STOPAH: Steroids or Pentoxifylline for Alcoholic Hepatitis (2015)

“Pentoxifylline did not improve survival in patients with alcoholic hepatitis. Prednisolone was associated with a reduction in the risk of death at 28 days that was not statistically significant; however, the drug was associated with a significant reduction in 90-day and 1-year mortality.”

— The STOPAH Trial Investigators

1. Publication Details

  • Trial Title: Prednisolone or pentoxifylline for alcoholic hepatitis.
  • Citation: Thursz MR, Richardson P, Allison M, et al; for the STOPAH Trial. Prednisolone or pentoxifylline for alcoholic hepatitis. N Engl J Med. 2015;372(17):1619-1628. doi:10.1056/NEJMoa1412278.
  • Published: April 23, 2015, in The New England Journal of Medicine.
  • Author: Mark R. Thursz, M.D.
  • Funding: UK National Institute for Health Research.

2. Keywords

Alcoholic Hepatitis, Liver Failure, Corticosteroids, Prednisolone, Pentoxifylline, Infection.

3. The Clinical Question

In patients with severe alcoholic hepatitis (Population), does treatment with prednisolone or pentoxifylline (Interventions) compared to placebo (Comparison) reduce 28-day mortality (Outcome)?

4. Background and Rationale

  • Existing Knowledge: Severe alcoholic hepatitis has a very high short-term mortality. Corticosteroids were recommended in guidelines based on meta-analyses of small, conflicting trials. Pentoxifylline was also used, primarily with the aim of reducing the incidence of hepatorenal syndrome.
  • Knowledge Gap: The true efficacy and safety of both corticosteroids and pentoxifylline remained uncertain due to the lack of a large, adequately powered, multicenter randomized trial.
  • Proposed Hypothesis: The authors hypothesized that either prednisolone or pentoxifylline would reduce 28-day mortality compared to placebo.

5. Study Design and Methods

  • Design: A prospective, multicenter, double-blind, 2×2 factorial design, randomized controlled trial.
  • Setting: 65 hospitals in the United Kingdom.
  • Trial Period: Enrollment from February 2011 to February 2014.
  • Population:
    • Inclusion Criteria: Adult patients (>18 years) with a clinical diagnosis of severe alcoholic hepatitis, defined by a Maddrey’s discriminant function (DF) score of ≥32.
    • Exclusion Criteria: Active gastrointestinal bleeding, untreated infection, hepatorenal syndrome, or contraindications to either study drug.
  • Intervention: Patients were randomized to one of four groups:
  • Prednisolone-matched placebo and pentoxifylline-matched placebo.
  • Prednisolone (40 mg daily) and pentoxifylline-matched placebo.
  • Prednisolone-matched placebo and pentoxifylline (400 mg three times daily).
  • Prednisolone and pentoxifylline.
  • Treatment duration was 28 days.
  • Control: Placebo groups for each active drug.
  • Management Common to Both Groups: All patients received supportive care, including nutritional support and management of alcohol withdrawal.
  • Power and Sample Size: The trial was powered to detect an absolute reduction of 8 percentage points in 28-day mortality for each drug, requiring approximately 1088 patients.
  • Outcomes:
    • Primary Outcome: All-cause mortality at 28 days.
    • Secondary Outcomes: Mortality at 90 days and 1 year, incidence of hepatorenal syndrome, and incidence of infection.

6. Key Results

  • Enrollment and Baseline: 1103 patients underwent randomization. The groups were well-matched at baseline.
  • Trial Status: The trial was completed as planned.
  • Primary Outcome:
    • Pentoxifylline: Had no effect on 28-day mortality (19.5% with pentoxifylline vs. 14.1% without; P=0.69).
    • Prednisolone: Was associated with a non-significant reduction in 28-day mortality (14.3% with prednisolone vs. 19.4% without; P=0.06).
  • Secondary Outcomes: Prednisolone was associated with a significant reduction in mortality at 90 days and 1 year. Pentoxifylline had no effect on any secondary outcome.
  • Adverse Events: Serious infections were significantly more common in patients receiving prednisolone than in those who did not (13% vs. 7%; P=0.002).

7. Medical Statistics

  • Analysis Principle: An intention-to-treat analysis was performed.
  • Statistical Tests Used: The primary outcome was analyzed using logistic regression.
  • Primary Outcome Analysis: The proportion of deaths at day 28 was compared for each drug versus its absence.
  • Key Statistic(s) Reported:
    • Prednisolone vs. No Prednisolone (28-day mortality): Odds Ratio (OR) 0.72 (95% CI, 0.52 to 1.01; P=0.06).
    • Pentoxifylline vs. No Pentoxifylline (28-day mortality): OR 1.07 (95% CI, 0.77 to 1.49; P=0.69).
  • Interpretation of Key Statistic(s):
    • P-value: For the primary outcome, neither drug showed a statistically significant benefit at 28 days. The p-value of 0.06 for prednisolone indicates a strong trend toward benefit that did not meet the pre-specified threshold for significance.
  • Clinical Impact Measures: Not applicable for the primary outcome. For the secondary outcome of 90-day mortality, the NNT with prednisolone was approximately 13.
  • Subgroup Analyses: No significant interactions were found.

