Corticosteroids Reduce Risk of Death Within 28 Days for Patients With Severe Alcoholic Hepatitis, Compared With Pentoxifylline or Placebo—a Meta-analysis of Individual Data From Controlled Trials

Alexandre Louvet, Mark R. Thursz, Dong Joon Kim, Julien Labreuche, Stephen R. Atkinson, Sandeep Singh Sidhu, John G. O'Grady, Evangelos Akriviadis, Emmanouil Sinakos, Robert L. Carithers, Marie José Ramond, Willis C. Maddrey, Timothy R. Morgan, Alain Duhamel, Philippe Mathurin

Research output: Contribution to journalArticle

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Abstract

Background & Aims: We performed a meta-analysis of individual patient data from 11 randomized controlled trials comparing corticosteroids, pentoxifylline, or their combination in patients with severe alcoholic hepatitis. We compared the effects of the treatments on survival for 28 days or 6 months, and response to treatment based on the Lille model. Methods: We searched PubMed for randomized controlled trials of pharmacologic therapy for severe alcoholic hepatitis. Our final analysis comprised 11 studies, of 2111 patients. We performed 4 meta-analyses of the effects of corticosteroids vs placebo or control, corticosteroids vs pentoxifylline, corticosteroids and pentoxifylline vs corticosteroids and placebo or control, and pentoxifylline vs placebo. In each meta-analysis, the effect of treatment on the primary outcome (overall survival at 28 days, defined as the period from the first day of assigned treatment to 28 days) was estimated using a Cox proportional hazards regression model, including trials as random effect. Results: Corticosteroid treatment significantly decreased risk of death within 28 days compared with controls (hazard ratio [HR] 0.64; 95% confidence interval [CI] 0.48–0.86) or to pentoxifylline (HR 0.64; 95% CI 0.43–0.95). In multiple-imputation and complete case analyses, the effect of corticosteroids compared with controls remained significant. When we compared corticosteroids vs pentoxifylline, the corticosteroid effect remained significant in the complete case analysis (HR 0.66; P =.04) but not in multiple-imputation analysis (HR 0.71; P =.08). There was no difference in 28-day mortality when patients were given a combination of corticosteroids and pentoxifylline vs corticosteroids alone or between patients given pentoxifylline vs control. In our analysis of secondary outcomes, we found no significant differences in 6-month mortality when any treatments or controls were compared. Corticosteroids were significantly associated with increased response to therapy compared with controls (relative risk 1.24; 95% CI 1.10–1.41) or pentoxifylline (relative risk 1.43; 95% CI 1.20–1.68). We found no difference in response to therapy between patients given a combination of corticosteroids and pentoxifylline vs corticosteroids alone or pentoxifylline vs controls. Conclusions: In a meta-analysis of 4 controlled trials, we found corticosteroid use to reduce risk of death within 28 days of treatment, but not in the following 6 months. This loss of efficacy over time indicates a need for new therapeutic strategies to improve medium-term outcomes.

Original languageEnglish (US)
Pages (from-to)458-468.e8
JournalGastroenterology
Volume155
Issue number2
DOIs
StatePublished - Aug 1 2018

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Alcoholic Hepatitis
Pentoxifylline
Meta-Analysis
Adrenal Cortex Hormones
Therapeutics
Confidence Intervals
Placebos
Randomized Controlled Trials
Safety Management
Survival
Mortality

Keywords

  • Alcoholic Hepatitis
  • Meta-Analysis
  • Prednisolone
  • Survival

ASJC Scopus subject areas

  • Gastroenterology

Cite this

Corticosteroids Reduce Risk of Death Within 28 Days for Patients With Severe Alcoholic Hepatitis, Compared With Pentoxifylline or Placebo—a Meta-analysis of Individual Data From Controlled Trials. / Louvet, Alexandre; Thursz, Mark R.; Kim, Dong Joon; Labreuche, Julien; Atkinson, Stephen R.; Sidhu, Sandeep Singh; O'Grady, John G.; Akriviadis, Evangelos; Sinakos, Emmanouil; Carithers, Robert L.; Ramond, Marie José; Maddrey, Willis C.; Morgan, Timothy R.; Duhamel, Alain; Mathurin, Philippe.

In: Gastroenterology, Vol. 155, No. 2, 01.08.2018, p. 458-468.e8.

