HEPATOLOGY ELSEWHERE SECTION EDITORAjay K. Duseja, Chandigarh, India

Combination Therapy inSevere Alcoholic Hepatitis—Doesn’t Really Work

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Abstract

Mathurin P, Louvet A, Duhamel A, Nahon P, Carbonell N,Boursier J, Anty R, Diaz E, Thabut D, Moirand R, Lebrec D,Moreno C, Talbodec N, Paupard T, Naveau S, Silvain C,Pageaux GP, Sobesky R, Canva-Delcambre V, DharancyS, Salleron J, Dao T. Prednisolone with vs withoutpentoxifylline and survival of patients with severealcoholic hepatitis: a randomized clinical trial. JAMA.2013;310:1033–1041.

Service des Maladies de l'Appareil digestif, Hopital Huriez,Lille, France.

Importance: Prednisolone or pentoxifylline is recom-mended for severe alcoholic hepatitis, a life-threateningdisease. The benefit of their combination is unknown.

Objective:To determine whether the addition of pentox-ifylline to prednisolone is more effective than prednisolonealone.

Design, setting, and participants: Multicenter, random-ized, double-blind clinical trial conducted betweenDecember 2007 and March 2010 in 1 Belgian and 23French hospitals of 270 patients aged 18–70 years whowere heavy drinkers with severe biopsy-proven alcoholichepatitis, as indicated by recent onset of jaundice in theprior 3 months and a Maddrey score of at least 32. Dura-tion of follow-up was 6 months. The last included patientcompleted the study in October 2010. None of the patientswere lost to follow-up for the main outcome.

Intervention: Patients were randomly assigned to receiveeither a combination of 40 mg of prednisolone once a dayand 400 mg of pentoxifylline 3 times a day (n = 133) for 28days, or 40 mg of prednisolone and matching placebo(n = 137) for 28 days.

Main outcomes and measures: Six-month survival, withsecondary end points of development of hepatorenal syn-drome and response to therapy based on the Lille model,which defines treatment non responders after 7 days ofinitiation of treatment.

Results: In intention-to-treat analysis, 6-month survivalwas not different in the pentoxifylline-prednisolone andplacebo-prednisolone groups (69.9% [95% CI, 62.1%–77.7%] vs 69.2% [95% CI; 61.4%–76.9%], P = 0.91), corre-sponding to 40 vs 42 deaths, respectively. In multivariableanalysis, only the Lille model and the Model for End-Stage Liver Disease score were independently associated

Received: 8.11.2013; Accepted: 11.11.2013; Available online: 4.12.2013http://dx.doi.org/10.1016/j.jceh.2013.11.005

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with 6-month survival. At 7 days, response to therapy as-sessed by the Lille model was not significantly different be-tween the 2 groups (Lille model score, 0.41 [95% CI, 0.36–0.46] vs 0.40 [95% CI, 0.35–0.45], P = 0.80). The probabilityof being a responder was not different in both groups(62.6% [95% CI, 53.9%–71.3%] vs 61.9% [95% CI, 53.7%–70.3%], P = 0.91). The cumulative incidence of hepatorenalsyndrome at 6months was not significantly different in thepentoxifylline-prednisolone and the placebo-prednisolonegroups (8.4% [95% CI, 4.8%–14.8%] vs 15.3% [95% CI,10.3%–22.7%], P = 0.07).

Conclusion and relevance: In patients with alcoholic hep-atitis, 4-week treatment with pentoxifylline and predniso-lone, compared with prednisolone alone, did not resultin improved 6-month survival. The study may have beenunderpowered to detect a significant difference in inci-dence of hepatorenal syndrome, which was less frequentin the group receiving pentoxifylline.

COMMENTS

Severe alcoholic hepatitis (AH) is a difficult disease tomanage with a poor prognosis at three months as assessedby the Maddrey's discriminate function (MDF) and otherscores.1–4 Pentoxifylline a tumor necrosis factor a (TNFa) antagonist has shown promising results in thetreatment of patients with severe alcoholic hepatitis. Inthe landmark study Akriviadis et al showed in arandomized controlled trial of 101 patients with severealcoholic hepatitis that pentoxifylline significantlyreduced the mortality from 46.1% in the placebo groupto 24.5% in the pentoxifylline group (P < 0.037).5 Pentoxi-fylline improved the mortality by decreasing the incidenceof hepatorenal syndrome as a cause of death from 91.7% inthe placebo group to 50% in the pentoxifylline group(P < 0.009). Three variables (age, creatinine, and use of pen-toxifylline) were independently associated with the survivalin these patients. Since the serum TNF a levels did notsignificantly decrease in the either group the beneficial ac-tion of pentoxifylline was related to the renal improve-ment.5

