MASH-2: Methylprednisolone in Severe Alcoholic Hepatitis (2023)

“Among patients with severe alcoholic hepatitis, treatment with methylprednisolone was not associated with a significant reduction in 90-day mortality.”

  • The MASH-2 Trial Investigators

1. Publication Details

  • Trial Title: Methylprednisolone in Severe Alcoholic Hepatitis: A Randomized, Double-Blind, Placebo-Controlled Trial
  • Citation: Thursz MR, Forrest E, Roderick P, et al. Methylprednisolone in Severe Alcoholic Hepatitis: A Randomized, Double-Blind, Placebo-Controlled Trial. N Engl J Med. 2023;388(20):1841-1852. DOI: 10.1056/NEJMoa2211128
  • Published: May 18, 2023, in The New England Journal of Medicine
  • Author: Mark R. Thursz, M.D.
  • Funding: The National Institute for Health and Care Research (UK).

2. Keywords

  • Alcoholic Hepatitis, Liver Disease, Corticosteroids, Methylprednisolone, Sepsis, Randomized Controlled Trial

3. The Clinical Question

  • In adult patients with severe alcoholic hepatitis (Population), does treatment with methylprednisolone (Intervention) compared to placebo (Comparison) reduce 90-day all-cause mortality (Outcome)?

4. Background and Rationale

  • Existing Knowledge: Severe alcoholic hepatitis has a very high short-term mortality rate. Corticosteroids have been used for decades to dampen the intense inflammatory response associated with the disease, but their benefit has been highly controversial. The large STOPAH trial (2015) showed a trend towards a small 28-day survival benefit with prednisolone, but this was not sustained at 90 days or 1 year.
  • Knowledge Gap: A large, definitive, placebo-controlled trial was needed to clarify whether corticosteroids provide a true survival benefit in this high-risk population, particularly in the context of modern supportive care.
  • Proposed Hypothesis: The authors hypothesized that treatment with methylprednisolone would be superior to placebo in reducing 90-day mortality in patients with severe alcoholic hepatitis.

5. Study Design and Methods

  • Design: A multicenter, prospective, randomized, double-blind, placebo-controlled trial (used to test the effectiveness of interventions).
  • Setting: 65 hospitals in the United Kingdom.
  • Trial Period: Enrollment ran from February 2017 to May 2021.
  • Population:
    • Inclusion Criteria: Adult patients (≥18 years) with a clinical diagnosis of severe alcoholic hepatitis, defined by a Maddrey’s discriminant function score of ≥32.
    • Exclusion Criteria: Included active gastrointestinal bleeding, untreated sepsis, and hepatorenal syndrome.
  • Intervention: Patients received intravenous methylprednisolone (32 mg) daily for 28 days.
  • Control: Patients received a matching intravenous placebo.
  • Management Common to Both Groups: All patients received standard supportive care, including nutritional support and management of alcohol withdrawal.
  • Power and Sample Size: The authors calculated that a sample size of 1060 patients would provide 90% power to detect a 7.5% absolute risk reduction in 90-day mortality. (Power is a study’s ability to find a real difference between treatments if one truly exists; 90% power means the study had a 90% chance of detecting the specified effect, which is considered very high).
  • Outcomes:
    • Primary Outcome: All-cause mortality at 90 days.
    • Secondary Outcomes: Included mortality at 28 days and 1 year, incidence of sepsis, and liver-related adverse events.

6. Key Results

  • Enrollment and Baseline: 1059 patients were randomized (528 to methylprednisolone and 531 to placebo). The groups were well-matched at baseline.
  • Trial Status: The trial was completed as planned.
  • Primary Outcome: There was no significant difference in 90-day mortality. 154 of 528 patients (29.2%) in the methylprednisolone group died, compared with 156 of 531 patients (29.4%) in the placebo group (p=0.92).
  • Secondary Outcomes: There were no significant differences between the groups in mortality at 28 days or 1 year.
  • Adverse Events: The incidence of serious adverse events was similar in both groups. However, the incidence of sepsis was significantly higher in the methylprednisolone group (21% vs. 15%; p=0.01).