Research output: Contribution to journalArticle

Louvet, A, Thursz, MR, Kim, DJ, Labreuche, J, Atkinson, SR, Sidhu, SS, O'Grady, JG, Akriviadis, E, Sinakos, E, Carithers, RL, Ramond, MJ, Maddrey, WC, Morgan, TR, Duhamel, A & Mathurin, P 2018, 'Corticosteroids Reduce Risk of Death Within 28 Days for Patients With Severe Alcoholic Hepatitis, Compared With Pentoxifylline or Placebo—a Meta-analysis of Individual Data From Controlled Trials', Gastroenterology, vol. 155, no. 2, pp. 458-468.e8. https://doi.org/10.1053/j.gastro.2018.05.011
Louvet, Alexandre ; Thursz, Mark R. ; Kim, Dong Joon ; Labreuche, Julien ; Atkinson, Stephen R. ; Sidhu, Sandeep Singh ; O'Grady, John G. ; Akriviadis, Evangelos ; Sinakos, Emmanouil ; Carithers, Robert L. ; Ramond, Marie José ; Maddrey, Willis C. ; Morgan, Timothy R. ; Duhamel, Alain ; Mathurin, Philippe. / Corticosteroids Reduce Risk of Death Within 28 Days for Patients With Severe Alcoholic Hepatitis, Compared With Pentoxifylline or Placebo—a Meta-analysis of Individual Data From Controlled Trials. In: Gastroenterology. 2018 ; Vol. 155, No. 2. pp. 458-468.e8.
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abstract = "Background & Aims: We performed a meta-analysis of individual patient data from 11 randomized controlled trials comparing corticosteroids, pentoxifylline, or their combination in patients with severe alcoholic hepatitis. We compared the effects of the treatments on survival for 28 days or 6 months, and response to treatment based on the Lille model. Methods: We searched PubMed for randomized controlled trials of pharmacologic therapy for severe alcoholic hepatitis. Our final analysis comprised 11 studies, of 2111 patients. We performed 4 meta-analyses of the effects of corticosteroids vs placebo or control, corticosteroids vs pentoxifylline, corticosteroids and pentoxifylline vs corticosteroids and placebo or control, and pentoxifylline vs placebo. In each meta-analysis, the effect of treatment on the primary outcome (overall survival at 28 days, defined as the period from the first day of assigned treatment to 28 days) was estimated using a Cox proportional hazards regression model, including trials as random effect. Results: Corticosteroid treatment significantly decreased risk of death within 28 days compared with controls (hazard ratio [HR] 0.64; 95{\%} confidence interval [CI] 0.48–0.86) or to pentoxifylline (HR 0.64; 95{\%} CI 0.43–0.95). In multiple-imputation and complete case analyses, the effect of corticosteroids compared with controls remained significant. When we compared corticosteroids vs pentoxifylline, the corticosteroid effect remained significant in the complete case analysis (HR 0.66; P =.04) but not in multiple-imputation analysis (HR 0.71; P =.08). There was no difference in 28-day mortality when patients were given a combination of corticosteroids and pentoxifylline vs corticosteroids alone or between patients given pentoxifylline vs control. In our analysis of secondary outcomes, we found no significant differences in 6-month mortality when any treatments or controls were compared. Corticosteroids were significantly associated with increased response to therapy compared with controls (relative risk 1.24; 95{\%} CI 1.10–1.41) or pentoxifylline (relative risk 1.43; 95{\%} CI 1.20–1.68). We found no difference in response to therapy between patients given a combination of corticosteroids and pentoxifylline vs corticosteroids alone or pentoxifylline vs controls. Conclusions: In a meta-analysis of 4 controlled trials, we found corticosteroid use to reduce risk of death within 28 days of treatment, but not in the following 6 months. This loss of efficacy over time indicates a need for new therapeutic strategies to improve medium-term outcomes.",
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T1 - Corticosteroids Reduce Risk of Death Within 28 Days for Patients With Severe Alcoholic Hepatitis, Compared With Pentoxifylline or Placebo—a Meta-analysis of Individual Data From Controlled Trials

AU - Louvet, Alexandre

AU - Thursz, Mark R.

AU - Kim, Dong Joon

AU - Labreuche, Julien

AU - Atkinson, Stephen R.

AU - Sidhu, Sandeep Singh

AU - O'Grady, John G.

AU - Akriviadis, Evangelos

AU - Sinakos, Emmanouil

AU - Carithers, Robert L.

AU - Ramond, Marie José

AU - Maddrey, Willis C.

AU - Morgan, Timothy R.