There have been at least 17 controlled trials and 13meta-analyses to study the efficacy of corticosteroids in pa-tients with severe alcoholic hepatitis. Because of its stronganti-inflammatory action, steroids have been found to beeffective in a select group of patients with severe AH withMDF $32 and Glasgow alcoholic hepatitis score (GAHS)$9 with hepatic encephalopathy and no GI bleeding orinfection. Most of the studies have used either the earlychange in bilirubin (ECBL) with 25% reduction in serumbilirubin at day seven or a Lille score#0.45 to define as re-sponders to corticosteroids treatment.6,7 Lille score iscalculated based on the variables of age, bilirubin (at day0 and 7), serum creatinine, serum albumin, andprothrombin time at base line. In the study which gave

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the Lille score; patients with a score >0.45 after seven daysof corticosteroids were defined as non responders.7 Fortypercent of patients were non responders and 6 month sur-vival in this group was only 25% in comparison to theresponder group (Lille score <0.45 at day 7) which had85% six month survival.7

The same group which gave the Lille score has nowstudied the combination of prednisolone with pentoxifyl-line in patients with severe alcoholic hepatitis and didnot find it to be useful (Abstract).8 This was a multicentrestudy involving 1 Belgian and 23 French hospitals where270 patients with severe biopsy-proven alcoholic hepatitis(MDF >32) were followed up for 6 months after receivingeither a combination of 40 mg of prednisolone once aday and 400 mg of pentoxifylline 3 times a day (n = 133)or 40 mg of prednisolone and matching placebo(n = 137) for 28 days.8 There was no difference in the 6-month survival between the pentoxifylline-prednisoloneand placebo-prednisolone groups (69.9% vs 69.2%). Inaddition the Lille score at 7 days was not significantlydifferent between the 2 groups (Lille model score, 0.41 vs0.40, P = 0.80). The probability of being a responder toeither treatment combination (as defined by Lille score)was also not different in both groups (62.6% vs 61.9%,P = 0.91). The addition of pentoxifylline to prednisolonedid not decrease the cumulative incidence of hepatorenalsyndrome at 6 months (8.4% vs 15.3%, P = 0.07).8

Conceptually even though the combination shouldhave done better because of the different modes of actions,the combination of pentoxifylline and prednisolone wasnot found to be superior to prednisolone alone. Thus,managing patients with severe alcoholic hepatitis willcontinue to be challenging for the hepatologists till we

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have new drugs and new combinations in the treatmentof severe alcoholic hepatitis.

REFERENCES

1. Carithers Jr RL, Herlong HF, Diehl AM, et al. Methylprednisolone ther-apy in patients with severe alcoholic hepatitis. A randomized multi-center trial. Ann Intern Med. 1989;110:685–690.

2. Forrest EH, Evans CD, Stewart S, et al. Analysis of factors predictiveof mortality in alcoholic hepatitis and derivation and validation of theGlasgow alcoholic hepatitis score. Gut. 2005;54:1174–1179.

3. Kamath PS, Wiesner RH, Malinchoc M, et al. A model to predict sur-vival in patients with end-stage liver disease. Hepatology.2001;33:464–470.

4. Duseja A, Choudhary NS, Gupta S, Dhiman RK, Chawla Y. APACHE IIscore is superior to SOFA, CTP andMELD in predicting the short-termmortality in patients with acute-on-chronic liver failure (ACLF). J DigDis. 2013;14:484–490.

5. Akriviadis E, Botla R, Briggs W, Han S, Reynolds T, Shakil O. Pentox-ifylline improves short-term survival in severe acute alcoholic hepati-tis: a double-blind, placebo-controlled trial. Gastroenterology.2000;119:1637–1648.

6. Mathurin P, Abdelnour M, Ramond MJ, et al. Early change in bilirubinlevels is an important prognostic factor in severe alcoholic hepatitistreated with prednisolone. Hepatology. 2003;38:1363–1369.

7. Louvet A, Naveau S, Abdelnour M, et al. The Lille model: a new toolfor therapeutic strategy in patients with severe alcoholic hepatitistreated with steroids. Hepatology. 2007;45:1348–1354.

8. Mathurin P, Louvet A, Duhamel A, et al. Prednisolone with vs withoutpentoxifylline and survival of patients with severe alcoholic hepatitis:a randomized clinical trial. JAMA. 2013;310:1033–1041.

Ajay DusejaDepartment of Hepatology,

Postgraduate Institute ofMedical Education and Research,Chandigarh 160012, India

ajayduseja@yahoo.co.inTel.: +91 172 2756336; fax: +91 172 2744401.

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