Gastroenterology

Gastroenterology

Volume 149, Issue 4, October 2015, Pages 958-970.e12
Gastroenterology

Original Research
Full Report: Clinical—Liver
Comparative Effectiveness of Pharmacological Interventions for Severe Alcoholic Hepatitis: A Systematic Review and Network Meta-analysis

https://doi.org/10.1053/j.gastro.2015.06.006Get rights and content

Background & Aims

Severe alcoholic hepatitis (AH) has high mortality. We assessed the comparative effectiveness of pharmacological interventions for severe AH, through a network meta-analysis combining direct and indirect treatment comparisons.

Methods

We conducted a systematic literature review, through February 2015, for randomized controlled trials of adults with severe AH (discriminant function ≥32 and/or hepatic encephalopathy) that compared the efficacy of active pharmacologic interventions (corticosteroids, pentoxifylline, and N-acetylcysteine [NAC], alone or in combination) with each other or placebo, in reducing short-term mortality (primary outcome) and medium-term mortality, acute kidney injury, and/or infections (secondary outcomes). We performed direct and Bayesian network meta-analysis for all treatments, and used Grading of Recommendations Assessment, Development and Evaluation criteria to appraise quality of evidence.

Results

We included 22 randomized controlled trials (2621 patients) comparing 5 different interventions. In a direct meta-analysis, only corticosteroids decreased risk of short-term mortality. In a network meta-analysis, moderate quality evidence supported the use of corticosteroids alone (relative risk [RR], 0.54; 95% credible interval [CrI], 0.39-0.73) or in combination with pentoxifylline (RR, 0.53; 95% CrI, 0.36-0.78) or NAC (RR, 0.15; 95% CI, 0.05-0.39), to reduce short-term mortality; low quality evidence showed that pentoxifylline also decreased short-term mortality (RR, 0.70; 95% CrI, 0.50-0.97). The addition of NAC, but not pentoxifylline, to corticosteroids may be superior to corticosteroids alone for reducing short-term mortality. No treatment was effective in reducing medium-term mortality. Imprecise estimates and the small number of direct trials lowered the confidence in several comparisons.

Conclusions

In patients with severe AH, pentoxifylline and corticosteroids (alone and in combination with pentoxifylline or NAC) can reduce short-term mortality. No treatment decreases risk of medium-term mortality.

Section snippets

Methods

This systematic review is reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement and was conducted following a priori established protocol.17, 18 We also followed good research practices as outlined in the ISPOR (International Society for Pharmacoeconomics and Outcomes Research) report on interpreting indirect treatment comparisons and network meta-analysis for health-care decision making.19

Results

From a total of 614 unique studies identified using the search strategy, we included 22 RCTs in this network meta-analysis.2, 4, 5, 6, 7, 8, 9, 10, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41 Six RCTs of CS therapy were excluded (because of unclear definition of severe AH or inclusion of non-severe AH,42, 43, 44, 45 too short duration of CS therapy).46, 47 Two RCTs comparing prednisolone to budesonide and combination of prednisolone and metadoxine were excluded due to lack of

Discussion

In this systematic review and network meta-analysis, we combined direct and indirect evidence from 22 RCTs involving 2,621 patients with severe AH, to estimate the relative efficacy of all pharmacological interventions for decreasing short-term mortality. We made several key observations: (a) CS alone, CS+NAC and CS+PTX decrease short-term mortality in patients with severe AH, with moderate confidence in estimates; PTX alone also reduces short-term mortality, but with low confidence in

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    This article has an accompanying continuing medical education activity on page e15. Learning Objective: Upon completion of this exam, successful learners will be able to (1) compare the relative efficacy of treatments for acute severe alcoholic hepatitis, (2) assess the efficacy of pharmacologic treatment for medium-term mortality for severe alcoholic hepatitis, (3) assess the impact of pharmacologic treatment on acute kidney injury, and (4) assess the impact of pharmacologic treatment on infection in patients with severe alcoholic hepatitis.

    Conflicts of interest None of the authors have any conflicts of interest to declare.

    Funding This work was supporte in part by National Institutes of Health/National Institute on Alcohol Abuse and Alcoholism grant U01AA021788 (V.H.S.).

    Author names in bold designate shared co-first authors.

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