8. Strengths of the Study

  • Study Design and Conduct: This was a large, multicenter, double-blind, placebo-controlled trial with a pragmatic 2×2 factorial design, which allowed for the efficient evaluation of two separate interventions.
  • Generalizability: The inclusion of 65 diverse hospitals increases the external validity of the findings to real-world practice.
  • Patient-Centered Outcomes: The trial focused on the crucial outcome of mortality at multiple time points.

9. Limitations and Weaknesses

  • Internal Validity (Bias): No major limitations to internal validity.
  • External Validity (Generalizability): The diagnosis of alcoholic hepatitis was clinical and not biopsy-proven in most cases, which reflects real-world practice but may introduce some diagnostic heterogeneity.
  • Other: The trial was technically “negative” for its primary endpoint for both drugs, although the result for prednisolone was borderline.

10. Conclusion of the Authors

“Pentoxifylline did not improve survival in patients with alcoholic hepatitis. Prednisolone was associated with a reduction in the risk of death at 28 days that was not statistically significant; however, the drug was associated with a significant reduction in 90-day and 1-year mortality. The survival benefit for prednisolone was offset by an increase in the risk of serious infection.”

11. To Summarize

  • Impact on Current Practice: This was a landmark, practice-changing trial. It definitively demonstrated that pentoxifylline is ineffective and should not be used for severe alcoholic hepatitis. For prednisolone, despite the non-significant primary outcome, the strong trend and significant medium-term survival benefit provided the most robust evidence to date to support its use, while also clearly quantifying the associated risk of infection.
  • Specific Recommendations:
    • Patient Selection: For patients with severe alcoholic hepatitis (DF ≥32) without active infection or GI bleeding.
    • Actionable Intervention: Pentoxifylline should not be used. A 28-day course of prednisolone can be considered to improve 90-day and 1-year survival.
    • Expected Benefit: No statistically significant benefit on 28-day mortality, but a significant reduction in mortality at 90 days and 1 year.
  • What This Trial Does NOT Mean: This trial does not mean all patients with alcoholic hepatitis should receive steroids. The decision requires a careful risk-benefit calculation, balancing the potential survival benefit against the significant and real risk of serious infection.
  • Implementation Caveats: Patients treated with prednisolone require close monitoring for the development of infection.

12. Context and Related Studies

  • Building on Previous Evidence: The STOPAH trial was designed to be the definitive study to resolve the long-standing uncertainty surrounding the use of both prednisolone and pentoxifylline, which was based on numerous small and conflicting previous trials.
  • Influence on Subsequent Research: This trial largely ended research into pentoxifylline for this indication. It has focused the debate on corticosteroids around better patient selection (e.g., using the Lille model to identify non-responders early) and exploring alternative anti-inflammatory or regenerative therapies.

13. Unresolved Questions & Future Directions

  • Unresolved Questions: How can we better identify patients who are most likely to benefit from corticosteroids and least likely to be harmed by infection? Are there alternative or adjunctive therapies that can improve outcomes?
  • Future Directions: Research is focused on biomarkers to predict response to steroids, therapies targeting gut-liver axis inflammation, and regenerative medicine approaches.

14. External Links

15. Framework for Critical Appraisal

  • Clinical Question: The question was highly relevant, addressing two common but unproven therapies for a high-mortality condition.
  • Methods: The large, multicenter, double-blind, 2×2 factorial RCT design was methodologically superb and highly efficient.
  • Results: The trial provided clear, definitive evidence of no benefit for pentoxifylline. For prednisolone, the results were more nuanced: a non-significant primary outcome but a significant medium-term survival benefit at the cost of increased infections.
  • Conclusions and Applicability: The authors’ conclusion is a precise and balanced summary of the findings. The trial is highly applicable and has directly informed international guidelines, leading to the abandonment of pentoxifylline and providing a much stronger (though still cautious) evidence base for the use of prednisolone.

16. Disclaimer and Contact

This summary is provided by the Academic Committee of ESBICM (ACE) to facilitate the understanding of this study; readers are advised to refer to the original trial document for a deeper understanding. If you find any information incorrect, or missing, or it needs an update or have a request for a specific critical care trial summary, kindly write to us at academics[at]esbicm.org.

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