Comparative Effectiveness of Different Pharmacological Interventions for the Treatment of Minimal Hepatic Encephalopathy: A Systematic Review With Network Meta-analysis

Abstract

Background and Aims: Minimal hepatic encephalopathy (MHE) is the mildest presentation of hepatic encephalopathy (HE), which includes a spectrum of neuropsychiatric manifestations ranging from subtle cognitive decline to deep coma. MHE has been shown to impair quality of life, predict overt HE (OHE), and even death. Various treatment modalities including lactulose, rifaximine, probiotics, branched chain amino acids and ammonia scavengers have shown benefit in MHE. However, due to a paucity of comparative studies, a clear consensus on the optimal treatment of MHE is yet to be reached. To address this deficiency, we evaluated the comparative effectiveness of all agents used for treatment of MHE using a network meta-analysis, combining direct and indirect treatment comparisons of all available randomized clinical trials(RCTs). Methods: We performed a systematic search of the PubMed, EMBASE, OvidSP and CENTRAL databases for RCTs of adults with MHE that compared the effectiveness of active interventions [Lactulose, l-Ornithine l-Aspartate (LOLA), rifaximine, pre-/pro-/synbiotics (PPS), branched chain amino acids(BCAA), alone or in combination] with each other or placebo. We used Bayesian network meta-analysis to combine direct and indirect evidence to estimate odds ratios (ORs) between treatments, and used Grading of Recommendations Assessment, Development and Evaluation criteria to appraise quality of evidence. Results: We identified 27 RCTs (2056 participants) comparing 5 different interventions for reversal of minimal HE and 21 RCTs (1162 participants) comparing 4 different interventions to prevent the development of overt HE. In network meta-analysis, in the order of superiority, rifaximine [odds ratio (OR), 8.14; 95% predictive interval (PrI), 4.49–14.74], lactulose (OR, 5.64; 95% PrI, 3.64–8.73), probiotics + lactulose (OR, 4.72; 95% PrI, 1.22–18.28), LOLA (OR, 4.43; 95% PrI, 2.39–8.22), PPS (OR, 4.37; 95% PrI, 2.66–7.19) and BCAA (OR, 2.16; 95% PrI, 1.03–4.56), showed significant improvement in reversal of minimal HE compared to placebo or no intervention. Rifaximin was superior to BCAA (OR, 0.27; 95% PrI, 0.10–0.69), PPS (OR, 0.54; 95% PrI, 0.28–1.03), LOLA (OR, 0.54; 95% PrI, 0.26–1.14), probiotics + lactulose (OR, 0.58; 95% PrI, 0.14–2.38, lactulose (OR, 0.69; 95% PrI, 0.38–1.25) in reversing MHE. In terms of prevention of development of OHE, LOLA (OR 0.16; 95% PrI, 0.04–0.64), lactulose (OR, 0.21; 95% PrI, 0.09–0.48), PPS (OR, 0.25; 95% PrI, 0.11–0.59), but not rifaximine (OR 0.44; 95% PrI, 0.09–2.04), significantly reduced the risk when compared to placebo or no treatment. However, none of the agents were found to be superior to the others in prevention of OHE. Conclusion: There is a moderate quality evidence to suggest that rifaximine followed by lactulose are the most effective interventions for reversal of MHE. For prevention of development of OHE, LOLA (low quality) followed by lactulose (moderate quality) were most effective. Lactulose is the only agent that is effective both in improving reversal of minimal HE and reducing the risk of development of overt HE (Figure 1, Figure 2).Figure 2SUCRA plots of the under the cumulative ranking curves for all treatments in (a) minimal HE reversal network and (b) development of overt HE network.View Large Image Figure ViewerDownload Hi-res image Download (PPT) The authors have none to declare.