Pentoxifylline in Severe Alcoholic Hepatitis

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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.
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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[1] concluded that insufficient evidence exists to demonstrate that pentoxifylline reduces mortality. The 2015 STOPAH trial[2] 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)[3]

  • 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[4], [5]

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)

Further Reading

  1. Whitfield, Kate, et al. "Pentoxifylline for alcoholic hepatitis." Cochrane Database Syst Rev 4 (2009).
  2. Thursz MR, et al. "Prednisolone or pentoxifylline for alcoholic hepatitis." The New England Journal of Medicine. 2015;371(17):1619-1628.
  3. O'Shea RS, et al. "Alcoholic Liver Disease." Hepatology. 2010;51(1):307-328.
  4. http://www.ncbi.nlm.nih.gov/pubmed/352788
  5. http://en.wikipedia.org/wiki/Modified_Maddrey's_discriminant_function