CLINICAL OPINION Annals of Gastroenterology (2016) 29, 1-2

Treatment of alcoholic hepatitis: is this a “dead-end”?

Evangelos Akriviadis, Emmanouil Sinakos Aristotle University of Th essaloniki, Greece

Title: Prednisolone or pentoxifylline for alcoholic hepatitis Authors: Th ursz MR, Richardson P, Allison M, Austin A, Bowers M, Day CP, Downs N, Gleeson D, MacGilchrist A, Grant A, Hood S, Masson S, McCune A, Mellor J, O’Grady J, Patch D, Ratcliff e I, Roderick P, Stanton L, Vergis N, Wright M, Ryder S, Forrest EH; STOPAH Trial Journal: N Engl J Med 2015;372:1619-1628

Summary from the trial. All patients were followed for 12 months or until their death with the exception of patients enrolled at Alcoholic hepatitis (AH) is a clinical syndrome the end of the trial. Th e primary endpoint was mortality at characterized by jaundice and liver failure that develops in 28 days and secondary endpoints included mortality or liver subjects with chronic and active alcohol abuse [1]. Th e short- transplantation at 90 days and aft er 1 year. term mortality in patients with severe disease, as defi ned by the Neither drug showed mid- (90 days) or long-term Maddrey’s discriminant function, exceeds 30% [2]. Up to now, (12 months) survival benefi t. However, prednisolone was only two drugs, prednisolone and pentoxifylline, have shown associated with an improvement in 28-day mortality with an some effi cacy for the treatment of this condition. In a Cochrane odds ratio of 0.72 (95%CI 0.52-1.01; P=0.06). In multivariate meta-analysis published in 2008, glucocorticoids showed a non- analysis, baseline age, encephalopathy, white cell count, signifi cant trend toward a benefi t in mortality [3]. However, prothrombin ratio and levels of bilirubin, creatinine and urea a later reanalysis of the fi ve largest studies that evaluated were found to be additional signifi cant factors for mortality. In glucocorticoids indicated a signifi cant benefi t [4]. On the other a secondary analysis adjusting for these prognostic variables hand, pentoxifylline has been shown to signifi cantly increase the odds ratio for 28-day mortality among the patients who survival in patients with severe AH, without any serious received prednisolone compared with those who did not adverse eff ects [5]. Th is favorable outcome is mediated through was 0.61 (95%CI 0.41-0.91; P=0.02). Serious adverse events a decrease in the rate of hepatorenal syndrome. Controversy were reported in 42% of the patients with approximately half over the treatment of choice for AH persists for many years of them resulting in death. No signifi cant diff erences in the as neither drug has convincingly shown superiority. Th is rate of adverse events were noted between treatment groups. trial -the STOPAH trial- evaluating the eff ect of treatment of However, infection occurred more frequently in patients who AH with prednisolone or pentoxifylline has long been awaited received prednisolone compared with those who did not (13% with eagerness as it was expected to answer the question which vs. 7%, P=0.002). Of note, infections were the main reason for drug is more effi cient [6]. death in this trial (24% of deaths). Finally, pentoxifylline was STOPAH trial was a large (1103 patients), multicenter, associated with numerically fewer cases of acute kidney injury. double-blind, randomized trial using a 2-by-2 factorial design. Four arms (placebo, prednisolone, pentoxifylline and prednisolone plus pentoxifylline) were incorporated. Opinion All drugs were prescribed for 28 days at doses of 40 mg daily for prednisolone and 400 mg three times daily for pentoxifylline. Patients with renal failure (serum creatinine Contrary to what was expected from the trial, the results >5.7 mg/dL or requiring renal replacement therapy) or other left uncertainties in the fi eld as neither drug showed a long- dismal characteristics such as untreated sepsis were excluded term survival benefi t. Clinicians should interpret cautiously the fi ndings of STOPAH trial and weigh the possible benefi t 4th Department of Internal Medicine, Aristotle University of of prednisolone therapy against its adverse events, notably Th essaloniki, Greece infectious complications. Patients were included in the study based solely on a Confl ict of Interest: None clinical diagnosis of AH. According to the authors, this was Correspondence to: Emmanouil Sinakos, M.D., Lecturer, Aristotle elected because liver biopsy is not usually used in this setting University of Th essaloniki, 49 Konstantinoupoleos Str, 54642 in clinical practice. Although strict clinical criteria are thought Th essaloniki, Greece, Tel.: +30 2310 950680, Fax: +30 2310 992940, to accurate diagnose AH, distinction from decompensated e-mail: [email protected] cirrhosis in the setting of sepsis remains challenging. Th us, Received 24 December 2015; accepted 6 January 2016 some enrolled patients in the STOPAH trial could have

