

Results: Demographic and baseline characteristics were generally comparable between rifaximin (n = 140) and PBO (n = 159) groups. More than half (53.6%) of rifaximin group had baseline MELD score ≥12 and INR ≥1.2 vs 49.1% in PBO group. Baseline ascites was observed in 36.4% (rifaximin group) and 34.6% (PBO group) of patients. In patients with both a MELD score ≥12 and INR ≥1.2, rifaximin reduced the relative risk of any complication by 60% (hazard ratio [HR], 0.40; 95% confidence interval [CI], 0.24-0.66; P<0.001) and the individual complication of overt HE by 68% (HR, 0.32; 95% CI, 0.19-0.56; P<0.0001) vs PBO during 6 months of treatment. In this subgroup, during 6 months of treatment, complications were reported in 32% (24/75) of patients in rifaximin group versus 59% (46/78) of patients in PBO group. For patients with a MELD score <12 and INR <1.2, rifaximin reduced the relative risk of any complication by 76% (HR, 0.24; 95% CI, 0.05-1.08; P < 0.05) vs PBO during 6 months of treatment. For patients with baseline ascites, rifaximin reduced the relative risk of any complication by 42% (HR, 0.58; 95% CI, 0.34-1.0; P=0.045) vs PBO during 6 months of treatment; in patients without baseline ascites, the risk reduction with rifaximin was 65% (HR, 0.35; 95% CI, 0.198-0.619; P<0.001).

Conclusions: Data suggest that rifaximin may be efficacious in preventing complications of cirrhosis, in addition to the complication of overt HE. Prospective studies are warranted to assess rifaximin as prophylaxis for cirrhosis-related complications.