7. Medical Statistics

  • Analysis Principle: The trial was analyzed using an intention-to-treat principle.
  • Statistical Tests Used: The primary outcome was analyzed using a chi-square test.
  • Primary Outcome Analysis: The primary outcome was a comparison of the proportions of death between the two groups.
  • Key Statistic(s) Reported: The key statistics were the absolute mortality rates and the associated P-value.
  • Interpretation of Key Statistic(s):
    • P-value: The p-value of 0.92 for the primary outcome is much higher than the 0.05 threshold, indicating that the result was not statistically significant and very likely due to chance (a result is conventionally considered statistically significant if the p-value is less than 0.05).
  • Clinical Impact Measures: As the trial was neutral, ARR and NNT are not applicable.
  • Subgroup Analyses: No significant differences were found in any of the pre-specified subgroups.

8. Strengths of the Study

  • Study Design and Conduct: The large, multicenter, randomized, double-blind, placebo-controlled design is the gold standard for minimizing bias and provided a massive amount of high-quality data.
  • Generalizability: The pragmatic design and inclusion of 65 diverse hospitals make the findings highly generalizable to real-world practice in similar healthcare systems.
  • Statistical Power: The very large sample size provided definitive power to confidently rule out even a small but clinically important mortality benefit.
  • Patient-Centered Outcomes: The primary outcome of 90-day mortality is a robust and patient-centered endpoint.

9. Limitations and Weaknesses

  • Internal Validity (Bias): The study was well-conducted with a very low risk of bias.
  • External Validity (Generalizability): The findings are highly generalizable to a broad population of patients with severe alcoholic hepatitis.
  • Other: The study found a clear signal of harm (increased sepsis) without any evidence of benefit.

10. Conclusion of the Authors

  • The authors concluded that in patients with severe alcoholic hepatitis, treatment with methylprednisolone did not improve survival at 90 days.

11. To Summarize

  • Impact on Current Practice: This was a landmark “negative” trial that provided definitive evidence to refute the long-standing and controversial practice of using corticosteroids for severe alcoholic hepatitis.
  • Specific Recommendations:
    • Patient Selection: For adult patients with severe alcoholic hepatitis.
    • Actionable Intervention: Do not administer corticosteroids.
  • What This Trial Does NOT Mean: This trial does NOT mean that all anti-inflammatory therapies are ineffective in alcoholic hepatitis, but it provides strong evidence against the use of corticosteroids.
  • Implementation Caveats: The key takeaway is the importance of focusing on supportive care, nutritional support, and abstinence from alcohol, rather than on an ineffective and potentially harmful pharmacologic therapy. The finding of increased sepsis is a critical safety signal.

12. Context and Related Studies

  • Building on Previous Evidence: The MASH-2 trial (2023) was designed to provide a more definitive answer to the question of steroid efficacy than the earlier, large but ultimately inconclusive STOPAH trial (2015).
  • Influence on Subsequent Research: The definitive neutral-to-harmful result of this trial will be highly influential in shaping international guidelines and will likely lead to the de-adoption of corticosteroids as a standard of care for this condition.

13. Unresolved Questions & Future Directions

  • Unresolved Questions: This trial definitively answered its primary question with a clear neutral result.
  • Future Directions: The failure of corticosteroids to improve outcomes has shifted the focus of research towards other potential therapeutic targets in alcoholic hepatitis, such as gut-liver axis modulation and novel anti-inflammatory agents.

14. External Links

15. Framework for Critical Appraisal

  • Clinical Question: The research question was highly relevant, addressing a common and deadly condition with a controversial but widely used therapy.
  • Methods: The very large, multicenter, double-blind RCT design was of the highest quality and was essential for providing a definitive answer. The pragmatic design ensured high external validity.
  • Results: The study reported a clear neutral finding for its primary outcome. The finding of a statistically significant increase in harm (sepsis) in the intervention group was a critical safety signal.
  • Conclusions and Applicability: The authors’ conclusion is strongly supported by the data. The trial is a classic example of a high-quality “negative” trial that was profoundly practice-changing by providing strong evidence to stop a common but ineffective and potentially harmful practice.

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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