© 2016 Hellenic Society of Gastroenterology www.annalsgastro.gr 2 E. Akriviadis and E. Sinakos been incorrectly diagnosed with AH. It is conceivable that for AH. Pentoxifylline was also shown to be eff ective although histological confi rmation instead of clinical diagnosis would its use is supported by weaker evidence than prednisolone [8]. have been the optimal inclusion criterion in such a signifi cant We propose that the use of each agent in clinical practice should study in order to ensure correct patient disposition. be tailored to each individual patient’s characteristics. Careful A score of 32 or higher for Maddrey’s discriminant function selection of drug, close monitoring and early assessment of was used as an inclusion criterion in this trial, as in most response (when prednisolone is used) can increase success previous trials. Nonetheless, some baseline characteristics of rates in the treatment of this dreadful condition. the patients known to infl uence mortality were favorable in the STOPAH trial. No patients with renal failure -as defi ned in the study- or hepatic encephalopathy grade 4 and few patients with sepsis were included. Subsequently, the overall death rate References at day 28 (15.2%) was remarkably low compared with previous studies using steroids (26.3%) or pentoxifylline (40%) [4,5]. 1. Lucey MR, Mathurin P, Morgan TR. Alcoholic hepatitis. N Engl J Th e diff erence in mortality is more striking when compared to Med 2009;360:2758-2769. the pivotal pentoxifylline study where the death rate was 24.5% 2. Maddrey WC, Boitnott JK, Bedine MS, Weber FL Jr, Mezey E, in the pentoxifylline group and 46.1% in the placebo group [5]. White RI Jr. Corticosteroid therapy of alcoholic hepatitis. Gastroenterology 1978;75:193-199. Th ese diff erences in patient characteristics could have masked 3. Rambaldi A, Saconato HH, Christensen E, Th orlund K, Wetterslev J, the protective role of pentoxifylline in renal function as this Gluud C. Systematic review: glucocorticosteroids for alcoholic agent was shown to improve survival in patients with far worse hepatitis--a Cochrane Hepato-Biliary Group systematic review characteristics. with meta-analyses and trial sequential analyses of randomized As already outlined, prednisolone treatment increased the clinical trials. Aliment Pharmacol Th er 2008;27:1167-1178. rate of infectious complications in the STOPAH trial. Th is 4. Mathurin P, O’Grady J, Carithers RL, et al. Corticosteroids improve adverse eff ect paired with the absence of long-term benefi t short-term survival in patients with severe alcoholic hepatitis: should make clinicians use prednisolone with vigilance. Th e meta-analysis of individual patient data. Gut 2011;60:255-260. 5. Akriviadis E, Botla R, Briggs W, Han S, Reynolds T, Shakil O. Lille model, using common baseline variables and the evolution Pentoxifylline improves short-term survival in severe acute of bilirubin aft er one week of treatment, can identify patients at alcoholic hepatitis: a double-blind, placebo-controlled trial. risk of death early in the course of prednisolone treatment thus Gastroenterology 2000;119:1637-1648. providing a tool for adjusting treatment [7]. In contrast, use 6. Th ursz MR, Richardson P, Allison M, et al. Prednisolone of pentoxifylline can be completed uneventfully and without or pentoxifylline for alcoholic hepatitis. N Engl J Med enhanced monitoring. 2015;372:1619-1628. Overall, we believe that prednisolone did not show adequate 7. Louvet A, Naveau S, Abdelnour M, et al. Th e Lille model: a new tool for therapeutic strategy in patients with severe alcoholic hepatitis eff ectiveness to be generally recommended and pentoxifylline treated with steroids. Hepatology 2007;45:1348-1354. may have been tested in a population that did not allow its 8. Singh S, Murad MH, Chandar AK, et al. Comparative eff ectiveness benefi cial eff ect on renal function to be exerted. A recent of pharmacological interventions for severe alcoholic hepatitis: a systematic review and network meta-analysis showed that systematic review and network meta-analysis. Gastroenterology prednisolone is not the only eff ective pharmacological agent 2015;149:958-970.

Annals of Gastroenterology 29