COMMIT: Metoprolol in Acute Myocardial Infarction (2005)

“In a wide range of patients with acute myocardial infarction, early intravenous then oral metoprolol was well tolerated but did not significantly reduce 28-day mortality.”

  • The COMMIT Collaborative Group

1. Publication Details

  • Trial Title: Intravenous and oral metoprolol in acute myocardial infarction (COMMIT/CCS-2)
  • Citation: Chen ZM, Pan HC, Chen YP, et al. Early intravenous then oral metoprolol in 45,852 patients with acute myocardial infarction: randomised placebo-controlled trial. Lancet. 2005;366(9497):1622-1632. DOI: 10.1016/S0140-6736(05)67661-1
  • Published: November 5, 2005, in The Lancet
  • Author: Zheng-Ming Chen, on behalf of the COMMIT collaborative group
  • Funding: The British Heart Foundation; UK Medical Research Council; and others.

2. Keywords

  • Acute Myocardial Infarction, Beta-Blockers, Metoprolol, Cardiogenic Shock, Randomized Controlled Trial

3. The Clinical Question

  • In adult patients with acute myocardial infarction (MI) (Population), does early treatment with intravenous followed by oral metoprolol (Intervention) compared to placebo (Comparison) reduce the composite outcome of death, reinfarction, or cardiac arrest at 28 days (Outcome)?

4. Background and Rationale

  • Existing Knowledge: Beta-blockers were known to be beneficial for the long-term secondary prevention of death after MI. However, the role of initiating beta-blockers very early (intravenously) in the acute phase of an MI was highly uncertain. Smaller, older trials had suggested a benefit, but there were significant concerns about causing harm, particularly hypotension and cardiogenic shock.
  • Knowledge Gap: A very large, pragmatic randomized controlled trial was needed to definitively determine the risk-benefit balance of early intravenous beta-blocker therapy in a broad range of patients with acute MI.
  • Proposed Hypothesis: The authors hypothesized that early intravenous followed by oral metoprolol would be superior to placebo in reducing the risk of death, reinfarction, or cardiac arrest.

5. Study Design and Methods

  • Design: A very large, multicenter, prospective, randomized, double-blind, placebo-controlled trial (used to test the effectiveness of interventions).
  • Setting: 1250 hospitals in China.
  • Trial Period: Enrollment ran from July 1999 to June 2005.
  • Population:
    • Inclusion Criteria: Adult patients (no upper age limit) presenting within 24 hours of the onset of suspected acute MI with either ST-segment elevation or left bundle-branch block.
    • Exclusion Criteria: Included systolic blood pressure <100 mm Hg, heart rate <60 bpm, and other contraindications to beta-blockers.
  • Intervention: Patients received up to three intravenous boluses of metoprolol (5 mg each), followed by oral metoprolol (200 mg daily).
  • Control: Patients received matching intravenous and oral placebos.
  • Management Common to Both Groups: All patients received standard care for acute MI, which could include aspirin, clopidogrel, and fibrinolytic therapy.
  • Power and Sample Size: The authors planned to enroll 46,000 patients, which would provide very high power to detect even a small but clinically important difference in the primary outcome. (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: A composite of death, reinfarction, or cardiac arrest during the hospital stay (up to 28 days).
    • Secondary Outcomes: Included death from any cause and the incidence of cardiogenic shock.

6. Key Results

  • Enrollment and Baseline: 45,852 patients were randomized (22,929 to metoprolol and 22,923 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 the primary composite outcome. The primary outcome occurred in 2166 patients (9.4%) in the metoprolol group and in 2223 patients (9.7%) in the placebo group (p=0.39).
  • Secondary Outcomes: There was no significant difference in overall mortality. However, treatment with metoprolol was associated with a significant reduction in the risk of reinfarction and ventricular fibrillation, but this was offset by a significant increase in the risk of developing cardiogenic shock (5.0% in the metoprolol group vs. 3.9% in the placebo group; p<0.0001).
  • Adverse Events: The primary adverse event was cardiogenic shock, which was significantly more common in the metoprolol group.

