This NIHR funded trial found that neither prednisolone nor pentoxifylline improved mortality for people with severe alcoholic hepatitis. No differences were found in mortality at 28 or 90 days, or in the need for liver transplant at one year.
Overall mortality was high. Nearly three in ten people died before 90 days and more than half (56%) at one year.
This shows that other new treatments are needed and more needs to be done to encourage complete abstinence from alcohol following severe alcoholic hepatitis.
Why was this study needed?
UK estimates from 2009 show a quarter of adults drink in a hazardous or harmful way. People with prolonged and heavy alcohol use can develop alcoholic hepatitis, with its high risk of being fatal.
Corticosteroids such as prednisolone have been investigated for treatment of alcoholic hepatitis over the last four decades but there is controversy about their use in people with severe alcoholic hepatitis. A 2009 Cochrane review of pentoxifylline found inconclusive evidence of effectiveness for alcoholic hepatitis and recommended that large randomised clinical trials were needed. The NIHR funded this study to determine whether prednisolone or pentoxifylline treatment for a 28-day period reduced short-term and medium-term mortality among people admitted to hospital with severe alcoholic hepatitis.
What did this study do?
This large randomised controlled trial (STeroids Or Pentoxifylline for Alcoholic Hepatitis - STOPAH) was conducted in 65 hospitals in the UK and included 1103 people with a clinical diagnosis of severe alcoholic hepatitis. It compared 28 days of each drug against a placebo. Prednisolone was given in a dose of 40mg. The participants and the healthcare staff were not aware of which treatment was being given. Each group received standard supportive care and nutritional support. Most people were followed up for a year and treatment allocation was concealed. The trial was conducted in the NHS and we can consider the results reliable and relevant to UK practice.
What did it find?
- At 28 days, neither pentoxifylline nor prednisolone improved survival. However the authors did note that prednisolone was associated with a slight but non-significant reduction in mortality (odds ratio 0.72, 95% CI, 0.52 to 1.01).
- Neither prednisolone nor pentoxifylline was found to influence mortality or the need for liver transplantation at 90 days or one year.
- The mortality rate was high, with 418 deaths. Of these, 40% occurred in the first 28 days, 28% between day 28 and day 90, and 32% between day 91 and one year.
- Serious adverse events occurred in around 42% of the people in each treatment group, including infections and gastrointestinal bleeding.
What does current guidance say on this issue?
NICE clinical guideline on alcohol-use disorders recommends the use of corticosteroid treatment, including prednisolone, in people with severe acute alcohol-related hepatitis. The guideline mentioned that the results of this trial would be considered for future updates. It includes no recommendations relating to pentoxifylline.
What are the implications?
The results of this large trial do not fully resolve the uncertainty about the use of corticosteroids in severe alcoholic hepatitis. There is no significant benefit from the drug but an indication that prednisolone 40mg given for 28 days may have a slight beneficial effect on short-term mortality.
Therefore prednisolone may continue to be used. However, the NICE guidelines emphasise that the applicability of corticosteroid therapy may be limited by the potential side effects, which include poor wound healing and susceptibility to infection. These side effects are of particular concern as bleeding and sepsis are common complications of severe alcoholic hepatitis. Serious side effects were common in this trial, affecting nearly one in two participants.
This study found that the overall mortality was high and more needs to be done to promote abstinence from alcohol in this group of people with severe disease. Management of alcohol abuse or dependence is warranted in all people with alcoholic hepatitis. Also, new treatments are needed.
Thursz MR, Richardson P, Allison M et al. Prednisolone or pentoxifylline for alcoholic hepatitis. N Engl J Med. 2015;372(17):1619-28. This project was funded by the National Institute for Health Research HTA Programme (project number 08/14/44).
European Association for the Study of Liver (EASL). EASL clinical practical guidelines: management of alcoholic liver disease. J Hepatol. 2012 Aug;57(2):399-420.
NICE. Alcohol-use disorders: Diagnosis and clinical management of alcohol-related physical complications. NICE guidelines [CG100]. London: National Institute for Health and Care Excellence; 2010.
NICE. Alcohol-use disorders: diagnosis, assessment and management of harmful drinking and alcohol dependence. NICE guidelines [CG115]. London: National Institute for Health and Care Excellence; 2011.
Alcohol treatment in England 2013-14. London: Public Health England; 2014.
Rambaldi A, Saconato HH, Christensen E, Thorlund K, Wetterslev J, Gluud C. Systematic review: glucocorticosteroids for alcoholic hepatitis--a Cochrane Hepato-Biliary Group systematic review with meta-analyses and trial sequential analyses of randomized clinical trials. Aliment Pharmacol Ther. 2008;27(12):1167-78.
Whitfield K, Rambaldi A, Wetterslev J, Gluud C. Pentoxifylline for alcoholic hepatitis. Cochrane Database of Systematic Reviews 2009, Issue 4. Art. No.: CD007339.
Produced by the University of Southampton and Bazian on behalf of NIHR through the NIHR Dissemination Centre