Prednisolone vs. pentoxifylline for severe alcoholic hepatitis
Authors: Alexandre Louvet
Journal: Journal of Hepatology (2014)

Pentoxifylline vs. corticosteroid to treat severe alcoholic hepatitis: A randomised, non-inferiority, open trialJournal of HepatologyVol. 61Issue 4PreviewBoth corticosteroid and pentoxifylline reduce short-term mortality in severe alcoholic hepatitis. However, few studies have directly compared the efficacy of pentoxifylline and corticosteroid in patients with this condition. Full-Text PDF In this issue, the Journal of Hepatology is publishing a non-inferiority trial by a Korean group on severe alcoholic hepatitis addressing the question of the efficacy of pentoxifylline and corticosteroids. Although several studies have been performed in this field, this subject remains controversial. The European Association for the Study of the Liver (EASL) and the American Association for the Study of Liver Diseases (AASLD) have published guidelines [1European Association for the Study of the Liver EASL Clinical Practical Guidelines: management of alcoholic liver disease.J Hepatol. 2012; 57: 399-420Abstract Full Text Full Text PDF PubMed Scopus (548) Google Scholar, 2O'Shea R.S. Dasarathy S. McCullough A.J. Alcoholic liver disease.Hepatology. 2010; 51: 307-328Crossref PubMed Scopus (952) Google Scholar] stating that pentoxifylline and corticosteroids are effective in decreasing mortality in severe alcoholic hepatitis. Studies have shown that the efficacy of pentoxifylline is due to a reduction of the incidence of hepatorenal syndrome [[3]Akriviadis E. Botla R. Briggs W. Han S. Reynolds T. Shakil O. Pentoxifylline improves short-term survival in severe acute alcoholic hepatitis: a double-blind, placebo-controlled trial.Gastroenterology. 2000; 119: 1637-1648Abstract Full Text Full Text PDF PubMed Scopus (661) Google Scholar]. Several papers including meta-analyses [4Mathurin P. O'Grady J. Carithers R.L. Phillips M. Louvet A. Mendenhall C.L. et al.Corticosteroids improve short-term survival in patients with severe alcoholic hepatitis: meta-analysis of individual patient data.Gut. 2011; 60: 255-260Crossref PubMed Scopus (311) Google Scholar, 5Rambaldi A. Saconato H.H. Christensen E. Thorlund K. Wetterslev J. Gluud C. Systematic review: glucocorticosteroids for alcoholic hepatitis – A Cochrane Hepato-Biliary Group systematic review with meta-analyses and trial sequential analyses of randomized clinical trials.Aliment Pharmacol Ther. 2008; 27: 1167-1178Crossref PubMed Scopus (177) Google Scholar] have reported a benefit in survival in randomized patients treated with a 28-day course of corticosteroids. Nevertheless, regardless of the molecule, 6-month mortality rate remains high, around 30–40% [[4]Mathurin P. O'Grady J. Carithers R.L. Phillips M. Louvet A. Mendenhall C.L. et al.Corticosteroids improve short-term survival in patients with severe alcoholic hepatitis: meta-analysis of individual patient data.Gut. 2011; 60: 255-260Crossref PubMed Scopus (311) Google Scholar]. Very few studies have compared pentoxifylline and corticosteroids with a sufficiently large population, and it is difficult to definitely confirm that one drug is better than the other. Some clinicians are still reluctant to use corticosteroids because of the risk of infection. However, decompensated cirrhosis per se is associated with a marked risk of infection, mainly because of liver impairment [[6]Gustot T. Durand F. Lebrec D. Vincent J.L. Moreau R. Severe sepsis in cirrhosis.Hepatology. 2009; 50: 2022-2033Crossref PubMed Scopus (327) Google Scholar]. In the specific field of severe alcoholic hepatitis, our group has observed that up to 25% of patients are admitted with active sepsis, which strongly suggests that systematic screening for infection should be performed in these patients. Another 25% will develop infection after corticosteroid treatment has begun, mainly in case of non-response to this drug, supporting the strong link between liver impairment and the incidence of infection [[7]Louvet A. Wartel F. Castel H. Dharancy S. Hollebecque A. Canva-Delcambre V. et al.Infection in patients with severe alcoholic hepatitis treated with steroids: early response to therapy is the key factor.Gastroenterology. 2009; 137: 541-548Abstract Full Text Full Text PDF PubMed Scopus (257) Google Scholar]. This latter result is not in favour of a direct relationship between increased infection and the use of corticosteroids. An early assessment by the Lille model can help clinicians tailor therapeutic management according to the predicted risk of complications, including the risk of infection [[8]Louvet A. Naveau S. Abdelnour M. Ramond M.J. Diaz E. Fartoux L. et al.The Lille model: a new tool for therapeutic strategy in patients with severe alcoholic hepatitis treated with steroids.Hepatology. 2007; 45: 1348-1354Crossref PubMed Scopus (509) Google Scholar]. For example, in patients with a Lille model above 0.56, we strongly recommend withdrawing corticosteroids due to the lack of benefit of this drug in this subgroup [[4]Mathurin P. O'Grady J. Carithers R.L. Phillips M. Louvet A. Mendenhall C.L. et al.Corticosteroids improve short-term survival in patients with severe alcoholic hepatitis: meta-analysis of individual patient data.Gut. 2011; 60: 255-260Crossref PubMed Scopus (311) Google Scholar]. The study by Park et al. published in this issue of the Journal of Hepatology reports their work in 124 patients with severe alcoholic hepatitis. Patients were randomized to receive pentoxifylline or prednisolone according to conventional doses recommended in this field (1200 mg/day and 40 mg/day respectively). Survival was 64.5% in the pentoxifylline-treated group and 72.9% in the prednisolone group. These results are close to those in patients with severe alcoholic hepatitis published by other groups. Complications were low with no significant differences between the two groups. Response to treatment assessed by the Lille model [[8]Louvet A. Naveau S. Abdelnour M. Ramond M.J. Diaz E. Fartoux L. et al.The Lille model: a new tool for therapeutic strategy in patients with severe alcoholic hepatitis treated with steroids.Hepatology. 