Pentoxifylline in Severe Alcoholic Hepatitis

Published

Akriviadis E, et al. "Pentoxifylline improves short-term survival in severe acute alcoholic hepatitis: a double-blind, placebo-controlled trial". Gastroenterology. 2000. 119(6):1637-48.
PubMed • Full text • PDF

Clinical Question

In patients with severe acute alcoholic hepatitis, does pentoxifylline improve mortality?

Bottom Line

Pentoxifylline may improve short-term survival among patients with severe acute alcoholic hepatitis, although meta-analyses have been neutral.

Major Points

The 1992 study by Ramond et al, Prednisolone in Severe Alcoholic Hepatitis, demonstrated a mortality reduction when prednisolone was used to treat patients with severe acute alcoholic hepatitis, though mortality in the treatment group was still 12% at 60 days. The high mortality in this disease may be related to elevations in TNF and the subsequent severe inflammatory response. Pentoxifylline decreases TNF and may, therefore, play a role in improving outcomes in acute alcoholic hepatitis.

This trial published by Akriviadis et al in 2000 randomized 101 patients with severe alcoholic hepatitis at a single center to either pentoxifylline 400mg or placebo three times daily. At 4 weeks, pentoxifylline was associated with a 22% absolute reduction in mortality during the initial hospitalization, most of which was due to a decreased incidence of hepatorenal syndrome.

A 2009 Cochrane Review concluded that insufficient evidence exists to demonstrate that pentoxifylline reduces mortality. The 2015 STOPAH trial randomized patients to pentoxifylline, prednisolone, or placebo. There was no mortality benefit with pentoxifylline, but prednisolone was associated with a non-significant trend towards mortality reduction.

Guidelines

AASLD/ACG Alcoholic Liver Disease (2010, adapted)

• For patients with alcoholic hepatitis:
  • Alcohol abstinence counseling (class I, level B)
  • Assessment for nutritional, vitamin, and mineral deficiencies with aggressive repletion in those with severe disease (class I, level B)
  • If mild-moderate (Maddrey score <32), no hepatic encephalopathy, and improvement in bilirubin or decline in Maddrey score, unlikely to benefit from medical interventions except abstinence and nutritional support (class III, level A)
  • If severe (Maddrey score ≥32) regardless of hepatic encephalopathy, if no conraindications to corticosteroids, consider four weeks of prednisone at 40 mg/day for 28 days then discontinuation or tapering dose over two weeks (class I, level A)
  • If severe (Maddrey score ≥32), consider pentoxifylline 400 mg PO TID for 28 days, especially if corticosteroid contraindications (class I, level B)

Design

• Single center, double-blinded, parallel-group, randomized, placebo-controlled trial
• N=101 patients with severe alcoholic hepatitis
  • Pentoxifylline 400 mg PO TID (n=49)
  • Placebo (n=52)
• Setting: USC Liver Unit, California
• Enrollment: 1992-1997
• Analysis: intention-to-treat

Population

Baseline characteristics

Demographics:

• Male: 71%
• Age: 42.4 years

Medical data:

• Days of treatment: 21.5
• Days before randomization: 3.9
• Previous decompensation: 24%
• Hepatic encephalopathy: 8%
• Creatinine above 2.4 mg/dL: 6.1%
• Ascites: 76%
• Edema: 59%
• Varices: 80%
• Splenomegaly: 21%
• Fever (above 100⁰F): 13%
• Palpable hepatomegally
• Hepatic bruit: 59%

Inclusion Criteria

• History of heavy alcohol abuse
• Admission for acute alcoholic hepatitis
• Jaundice
• One or more of the following:
  • Palpable tender hepatomegaly
  • Fever
  • WBC >12,000 with left shift
  • Hepatic encephalopathy
  • Hepatic systolic bruit
• Maddrey discriminant factor ≥32,

Exclusion Criteria

• Concomitant bacterial infection
• Active GI bleed
• Severe cardiovascular or pulmonary disease
• Patients with decreasing bilirubin or rapid LFT improvement
• Advanced alcoholic cirrhosis

Interventions

• Randomized to pentoxifylline (400mg PO TID) vs. placebo
• Follow up: 4 weeks

Outcomes

Comparisons are pentoxifylline vs. placebo.

Primary Outcomes

Death during index hospitalization

24.5% vs. 46.1% (RR 0.59; 95% CI 0.35-0.97; P=0.037)

Death from hepatorenal syndrome

50% vs. 91.7% (RR 0.29; 95% CI 0.13-0.65; P=0.009)