Comparative Outcomes of Rifaximin Monotherapy and Lactulose in Cirrhosis: A Multicenter Cohort Study

Hepatic encephalopathy (HE) is a frequent complication of cirrhosis. Lactulose is guideline-recommended first-line therapy, whereas rifaximin is typically used adjunctively or when lactulose is not tolerated. We compared real-world outcomes of rifaximin monotherapy versus lactulose monotherapy for secondary HE prophylaxis. Using the TriNetX research network, we identified adults with cirrhosis (K74.6) and HE (K76.82) prescribed rifaximin or lactulose monotherapy, excluding patients with liver transplant, end-stage renal disease, or combination therapy. The index date was the first qualifying prescription after cirrhosis and HE documentation. After 1:1 propensity score matching for demographics, comorbidities, liver disease severity, polyethylene glycol-3350 use, and Model for End-Stage Liver Disease components, 1,734 matched pairs were analyzed. Outcomes were assessed using Cox proportional hazards models. Compared with lactulose, rifaximin was associated with lower all-cause mortality (hazard ratio [HR], 0.69; 95% confidence interval [CI], 0.60 to 0.79), hospitalization (HR, 0.46; 95% CI, 0.41 to 0.51), and SBP (HR, 0.29; 95% CI, 0.15 to 0.53), with similar recurrent HE (HR, 1.05; 95% CI, 0.94 to 1.16). These observational findings are hypothesis-generating and warrant prospective comparative and cost-effectiveness studies.