Combined therapy with pentoxifylline and prednisolone failed to improve 6-month survival in patients with severe alcoholic hepatitis, compared with prednisolone alone, according to a report published online Sept. 10 in JAMA.
In the largest and the only double-blind randomized clinical trial of this combination therapy performed to date, overall survival at 6 months was 69.9% for pentoxifylline plus prednisolone, compared with 69.2% for placebo plus prednisolone. "Our study does not support the use of a combination of pentoxifylline and prednisolone for severe alcoholic hepatitis," said Dr. Philippe Mathurin of Hopital Huriez, Lille (France), and his associates in their report (JAMA. 2013;310:1033-41. doi:10.1001/jama.2013.276300).
The two agents are believed to have two different and perhaps complementary mechanisms of action, so it was thought that combining them might have a synergistic therapeutic effect. Pentoxifylline appears to protect against the hepatorenal syndrome without exerting any significant effect on inflammatory cytokines or liver tests, while prednisolone improves liver function, inhibits inflammatory cytokines, and interferes with the activation of polymorphonuclear neutrophils.
Dr. Mathurin and his colleagues compared the combination therapy against prednisolone alone in 270 patients treated at 23 French and 1 Belgian hospital during a 3-year period. The study subjects were heavy drinkers with biopsy-proven alcoholic hepatitis whose disease was judged to be severe based on the recent onset of jaundice and a Maddrey score of at least 32.
The 163 men and 107 women were assigned randomly to receive either 40 mg prednisolone once daily plus 400 mg pentoxifylline three times daily (133 patients) or 40 mg prednisolone once daily plus a placebo three times daily (137 patients), for 28 days. If adverse effects developed, treatment could be reduced or interrupted at the discretion of the treating physician.
The primary endpoint was survival 6 months after initiating treatment.
There was no significant difference in this outcome between the combination-therapy group (69.9%) and the single-therapy group (69.2%) in the intention-to-treat analysis nor in the per-protocol analysis (72.4% and 70%, respectively).
The mean length of time until death also was not significantly different: 49.7 days with combination therapy and 51.4 days with single therapy, the investigators said.
Causes of death also were similar between the two study groups. Complications of liver failure were cited in approximately 82% of the entire study population and gastrointestinal bleeding in the remaining 18%.
Overall, 26% of the study subjects relapsed and began drinking alcohol again during 6-month follow-up. However, survival did not differ between patients who relapsed and those who did not.
Patients deemed to be treatment responders had markedly better 6-month survival (85%) than did nonresponders (46%), but the treatment response rate did not differ between the two study groups. Similarly, in an analysis restricted only to complete responders and null responders, survival did not differ significantly between patients who received the combination therapy and those who received prednisolone alone.
At the beginning of the study, it was thought that the combination of pentoxifylline plus prednisolone would improve survival chiefly by reducing the incidence of hepatorenal syndrome, relative to prednisolone alone. And at the conclusion of the 1-month course of treatment, the risk of hepatorenal syndrome was significantly lower with combination therapy (3.1%) than with prednisolone alone (11.7%). However, this difference disappeared by the end of follow-up.
But it is important to note that this study was only powered to detect a difference in survival, the primary outcome, and was likely underpowered to detect differences in secondary outcomes such as the rate of the hepatorenal syndrome. "Therefore, the difference in the incidence of hepatorenal syndrome in our study should not be interpreted as being null, and a larger study is necessary to evaluate this issue," according to Dr. Mathurin and his associates.
Regarding the adverse effects of treatment, 13 patients in each study group required temporary withdrawal from therapy. And the rate of complete withdrawal due to adverse treatment effects was not significantly different between the two study groups.
Adverse effects included infections, pruritus, diarrhea, and nausea.
The study findings do not support the use of combination therapy for severe alcoholic hepatitis, and suggest that other agents that target different pathways, such as those involved in liver regeneration, should be explored, the researchers said.
This study was supported by a grant from the French Ministry of Health to the Hospital-Based Clinical Research Program. Pentoxifylline and its matching placebo were supplied by Sanofi-Aventis. No financial conflicts of interest were reported.