2007; 45: 1348-1354Crossref PubMed Scopus (509) Google Scholar] adequately predicted outcome in both groups. This confirms the prognostic value of the Lille model for predicting outcome in these two randomized groups. The latter result emphasizes the importance of early improvement in liver function to improve survival. In the study design of this paper, results with pentoxifylline were not statistically equivalent to prednisolone and the authors concluded that corticosteroids were better than pentoxifylline for severe alcoholic hepatitis. The disappointing survival with pentoxifylline compared to prednisolone was also suggested by a recent randomized controlled trial showing a lack of benefit of the association of pentoxifylline with prednisolone compared to prednisolone alone [[9]Mathurin P. Louvet A. Duhamel A. Nahon P. Carbonell N. Boursier J. et al.Prednisolone with vs. without pentoxifylline and survival of patients with severe alcoholic hepatitis: a randomized clinical trial.JAMA. 2013; 310: 1033-1041Crossref PubMed Scopus (145) Google Scholar]. Six-month survival was the primary endpoint of this trial, as well as of previous trials in the field [10Boetticher N.C. Peine C.J. Kwo P. Abrams G.A. Patel T. Aqel B. et al.A randomized, double-blinded, placebo-controlled multicenter trial of etanercept in the treatment of alcoholic hepatitis.Gastroenterology. 2008; 135: 1953-1960Abstract Full Text Full Text PDF PubMed Scopus (248) Google Scholar, 11Naveau S. Chollet-Martin S. Dharancy S. Mathurin P. Jouet P. Piquet M.A. et al.A double-blind randomized controlled trial of infliximab associated with prednisolone in acute alcoholic hepatitis.Hepatology. 2004; 39: 1390-1397Crossref PubMed Scopus (347) Google Scholar, 12Nguyen-Khac E. Thevenot T. Piquet M.A. Benferhat S. Goria O. Chatelain D. et al.Glucocorticoids plus N-acetylcysteine in severe alcoholic hepatitis.N Engl J Med. 2011; 365: 1781-1789Crossref PubMed Scopus (273) Google Scholar]. However, in the Corpentox study, a decrease in the incidence of hepatorenal syndrome was suggested although the sample size was not calculated to address this issue. Because many studies have had interesting results but did not show an improvement in 6-month survival in severe alcoholic hepatitis [9Mathurin P. Louvet A. Duhamel A. Nahon P. Carbonell N. Boursier J. et al.Prednisolone with vs. without pentoxifylline and survival of patients with severe alcoholic hepatitis: a randomized clinical trial.JAMA. 2013; 310: 1033-1041Crossref PubMed Scopus (145) Google Scholar, 12Nguyen-Khac E. Thevenot T. Piquet M.A. Benferhat S. Goria O. Chatelain D. et al.Glucocorticoids plus N-acetylcysteine in severe alcoholic hepatitis.N Engl J Med. 2011; 365: 1781-1789Crossref PubMed Scopus (273) Google Scholar], an international consensus is needed to define new endpoints. This would help clinicians modify the design of future trials so that rather than short-term survival, other surrogates markers predicting survival would be the primary endpoint such as improvement in liver failure and/or the reduction of the incidence of severe complications leading to death. Although this study was well designed with a sufficient sample size, it comports some limitations, which were acknowledged and discussed by the authors. An important limitation was the absence of a histological diagnosis of alcoholic hepatitis. This issue is crucial in severe alcoholic hepatitis because there are no clinical or biological features to definitely establish the diagnosis. For example, in a recent work [[13]Katoonizadeh A. Laleman W. Verslype C. Wilmer A. Maleux G. Roskams T. et al.Early features of acute-on-chronic alcoholic liver failure: a prospective cohort study.Gut. 2010; 59: 1561-1569Crossref PubMed Scopus (209) Google Scholar], only 63% of patients admitted with acute-on-chronic deterioration of alcoholic cirrhosis had satellitosis defined by a neutrophil infiltration surrounding injured hepatocytes. This shows that all patients with cirrhosis admitted with jaundice who continue drinking should not be automatically considered as having alcoholic hepatitis. In a similar vein, EASL guidelines have stated that clinical trials evaluating new strategies in severe alcoholic hepatitis should be based on histological confirmation of the diagnosis [[1]European Association for the Study of the Liver EASL Clinical Practical Guidelines: management of alcoholic liver disease.J Hepatol. 2012; 57: 399-420Abstract Full Text Full Text PDF PubMed Scopus (548) Google Scholar]. The controversy on the prerequisite of liver biopsy for studies testing molecules emphasizes the urgent need for an expert consensus to establish the optimal design for future therapeutic studies in patients with severe alcoholic hepatitis. In summary, although this study has some limitations, the work by Park is an important step in this setting because of the quality of the design, the sufficient sample size and the quality of the data. It reports that results with pentoxifylline were not statistically equivalent to those of prednisolone. It supports that corticosteroids may be considered first-line therapy for severe alcoholic hepatitis, although this is still being actively debated by experts in this field. The authors who have taken part in this study declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.