Prednisolone or Pentoxifylline for Alcoholic Hepatitis

Abstract

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.

The Worsening Profile of Alcoholic Hepatitis in the United States

“…Steroids did, however, demonstrate modest efficacy in this “real-life” nonrandomized setting for those with severe AH (MELD ≥ 22) while pentoxifylline did not demonstrate any signal for improvement. Taken together with a large randomized clinical trial demonstrating a lack of efficacy of pentoxifylline as a stand-alone treatment as well in combination with steroids (Mathurin et al, 2013; Thursz et al, 2015), these data provide a strong rationale for discarding pentoxifylline from the therapeutic armamentarium for AH and investment of resources to develop additional therapies for AH.…”

Standard Definitions and Common Data Elements for Clinical Trials in Patients With Alcoholic Hepatitis: Recommendation From the NIAAA Alcoholic Hepatitis Consortia

“…A “standard drink” in the United States (12 oz of beer, 5 oz of wine, or 1 oz of liquor) contains 14 g of alcohol; volunteers drinking approximately 10 drinks per day for 2–3 weeks consistently developed steatosis. 1 This level of drinking, often for decades, is observed in AH, 2,3 but only a minority of such drinkers develop AH. The best established risk factors are female sex and increased body mass index; these and other factors have mainly been studied in the context of alcoholic liver disease (including steatosis and cirrhosis): nutritional deficiency, dietary composition (type of fat, caffeine), genetic factors (eg, PNPLA3 genotype), and smoking.…”

“…Recent trials with longer follow-up times noted complications developing between 30 and 90 days after stopping steroids, with mortality rates at 90 days that were no different from those given supportive therapy. 3 Thus, we recommend that future trials be designed with primary outcomes beyond 30-day mortality. Additional factors which contribute to medium term (≤1 year) mortality are not assessed by the Maddrey discriminant function and MELD scores, that is, different degrees of fibrosis.…”

Extracorporeal cellular therapy (ELAD) in severe alcoholic hepatitis: A multinational, prospective, controlled, randomized trial

“…A recent study, steroids or pentoxifylline for alcoholic hepatitis (STOPAH), aimed to show the effectiveness of the current methods of treating sAH using prednisolone and/or pentoxifylline5 and showed no overall impact on 90‐day survival 5. Because these results suggest no longterm survival increase from treatment with glucocorticoids, controversy exists regarding the benefits of these drugs in the sAH population because these patients are often at high risk of gastrointestinal bleeds or sepsis, complications that could be exacerbated by steroids 5, 6, 7. Increasingly, nonresponders to medical therapy are considered to be candidates for early transplantation8, 9 because the majority of these patients will not survive a 6‐month period of alcohol abstinence required by common protocols 10…”