Pentoxifylline versus prednisolone for severe alcoholic hepatitis: A randomized controlled trial

De, Binay K; Gangopadhyay, Somnath; Dutta, Deep; Baksi, Sumanta Das; Pani, A; Ghosh, Pramit

doi:10.3748/wjg.15.1613

Cited by 134 publications

(91 citation statements)

References 22 publications

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“…23,24 Three small studies [25][26][27] have compared steroids directly with PTX but the results were inconsistent. One study 28 explored the use of PTX as a rescue therapy once steroids had failed to improve liver function tests (LFTs) but this strategy did not influence survival.…”

Section: Steroids And/or Pentoxifyllinementioning

confidence: 99%

The clinical effectiveness and cost-effectiveness of STeroids Or Pentoxifylline for Alcoholic Hepatitis (STOPAH): a 2 × 2 factorial randomised controlled trial

Thursz

Forrest

Roderick

et al. 2015

Health Technol Assess

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BackgroundAlcoholic 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.ObjectivesThe 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.DesignThe trial was a randomised, double-blind, 2 × 2 factorial, multicentre design.SettingSixty-five gastroenterology and hepatology inpatient units across the UK.ParticipantsPatients 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.InterventionsThose 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.OutcomesThe 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.ResultsAt 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.ConclusionsWe 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.Trial registrationThis trial is registered as EudraCT 2009-013897-42 and Current Controlled Trials ISRCTN88782125.FundingThis project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full inHealth 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.

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Section: Steroids And/or Pentoxifyllinementioning

confidence: 99%

The clinical effectiveness and cost-effectiveness of STeroids Or Pentoxifylline for Alcoholic Hepatitis (STOPAH): a 2 × 2 factorial randomised controlled trial

Thursz

Forrest

Roderick

et al. 2015

Health Technol Assess

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“…11,12 Two small studies have compared glucocorticoids with pentoxifylline, but the results were inconsistent. 13,14 Two other studies have compared the effect of glucocorticoid monotherapy with that of combined treatment with glucocorticoids and pentoxifylline but showed no benefit from the addition of pentoxifylline. 15,16 The purpose of our trial -Steroids or Pentoxifylline for Alcoholic Hepatitis (STOPAH) -was to determine whether prednisolone or pentoxifylline administered for a 28-day period reduced short-term and medium-term mortality among patients admitted to a hospital with severe alcoholic hepatitis.…”

Section: In a 2008mentioning

confidence: 99%

Prednisolone or Pentoxifylline for Alcoholic Hepatitis

Thursz¹,

Forrest²,

Ryder³

2015

N Engl J Med

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BACKGROUNDAlcoholic 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. METHODSWe 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. RESULTSA 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). CONCLUSIONSPentoxifylline 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.

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“…However severe AH carries a high mortality rate: 35% at 28 d without effective treatment [63] . These high mor- [99] PRED vs placebo Randomized control No difference in mortality Ramond et al [100] PRED vs placebo Double-blinded, randomized control Improved mortality with PRED Akriviadis et al [69] PTX vs placebo Double-blinded, randomized control Improved mortality with PTX Sidhu et al [101] PTX vs placebo Randomized control Improved mortality with PTX De et al [102] PTX vs PRED Double-blinded, randomized control Reduced mortality with PTX Park et al [103] PTX vs PRED Randomized control Reduced mortality with PRED Mathurin et al [104] PRED vs PRED + PTX Multicenter, double-blinded, randomized control No difference in mortality De et al [105] PTX vs PTX + PRED Double-blinded, randomized control No difference in mortality Thursz et al [70] PTX vs PRED vs placebo Multicenter, double-blinded, randomized control No difference in mortality N-acetylcysteine Moreno et al [106] NAC vs placebo Multicenter, single-blinded, randomized control No difference in mortality Cytokine inhibitors Naveau et al [72] Infliximab vs placebo Double-blinded, randomized control Increased mortality with infliximab Boetticher et al [71] Etancercept vs placebo Multicenter, single-blinded, randomized control Increased mortality with etancercept PTX: Pentoxifylline; PRED: Prednisiolone; NAC: N-acetylcysteine.…”

Section: Current Treatment Of Alcoholic Hepatitismentioning

confidence: 99%

Alcoholic hepatitis: The pivotal role of Kupffer cells

Suraweera

Weeratunga

et al. 2015

WJGP

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Kupffer cells play a central role in the pathogenesis of alcoholic hepatitis (AH). It is believed that alcohol increases the gut permeability that results in raised levels of serum endotoxins containing lipopolysaccharides (LPS). LPS binds to LPS-binding proteins and presents it to a membrane glycoprotein called CD14, which then activates Kupffer cells via a receptor called tolllike receptor 4. This endotoxin mediated activation of Kupffer cells plays an important role in the inflammatory process resulting in alcoholic hepatitis. There is no effective treatment for AH, although notable progress has been made over the last decade in understanding the underlying mechanism of alcoholic hepatitis. We specifically review the current research on the role of Kupffer cells in the pathogenesis of AH and the treatment strategies. We suggest that the imbalance between the pro-inflammatory and the anti-inflammatory process as well as the increased production of reactive oxygen species eventually lead to hepatocyte injury, the final event of alcoholic hepatitis.

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Pentoxifylline versus prednisolone for severe alcoholic hepatitis: A randomized controlled trial

Cited by 134 publications

References 22 publications

The clinical effectiveness and cost-effectiveness of STeroids Or Pentoxifylline for Alcoholic Hepatitis (STOPAH): a 2 × 2 factorial randomised controlled trial

The clinical effectiveness and cost-effectiveness of STeroids Or Pentoxifylline for Alcoholic Hepatitis (STOPAH): a 2 × 2 factorial randomised controlled trial

Prednisolone or Pentoxifylline for Alcoholic Hepatitis

Alcoholic hepatitis: The pivotal role of Kupffer cells

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