Pentoxifylline vs. corticosteroid to treat severe alcoholic hepatitis: A randomised, non-inferiority, open trial

Park, Seung Ha; Kim, Dong Joon; Kim, Young Seok; Yim, Hyung Joon; Tak, Won Young; Lee, Heon Ju; Sohn, Joo Hyun; Yoon, Ki Tae; Kim, In Hee; Kim, Hyoung Su; Um, Soon Ho; Baik, Soon Koo; Lee, June Sung; Suk, Ki Tae; Kim, Sang Gyune; Suh, Sang Jun; Park, Soo Young; Kim, Tae Yeob; Jang, Jae Young

doi:10.1016/j.jhep.2014.05.014

Cited by 73 publications

(54 citation statements)

References 22 publications

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“…13,15,20 There was a lower incidence of infection and acute kidney injury in STOPAH than in some previous trials, a factor that may have contributed to the lower mortality. 21 A comparison of the baseline characteristics of the patients in our study with those of patients in other trials conducted in the past 4 years shows that in our trial, the mean age was slightly younger and the rate of encephalopathy lower; both characteristics have been consistently shown to influence mortality.…”

Section: Discussionmentioning

confidence: 76%

“…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%

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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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Section: Discussionmentioning

confidence: 76%

Section: In a 2008mentioning

confidence: 99%

Prednisolone or Pentoxifylline for Alcoholic Hepatitis

Thursz¹,

Forrest²,

Ryder³

2015

N Engl J Med

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“…The phosphodiesterase inhibitor, pentoxifylline, which has anti-inflammatory properties through inhibition of leukotriene and TNFα synthesis, was included in management for prevention of HRS. However, a recent randomised study demonstrated that pentoxifylline is not statistically equivalent to the efficacy of prednisolone in patients with severe alcoholic hepatitis (14).…”

Section: Prevention Of Hrsmentioning

confidence: 99%

An Update on Hepatorenal Syndrome

Chan¹,

Francis³

et al. 2017

jrenhep

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Hepatorenal syndrome (HRS) is one of the many potential causes of acute kidney injury (AKI) in patients with decompensated liver disease. HRS is associated with poor prognosis and represents the end-stage of a sequence of reductions in renal perfusion induced by progressively severe hepatic injury. The pathophysiology of HRS is complex with multiple mechanisms interacting simultaneously, although HRS is primarily characterised by renal vasoconstriction. A recently revised diagnostic criteria and management algorithm for AKI has been developed for patients with cirrhosis, allowing physicians to commence treatment promptly. Vasopressor therapy and other general management, such as antibiotic prophylaxis, need to be initiated whilst patients are assessed for eligibility for transplantation. Liver transplantation remains the treatment of choice for HRS but is limited by organ shortage. Other management options, such as transjugular intrahepatic portosystemic shunt, renal replacement therapy and molecular absorbent recirculating system, may provide short-term benefit for patients not responding to medical therapy whilst awaiting transplantation. Clinicians need to be aware of the pathophysiology and management principles of HRS to provide quality care for patients with multi-organ failure.

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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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Pentoxifylline vs. corticosteroid to treat severe alcoholic hepatitis: A randomised, non-inferiority, open trial

Cited by 73 publications

References 22 publications

Prednisolone or Pentoxifylline for Alcoholic Hepatitis

Prednisolone or Pentoxifylline for Alcoholic Hepatitis

An Update on Hepatorenal Syndrome

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

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