title: Pharmacological interventions for alcoholic liver disease (alcohol-related liver disease): an attempted network meta-analysis.
abstract: Alcohol-related liver disease is due to excessive alcohol consumption. It includes a spectrum of liver diseases such as alcohol-related fatty liver, alcoholic hepatitis, and alcoholic cirrhosis. Mortality associated with alcoholic hepatitis is high. The optimal pharmacological treatment of alcoholic hepatitis and other alcohol-related liver disease remains controversial.
  
  
  
  To assess the comparative benefits and harms of different pharmacological interventions in the management of alcohol-related liver disease through a network meta-analysis and to generate rankings of the available pharmacological interventions according to their safety and efficacy in order to identify potential treatments. However, even in the subgroup of participants when the potential effect modifiers appeared reasonably similar across comparisons, there was evidence of inconsistency by one or more methods of assessment of inconsistency. Therefore, we did not report the results of the network meta-analysis and reported the comparative benefits and harms of different interventions using standard Cochrane methodology.
  
  
  
  We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, Science Citation Index Expanded, World Health Organization International Clinical Trials Registry Platform and randomised controlled trials registers until February 2017 to identify randomised clinical trials on pharmacological treatments for alcohol-related liver diseases.
  
  
  
  Randomised clinical trials (irrespective of language, blinding, or publication status) including participants with alcohol-related liver disease. We excluded trials that included participants who had previously undergone liver transplantation and those with co-existing chronic viral diseases. We considered any of the various pharmacological interventions compared with each other or with placebo or no intervention.
  
  
  
  Two review authors independently identified trials and independently extracted data. We calculated the odds ratio (OR) and rate ratio with 95% confidence intervals (CIs) using both fixed-effect and random-effects models based on available-participant analysis with Review Manager. We assessed risk of bias according to Cochrane, controlled risk of random errors with Trial Sequential Analysis, and assessed the quality of the evidence using GRADE.
  
  
  
  We identified a total of 81 randomised clinical trials. All the trials were at high risk of bias, and the overall quality of the evidence was low or very low for all outcomes. Alcoholic hepatitisFifty randomised clinical trials included 4484 participants with alcoholic hepatitis. The period of follow-up ranged from one to 12 months. Because of concerns about transitivity assumption, we did not perform the network meta-analysis. None of the active interventions showed any improvement in any of the clinical outcomes reported in the trials, which includes mortality (at various time points), cirrhosis, decompensated cirrhosis, liver transplantation. None of the trials reported health-related quality of life or incidence of hepatocellular carcinoma. Severe alcoholic hepatitisOf the trials on alcoholic hepatitis, 19 trials (2545 participants) included exclusively participants with severe alcoholic hepatitis (Maddrey Discriminat Function > 32). The period of follow-up ranged from one to 12 months. There was no alteration in the conclusions when only people with severe alcoholic hepatitis were included in the analysis.
  
  
  
  Eleven trials were funded by parties with vested interest in the results. Sixteen trials were funded by parties without vested interest in the results. The source of funding was not reported in 23 trials. Other alcohol-related liver diseasesThirty-one randomised clinical trials included 3695 participants with other alcohol-related liver diseases (with a wide spectrum of alcohol-related liver diseases). The period of follow-up ranged from one to 48 months. The mortality at maximal follow-up was lower in the propylthiouracil group versus the no intervention group (OR 0.45, 95% CI 0.26 to 0.78; 423 participants; 2 trials; low-quality evidence). However, this result is based on two small trials at high risk of bias and further confirmation in larger trials of low risk of bias is necessary to recommend propylthiouracil routinely in people with other alcohol-related liver diseases. The mortality at maximal follow-up was higher in the ursodeoxycholic acid group versus the no intervention group (OR 2.09, 95% CI 1.12 to 3.90; 226 participants; 1 trial; low-quality evidence).
  
  
  
  Twelve trials were funded by parties with vested interest in the results. Three trials were funded by parties without vested interest in the results. The source of funding was not reported in 16 trials.
  
  
  
  Because of very low-quality evidence, there is uncertainty in the effectiveness of any pharmacological intervention versus no intervention in people with alcoholic hepatitis or severe alcoholic hepatitis. Based on low-quality evidence, propylthiouracil may decrease mortality in people with other alcohol-related liver diseases. However, these results must be confirmed by adequately powered trials with low risk of bias before propylthiouracil can be considered effective.Future randomised clinical trials should be conducted with approximately 200 participants in each group and follow-up of one to two years in order to compare the benefits and harms of different treatments in people with alcoholic hepatitis. Randomised clinical trials should include health-related quality of life and report serious adverse events separately from adverse events. Future randomised clinical trials should have a low risk of bias and low risk of random errors.
authors.affiliation: Sheila Sherlock Liver Centre, Royal Free Hospital and the UCL Institute of Liver and Digestive Health, London, UK.
authors.forename: Elena
authors.initials: E
authors.lastname: Buzzetti
authors.affiliation: Sheila Sherlock Liver Centre, Royal Free Hospital and the UCL Institute of Liver and Digestive Health, London, UK.
authors.forename: Maria
authors.initials: M
authors.lastname: Kalafateli
authors.affiliation: Sheila Sherlock Liver Centre, Royal Free Hospital and the UCL Institute of Liver and Digestive Health, London, UK.
authors.forename: Douglas
authors.initials: D
authors.lastname: Thorburn
authors.affiliation: Department of Surgery, Royal Free Campus, UCL Medical School, Pond Street, London, UK, NW3 2QG.
authors.forename: Brian R
authors.initials: BR
authors.lastname: Davidson
authors.affiliation: Department of Gastroenterology and Hepatology, Odense University Hospital, Sdr. Boulevard 29, Entrance 126, Odense, Denmark, 5000.
authors.forename: Maja
authors.initials: M
authors.lastname: Thiele
authors.affiliation: Gastrounit, Medical Division, Copenhagen University Hospital Hvidovre, Kettegaards Alle, Hvidovre, Denmark, 2650.
authors.forename: Lise Lotte
authors.initials: LL
authors.lastname: Gluud
authors.affiliation: Cochrane Italy, Department of Diagnostic, Clinical and Public Health Medicine, University of Modena and Reggio Emilia, Via del Pozzo 71, Modena, Italy, 41124.
authors.forename: Cinzia
authors.initials: C
authors.lastname: Del Giovane
authors.affiliation: Department of Hepatology, Rigshospitalet, Blegdamsvej 9, København Ø, Denmark, 2100.
authors.forename: Gro
authors.initials: G
authors.lastname: Askgaard
authors.affiliation: Department of Gastroenterology and Hepatology, Odense University Hospital, Sdr. Boulevard 29, indgang 126, Odense C, Denmark, 5000.
authors.forename: Aleksander
authors.initials: A
authors.lastname: Krag
authors.affiliation: Sheila Sherlock Liver Centre, Royal Free Hospital and the UCL Institute of Liver and Digestive Health, London, UK.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Tsochatzis
authors.affiliation: Department of Surgery, Royal Free Campus, UCL Medical School, Pond Street, London, UK, NW3 2QG.
authors.forename: Kurinchi Selvan
authors.initials: KS
authors.lastname: Gurusamy