The sum of two treatments for alcoholic hepatitis is no greater than the parts, researchers reported.
In a randomized, placebo-controlled trial, adding pentoxifylline (Pentoxil, Trental) to prednisolone did not improve 6-month survival compared with prednisolone alone, according to Philippe Mathurin, MD, of the Hopital Huriez in Lille, France and colleagues.
The combination was also not better in terms of early response to treatment or the incidence of hepatorenal syndrome after 6 months, Mathurin and colleagues reported in the Sept. 11 issue of the Journal of the American Medical Association.
Both drugs have been shown to outperform placebo in patients with severe alcoholic hepatitis, the researchers noted. They are widely prescribed together because of the hope that synergistic effects might improve outcomes, but the issue had not been tested.
Mathurin and colleagues enrolled 270 patients, ages 18 to 70, at 24 hospitals in France and Belgium from December 2007 to March 2010. All were heavy drinkers with severe biopsy-proven alcoholic hepatitis, indicated by recent onset of jaundice and a Maddrey score of at least 32.
They were randomly assigned to receive 40 mg of prednisolone once a day plus either 400 mg of pentoxifylline three times a day or a matching placebo for 28 days. The primary outcome was survival after 6 months of follow-up, but the researchers also looked at response to treatment after 7 days, based on the so-called Lille model, and the incidence of hepatorenal syndrome after 6 months.
All told, 82 patients died during follow-up, 81.7% from complications of liver failure and 18.3% from other causes, including gastrointestinal bleeding.
But 6-month survival was not different between the groups -- 69.9% (95% CI 62.1%-77.7%) in the pentoxifylline-prednisolone group and 69.2% (95% CI 61.4%-76.9%) in the prednisolone-alone group.
The authors also reported, there was no significant difference in other endpoints.
At 7 days, the average response to therapy assessed by Lille model scores was 0.41 (95% CI 0.36-0.46) for combination therapy and 0.40 (95% CI 0.35-0.45) for prednisolone by itself.
In addition, 62.6% (95% CI 53.9%-71.3%) of patients in the combination group responded to treatment, compared with 61.9% (95% CI 53.7%-70.3%) in those getting prednisolone alone.
The cumulative incidence of hepatorenal syndrome at 6 months was 8.4% for combination therapy and 15.3% for prednisolone, which was not significant. But the researchers cautioned the study might have been underpowered to detect a difference.
But in an accompanying editorial, they argued the findings say little about the value of pentoxifylline, because of the absence of a pentoxifylline-placebo comparison.
"Pentoxifylline may remain a useful option for patients who have contraindications to receiving corticosteroids," they noted, but the issue wasn't studied by Mathurin and colleagues.
The study "does not support the use of a combination of pentoxifylline and prednisolone for severe alcoholic hepatitis," the study authors concluded, arguing that more research is needed to find new treatment strategies.
One such strategy might be early liver transplant, Mathurin and colleagues reported in 2011.
The study was supported by the French Minister of Health. Pentoxifylline and its matching placebo were both supplied by Sanofi-Aventis Pharmaceuticals. The journal said all authors completed the ICMJE Form for Disclosure of Potential Conflicts of Interest and none was reported.
The journal said the editorial authors completed the disclosure forms and none was reported.
- Reviewed by F. Perry Wilson, MD, MSCE Instructor of Medicine, Perelman School of Medicine at the University of Pennsylvania and Dorothy Caputo, MA, BSN, RN, Nurse Planner
Journal of the American Medical AssociationSource Reference: Mathurin P, et al "Prednisolone with vs without pentoxifylline and survival of patients with severe alcoholic hepatitis: A randomized clinical trial" JAMA 2013; 310(10): 1033-1041.
Journal of the American Medical AssociationSource Reference: Halegoua-De Marzio DL, Fenkel JM "Treatment of severe alcoholic hepatitis With corticosteroids and pentoxifylline" JAMA 2013; 310(10): 1029-1030.