Managing Hepatic Encephalopathy - Combination of Lactulose and Rifaximin Versus Lactulose Monotherapy: A Systematic Review and Meta-analysis

Background: Hepatic Encephalopathy (HE), a neuropsychiatric complication of hepatic failure, is currently managed with lactulose as a first-line treatment followed by other adjuncts if needed. In this meta-analysis, we determined the effect of lactulose and rifaximin combination in terms of efficacy and mortality reduction compared to lactulose alone. Materials and Methods: We searched databases (PubMed, BioMed Central, and Cochrane-Central) until July 2022 for original studies inspecting the effects of Rifaximin and Lactulose (combination therapy) vs. lactulose as a monotherapy in the treatment of HE on outcomes of clinical efficacy, hospital stay length, HE recurrence, drugs’ side effects and mortality. Data was analyzed via Review Manager (version 5.4.1) and OpenMetaAnalyst. Relative risks (RR) and weighted mean differences (WMD) with 95% confidence intervals were calculated. Results: Fifteen studies with 4327 patients were included. Pooled analysis showed combination therapy to be associated with a significantly lower mortality rate in patients having HE when compared to lactulose alone (RR 0.71 95% CI 0.58-0.88, P=0.002, I2= 68%), and clinical efficacy was also improved in the combination group (RR 1.33, 95%CI 1.19-1.48, P <0.00001, I2= 52%). HE recurrence rate, adverse events, and length of hospital stay did not significantly differ among the two groups (RR= 0.61, 95 % CI= 0.35 to 1.05, P= 0.08, I2= 84%), (RR= 0.92, 95% CI= 0.51 to 1.69, P= 0.80, I2 = 0) and (WMD −1.52, 95% CI −3.22 to 0.18, P=0.08, I2 = 83%) respectively. Conclusions: Combination therapy shows survival benefits and superior clinical efficacy over lactulose monotherapy in managing hepatic encephalopathy.