Systematic Review and Meta‐Analysis of Lactulose for the Prevention and Treatment of Hepatic Encephalopathy

BACKGROUND AND AIMS: Hepatic encephalopathy (HE) is morbid and increases mortality in cirrhosis. Lactulose is first-line therapy for HE treatment and secondary prophylaxis; however, data supporting its role in primary prevention of incident HE is less definitive. We therefore conducted a systematic review and meta-analysis of the most current evidence evaluating lactulose for the prevention and treatment of HE to guide future management. METHODS: Medline, EMBASE, and Cochrane Library databases were searched for randomized controlled trials comparing lactulose to placebo or non-drug control for the treatment or prevention of HE. 17 studies with 1428 patients were analyzed. Random effects meta-analysis evaluated four main outcomes: overt HE (OHE), mortality, treatment discontinuation, and serious adverse events. Bayesian meta-analysis assessed two main outcomes: risk of overt HE and mortality. RESULTS: We found that lactulose significantly reduces the incidence of OHE compared to no lactulose, with a pooled relative risk (RR) of 0.48 (95% CI 0.37-0.63) and RR of 0.43 (95% CI 0.27-0.69) for those focusing on primary prophylaxis. There was no increased risk of adverse events (RR 0.87, 95% CI 0.64-1.17). Further, using Bayesian statistics, there exists a high probability that lactulose reduces mortality in individuals with HE (pooled posterior RR 0.72-0.88). CONCLUSIONS: Lactulose therapy safely contributes to a significant reduction in incident HE and is highly likely to reduce mortality. These results should guide HE prevention and management, as well as inform future investigations regarding the long-term benefits of lactulose.