title: The clinical effectiveness and cost-effectiveness of STeroids Or Pentoxifylline for Alcoholic Hepatitis (STOPAH): a 2 × 2 factorial randomised controlled trial.
abstract: BACKGROUND
  Alcoholic hepatitis (AH) is a distinct presentation of alcoholic liver disease arising in patients who have been drinking to excess for prolonged periods, which is characterised by jaundice and liver failure. Severe disease is associated with high short-term mortality. Prednisolone and pentoxifylline (PTX) are recommended in guidelines for treatment of severe AH, but trials supporting their use have given heterogeneous results and controversy persists about their benefit.
  
  
  OBJECTIVE
  The aim of the clinical effectiveness and cost-effectiveness of STeroids Or Pentoxifylline for Alcoholic Hepatitis trial was to resolve the clinical dilemma on the use of prednisolone or PTX.
  
  
  METHODS
  The trial was a randomised, double-blind, 2 × 2 factorial, multicentre design.
  
  
  METHODS
  Sixty-five gastroenterology and hepatology inpatient units across the UK.
  
  
  METHODS
  Patients with a clinical diagnosis of AH who had a Maddrey's discriminant function value of ≥ 32 were randomised into four arms: A, placebo/placebo; B, placebo/prednisolone; C, PTX/placebo; and D, PTX/prednisolone. Of the 5234 patients screened for the trial, 1103 were randomised and after withdrawals, 1053 were available for primary end-point analysis.
  
  
  METHODS
  Those allocated to prednisolone were given 40 mg daily for 28 days and those allocated to PTX were given 400 mg three times per day for 28 days.
  
  
  RESULTS
  The primary outcome measure was mortality at 28 days. Secondary outcome measures included mortality or liver transplant at 90 days and at 1 year. Rates of recidivism among survivors and the impact of recidivism on mortality were assessed.
  
  
  RESULTS
  At 28 days, in arm A, 45 of 269 (16.7%) patients died; in arm B, 38 of 266 (14.3%) died; in arm C, 50 of 258 (19.4%) died; and in arm D, 35 of 260 (13.5%) died. For PTX, the odds ratio for 28-day mortality was 1.07 [95% confidence interval (CI) 0.77 to 1.40; p = 0.686)] and for prednisolone the odds ratio was 0.72 (95% CI 0.52 to 1.01; p = 0.056). In the logistic regression analysis, accounting for indices of disease severity and prognosis, the odds ratio for 28-day mortality in the prednisolone-treated group was 0.61 (95% CI 0.41 to 0.91; p = 0.015). At 90 days and 1 year there were no significant differences in mortality rates between the treatment groups. Serious infections occurred in 13% of patients treated with prednisolone compared with 7% of controls (p = 0.002). At the 90-day follow-up, 45% of patients reported being completely abstinent, 9% reported drinking within safety limits and 33% had an unknown level of alcohol consumption. At 1 year, 37% of patients reported being completely abstinent, 10% reported drinking within safety limits and 39% had an unknown level of alcohol consumption. Only 22% of patients had attended alcohol rehabilitation treatment at 90 days and 1 year.
  
  
  CONCLUSIONS
  We conclude that prednisolone reduces the risk of mortality at 28 days, but this benefit is not sustained beyond 28 days. PTX had no impact on survival. Future research should focus on interventions to promote abstinence and on treatments that suppress the hepatic inflammation without increasing susceptibility to infection.
  
  
  BACKGROUND
  This trial is registered as EudraCT 2009-013897-42 and Current Controlled Trials ISRCTN88782125.
  