AU - Duhamel, Alain

AU - Mathurin, Philippe

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N2 - Background & Aims: We performed a meta-analysis of individual patient data from 11 randomized controlled trials comparing corticosteroids, pentoxifylline, or their combination in patients with severe alcoholic hepatitis. We compared the effects of the treatments on survival for 28 days or 6 months, and response to treatment based on the Lille model. Methods: We searched PubMed for randomized controlled trials of pharmacologic therapy for severe alcoholic hepatitis. Our final analysis comprised 11 studies, of 2111 patients. We performed 4 meta-analyses of the effects of corticosteroids vs placebo or control, corticosteroids vs pentoxifylline, corticosteroids and pentoxifylline vs corticosteroids and placebo or control, and pentoxifylline vs placebo. In each meta-analysis, the effect of treatment on the primary outcome (overall survival at 28 days, defined as the period from the first day of assigned treatment to 28 days) was estimated using a Cox proportional hazards regression model, including trials as random effect. Results: Corticosteroid treatment significantly decreased risk of death within 28 days compared with controls (hazard ratio [HR] 0.64; 95% confidence interval [CI] 0.48–0.86) or to pentoxifylline (HR 0.64; 95% CI 0.43–0.95). In multiple-imputation and complete case analyses, the effect of corticosteroids compared with controls remained significant. When we compared corticosteroids vs pentoxifylline, the corticosteroid effect remained significant in the complete case analysis (HR 0.66; P =.04) but not in multiple-imputation analysis (HR 0.71; P =.08). There was no difference in 28-day mortality when patients were given a combination of corticosteroids and pentoxifylline vs corticosteroids alone or between patients given pentoxifylline vs control. In our analysis of secondary outcomes, we found no significant differences in 6-month mortality when any treatments or controls were compared. Corticosteroids were significantly associated with increased response to therapy compared with controls (relative risk 1.24; 95% CI 1.10–1.41) or pentoxifylline (relative risk 1.43; 95% CI 1.20–1.68). We found no difference in response to therapy between patients given a combination of corticosteroids and pentoxifylline vs corticosteroids alone or pentoxifylline vs controls. Conclusions: In a meta-analysis of 4 controlled trials, we found corticosteroid use to reduce risk of death within 28 days of treatment, but not in the following 6 months. This loss of efficacy over time indicates a need for new therapeutic strategies to improve medium-term outcomes.

AB - Background & Aims: We performed a meta-analysis of individual patient data from 11 randomized controlled trials comparing corticosteroids, pentoxifylline, or their combination in patients with severe alcoholic hepatitis. We compared the effects of the treatments on survival for 28 days or 6 months, and response to treatment based on the Lille model. Methods: We searched PubMed for randomized controlled trials of pharmacologic therapy for severe alcoholic hepatitis. Our final analysis comprised 11 studies, of 2111 patients. We performed 4 meta-analyses of the effects of corticosteroids vs placebo or control, corticosteroids vs pentoxifylline, corticosteroids and pentoxifylline vs corticosteroids and placebo or control, and pentoxifylline vs placebo. In each meta-analysis, the effect of treatment on the primary outcome (overall survival at 28 days, defined as the period from the first day of assigned treatment to 28 days) was estimated using a Cox proportional hazards regression model, including trials as random effect. Results: Corticosteroid treatment significantly decreased risk of death within 28 days compared with controls (hazard ratio [HR] 0.64; 95% confidence interval [CI] 0.48–0.86) or to pentoxifylline (HR 0.64; 95% CI 0.43–0.95). In multiple-imputation and complete case analyses, the effect of corticosteroids compared with controls remained significant. When we compared corticosteroids vs pentoxifylline, the corticosteroid effect remained significant in the complete case analysis (HR 0.66; P =.04) but not in multiple-imputation analysis (HR 0.71; P =.08). There was no difference in 28-day mortality when patients were given a combination of corticosteroids and pentoxifylline vs corticosteroids alone or between patients given pentoxifylline vs control. In our analysis of secondary outcomes, we found no significant differences in 6-month mortality when any treatments or controls were compared. Corticosteroids were significantly associated with increased response to therapy compared with controls (relative risk 1.24; 95% CI 1.10–1.41) or pentoxifylline (relative risk 1.43; 95% CI 1.20–1.68). We found no difference in response to therapy between patients given a combination of corticosteroids and pentoxifylline vs corticosteroids alone or pentoxifylline vs controls. Conclusions: In a meta-analysis of 4 controlled trials, we found corticosteroid use to reduce risk of death within 28 days of treatment, but not in the following 6 months. This loss of efficacy over time indicates a need for new therapeutic strategies to improve medium-term outcomes.

KW - Alcoholic Hepatitis

KW - Meta-Analysis

KW - Prednisolone

KW - Survival

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