NIHR Signal Two drug treatments for severe alcoholic hepatitis do not improve survival rates

Published on 23 April 2015

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.

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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.

Citation

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).

Bibliography

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.

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.

Citation

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).

Bibliography

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.

Prednisolone or pentoxifylline for alcoholic hepatitis

Published on 23 April 2015

Thursz, M. R.,Richardson, P.,Allison, M.,Austin, A.,Bowers, M.,Day, C. P.,Downs, N.,Gleeson, D.,MacGilchrist, A.,Grant, A.,Hood, S.,Masson, S.,McCune, A.,Mellor, J.,O'Grady, J.,Patch, D.,Ratcliffe, I.,Roderick, P.,Stanton, L.,Vergis, N.,Wright, M.,Ryder, S.,Forrest, E. H.

N Engl J Med Volume 372 , 2015

BACKGROUND: Alcoholic hepatitis is a clinical syndrome characterized by jaundice and liver impairment that occurs in patients with a history of heavy and prolonged alcohol use. The short-term mortality among patients with severe disease exceeds 30%. Prednisolone and pentoxifylline are both recommended for the treatment of severe alcoholic hepatitis, but uncertainty about their benefit persists. METHODS: We conducted a multicenter, double-blind, randomized trial with a 2-by-2 factorial design to evaluate the effect of treatment with prednisolone or pentoxifylline. The primary end point was mortality at 28 days. Secondary end points included death or liver transplantation at 90 days and at 1 year. Patients with a clinical diagnosis of alcoholic hepatitis and severe disease were randomly assigned to one of four groups: a group that received a pentoxifylline-matched placebo and a prednisolone-matched placebo, a group that received prednisolone and a pentoxifylline-matched placebo, a group that received pentoxifylline and a prednisolone-matched placebo, or a group that received both prednisolone and pentoxifylline. RESULTS: A total of 1103 patients underwent randomization, and data from 1053 were available for the primary end-point analysis. Mortality at 28 days was 17% (45 of 269 patients) in the placebo-placebo group, 14% (38 of 266 patients) in the prednisolone-placebo group, 19% (50 of 258 patients) in the pentoxifylline-placebo group, and 13% (35 of 260 patients) in the prednisolone-pentoxifylline group. The odds ratio for 28-day mortality with pentoxifylline was 1.07 (95% confidence interval [CI], 0.77 to 1.49; P=0.69), and that with prednisolone was 0.72 (95% CI, 0.52 to 1.01; P=0.06). At 90 days and at 1 year, there were no significant between-group differences. Serious infections occurred in 13% of the patients treated with prednisolone versus 7% of those who did not receive prednisolone (P=0.002). CONCLUSIONS: Pentoxifylline did not improve survival in patients with alcoholic hepatitis. Prednisolone was associated with a reduction in 28-day mortality that did not reach significance and with no improvement in outcomes at 90 days or 1 year. (Funded by the National Institute for Health Research Health Technology Assessment program; STOPAH EudraCT number, 2009-013897-42 , and Current Controlled Trials number, ISRCTN88782125 ).

The STOPAH trial included only patients with severe alcoholic hepatitis. The authors note that alcoholic hepatitis is a distinct manifestation of alcoholic liver disease that is characterized by jaundice and liver failure. It is a condition that typically develops in people with a history of prolonged and heavy alcohol use. The severity of alcoholic hepatitis is conventionally defined by “Maddrey’s discriminant function”, which is calculated using the patient’s prothrombin time and serum bilirubin level. A value of 32 or higher indicates severe alcoholic hepatitis. About a third of people with severe alcoholic hepatitis die within six months of presentation.

Commentary

The STOPAH trial highlights that people in the UK are still dying from alcohol-related liver disease and that there is a clear need for research into better treatments for this patient group, as well as better means of preventing people from developing this disease in the first place. The good news is that we are beginning to see new approaches in research in this area. Clinical studies are now looking at devices that can support the liver function while the liver recovers – in a similar way to kidney dialysis. This could provide us with new treatment options in the future.

Professor Steve Ryder, Consultant Physician in Hepatology and Gastroenterology, University of Nottingham