  
  BACKGROUND
  This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 19, No. 102. See the NIHR Journals Library website for further project information. The NIHR Clinical Research Network provided research nurse support and the Imperial College Biomedical Research Centre also provided funding.
authors.affiliation: Department of Surgery and Cancer, Imperial College London, London, UK.
authors.forename: Mark
authors.initials: M
authors.lastname: Thursz
authors.affiliation: Department of Gastroenterology, Glasgow Royal Infirmary, Glasgow, UK.
authors.forename: Ewan
authors.initials: E
authors.lastname: Forrest
authors.affiliation: Primary Care & Population Sciences, University of Southampton, Southampton, UK.
authors.forename: Paul
authors.initials: P
authors.lastname: Roderick
authors.affiliation: Institute of Cellular Medicine, The Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK.
authors.forename: Christopher
authors.initials: C
authors.lastname: Day
authors.affiliation: Department of Gastroenterology, Derby Royal Hospital, Derby, UK.
authors.forename: Andrew
authors.initials: A
authors.lastname: Austin
authors.affiliation: Institute of Liver Studies, King's College Hospital, London, UK.
authors.forename: John
authors.initials: J
authors.lastname: O'Grady
authors.affiliation: Department of Hepatology, Nottingham University Hospitals NHS Trust and National Institute for Health Research Biomedical Research Unit, Queens Medical Centre, Nottingham, UK.
authors.forename: Stephen
authors.initials: S
authors.lastname: Ryder
authors.affiliation: Department of Hepatology, Addenbrookes Hospital, Cambridge, UK.
authors.forename: Michael
authors.initials: M
authors.lastname: Allison
authors.affiliation: Department of Hepatology, Sheffield Teaching Hospitals Foundation Trust, Sheffield, UK.
authors.forename: Dermot
authors.initials: D
authors.lastname: Gleeson
authors.affiliation: Department of Hepatology, Bristol Royal Infirmary, Bristol, UK.
authors.forename: Anne
authors.initials: A
authors.lastname: McCune
authors.affiliation: Sheila Sherlock Liver Centre, Royal Free Hospital, London, UK.
authors.forename: David
authors.initials: D
authors.lastname: Patch
authors.affiliation: Department of Hepatology, University Hospital Southampton NHS Foundation Trust, Southampton, UK.
authors.forename: Mark
authors.initials: M
authors.lastname: Wright
authors.affiliation: Institute of Cellular Medicine, The Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK.
authors.forename: Steven
authors.initials: S
authors.lastname: Masson
authors.affiliation: Department of Hepatology, Royal Liverpool Hospital, Liverpool, UK.
authors.forename: Paul
authors.initials: P
authors.lastname: Richardson
authors.affiliation: Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: Luke
authors.initials: L
authors.lastname: Vale
authors.affiliation: Southampton Clinical Trials Unit, University of Southampton, Southampton, UK.
authors.forename: Jane
authors.initials: J
authors.lastname: Mellor
authors.affiliation: Southampton Clinical Trials Unit, University of Southampton, Southampton, UK.
authors.forename: Louise
authors.initials: L
authors.lastname: Stanton
authors.affiliation: Southampton Clinical Trials Unit, University of Southampton, Southampton, UK.
authors.forename: Megan
authors.initials: M
authors.lastname: Bowers
authors.affiliation: Southampton Clinical Trials Unit, University of Southampton, Southampton, UK.
authors.forename: Ian
authors.initials: I
authors.lastname: Ratcliffe
authors.affiliation: Southampton Clinical Trials Unit, University of Southampton, Southampton, UK.
authors.forename: Nichola
authors.initials: N
authors.lastname: Downs
authors.affiliation: Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: Scott
authors.initials: S
authors.lastname: Kirkman
authors.affiliation: Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: Tara
authors.initials: T
authors.lastname: Homer
authors.affiliation: Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: Laura
authors.initials: L
authors.lastname: Ternent
mesh_terms: D000328:Adult; D000368:Aged; D000428:Alcohol Drinking / Q000009:adverse effects / Q000453:epidemiology; D003362:Cost-Benefit Analysis; D004311:Double-Blind Method; D005260:Female; D005938:Glucocorticoids / Q000627:therapeutic use*; D006519:Hepatitis, Alcoholic / Q000188:drug therapy* / Q000401:mortality; D006801:Humans; D008297:Male; D008875:Middle Aged; D010431:Pentoxifylline / Q000627:therapeutic use*; D010975:Platelet Aggregation Inhibitors / Q000627:therapeutic use*; D011239:Prednisolone / Q000627:therapeutic use*; D012044:Regression Analysis; D016019:Survival Analysis; D006113:United Kingdom; D055815:Young Adult
chemical_list: D005938:Glucocorticoids; D010975:Platelet Aggregation Inhibitors; D011239:Prednisolone; D010431:Pentoxifylline