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 patients who met the composite endpoint between the two groups.
  • Key Statistic(s) Reported: The key statistics were the absolute rates of the primary outcome and the associated P-value.
  • Interpretation of Key Statistic(s):
    • P-value: The p-value of 0.39 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 for its primary outcome, ARR and NNT are not applicable.
  • Subgroup Analyses: The increased risk of cardiogenic shock was most pronounced in patients who presented with signs of hemodynamic instability (e.g., higher Killip class).

8. Strengths of the Study

  • Study Design and Conduct: The very large, multicenter, randomized, double-blind, placebo-controlled design is the gold standard and provided a massive amount of high-quality data.
  • Generalizability: The pragmatic design with very broad inclusion criteria makes the findings highly generalizable to a wide range of patients with acute MI.
  • Statistical Power: The enormous sample size provided definitive power to rule out even a small net benefit of the intervention.
  • Patient-Centered Outcomes: The study focused on the most important patient-centered outcomes: death, reinfarction, and cardiac arrest.

9. Limitations and Weaknesses

  • Internal Validity (Bias): The study was well-conducted with a very low risk of bias.
  • External Validity (Generalizability): The study was conducted in China, and the standard of care at the time (e.g., low rates of primary PCI) may be different from other parts of the world.
  • Other: The study tested a specific “front-loaded” intravenous beta-blocker strategy, and the results do not necessarily apply to starting oral beta-blockers later in the hospital course.

10. Conclusion of the Authors

  • The authors concluded that routine use of early intravenous metoprolol in patients with acute MI was not associated with any net benefit on the primary composite outcome. While it reduced the risk of reinfarction and ventricular fibrillation, this was counteracted by an increased risk of cardiogenic shock.

11. To Summarize

  • Impact on Current Practice: This was a profoundly practice-changing trial. It provided definitive evidence that the routine, early use of intravenous beta-blockers in all patients with acute MI is not beneficial and can be harmful in some. It led to a major shift in guidelines, which now recommend against this practice, particularly in hemodynamically unstable patients.
  • Specific Recommendations:
    • Patient Selection: For the broad population of adult patients with acute MI.
    • Actionable Intervention: Do not routinely administer early intravenous beta-blockers to all patients with acute MI.
  • What This Trial Does NOT Mean: This trial does NOT mean that beta-blockers are not beneficial after MI. It only argues against the routine, early intravenous administration. The benefit of starting oral beta-blockers later in hemodynamically stable patients is well-established.
  • Implementation Caveats: The key takeaway is to “first, do no harm.” Early IV beta-blockers should be avoided, especially in patients with any signs of hemodynamic instability.

12. Context and Related Studies

  • Building on Previous Evidence: The COMMIT trial (2005) was designed to provide a definitive answer to a question that had been debated for years, with previous smaller trials (like ISIS-1) suggesting a benefit.
  • Influence on Subsequent Research: The definitive neutral-to-harmful result of this massive trial has largely settled the question of early IV beta-blocker use in MI.

13. Unresolved Questions & Future Directions

  • Unresolved Questions: This trial definitively answered its primary question.
  • Future Directions: Research in the management of acute MI has shifted to focus on optimizing reperfusion strategies, antiplatelet therapy, and long-term secondary prevention.

14. External Links

15. Framework for Critical Appraisal

  • Clinical Question: The research question was highly relevant, testing a common and physiologically plausible intervention in a very common and deadly disease.
  • Methods: The very large, multicenter, double-blind RCT design was of the highest quality. The pragmatic and inclusive nature of the patient population is a major strength, enhancing generalizability.
  • Results: The study reported a clear neutral finding for its primary outcome. The key finding was the demonstration of a trade-off: a reduction in arrhythmic events was offset by an increase in cardiogenic shock, resulting in no net benefit.
  • Conclusions and Applicability: The authors’ conclusion is a direct and fair reflection of the data. The high external validity of this pragmatic trial means its findings are broadly applicable. This is a classic example of a high-quality “negative” trial that was profoundly practice-changing by providing strong evidence to stop a common but ultimately unhelpful 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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