Early intravenous then oral metoprolol in 45,852 patients with acute myocardial infarction: randomised placebo-controlled trial

Article Identification

Article Title: Early intravenous then oral metoprolol in 45,852 patients with acute myocardial infarction: randomised placebo-controlled trial

Authors: Chen ZM, Pan HC, Chen YP, et al.

Journal Name, Year, Volume, Issue: The Lancet, 2005, Volume 366, Issue 9497, Pages 1622–1632

Type of Study: Randomized Controlled Trial

DOI/PMID: DOI: 10.1016/S0140-6736(05)67661-1

Quick Reference Summary

Early β-blocker therapy in acute myocardial infarction (MI) did not significantly reduce the composite outcome of death, reinfarction, or cardiac arrest (p=0.1) but decreased reinfarction and ventricular fibrillation rates while increasing the risk of cardiogenic shock.

The reductions in adverse events emerged gradually after the first day, whereas the increased risk of cardiogenic shock was prominent during the initial 24 hours post-admission.

Core Clinical Question

In patients admitted with acute myocardial infarction, does the addition of early β-blocker therapy compared to placebo reduce the composite outcome of death, reinfarction, or cardiac arrest?

Background

Disease Overview

Acute myocardial infarction (MI) is a critical condition requiring timely intervention to reduce morbidity and mortality.

Prior Data

Previous randomized trials have evaluated early β-blocker therapy in the emergency treatment of MI.

Uncertainty remains regarding the added value of β-blockers to standard interventions like aspirin and fibrinolytic therapy.

Current Standard of Care

Administration of aspirin and fibrinolytic agents as primary treatments for acute MI.

Knowledge Gaps Addressed by Study

The balance between the benefits of β-blockers in reducing reinfarction and ventricular fibrillation versus the risk of inducing cardiogenic shock.

Optimal timing for initiating β-blocker therapy to maximize benefits and minimize risks.

Study Rationale

To clarify the efficacy and safety of early β-blocker therapy in the context of existing standard treatments for acute MI.

Methods Summary

Study Design: Randomized, placebo-controlled trial.

Setting and Time Period: 1,250 hospitals; patients admitted within 24 hours of suspected acute MI onset.

Population Characteristics: 45,852 patients with suspected acute MI.

Inclusion/Exclusion Criteria: Not specified.

Intervention Details: Metoprolol (up to 15 mg intravenous followed by 200 mg oral daily; n=22,929).

Control/Comparison Group Details: Matching placebo (n=22,923).

Primary and Secondary Outcomes

Co-Primary Outcomes:

1. Composite of death, reinfarction, or cardiac arrest.
2. Death from any cause during the treatment period.

Secondary Outcomes: Reinfarction, ventricular fibrillation, cardiogenic shock.

Statistical Analysis Approach

Intention-to-treat analysis using the log-rank method.

Sample Size Calculations

Not detailed.

Ethics and Funding Information

Registered with ClinicalTrials.gov (NCT00222573); additional ethics and funding details not provided.

Detailed Results

Outcome	Metoprolol Group	Placebo Group	Difference (95% CI)	P-value
Death, reinfarction, or cardiac arrest	2166 (9.4%)	2261 (9.9%)	OR 0.96 (0.90–1.01)	0.1
Death	1774 (7.7%)	1797 (7.8%)	OR 0.99 (0.92–1.05)	0.69
Reinfarction	464 (2.0%)	568 (2.5%)	OR 0.82 (0.72–0.92)	0.001
Ventricular Fibrillation	581 (2.5%)	698 (3.0%)	OR 0.83 (0.75–0.93)	0.001
Cardiogenic Shock	1141 (5.0%)	885 (3.9%)	OR 1.30 (1.19–1.41)	<0.00001

Participant Flow and Demographics

89% of patients completed the treatment; mean treatment duration was 15 days in survivors.

Primary Outcome Results

No significant reduction in the composite outcome (p=0.1).

No significant reduction in mortality (p=0.69).

Secondary Outcome Results

Significant reductions in reinfarction and ventricular fibrillation (p=0.001 each).

Significant increase in cardiogenic shock (p<0.00001).

Subgroup Analyses

Increased risk of cardiogenic shock was primarily during the first 24 hours post-admission, whereas benefits in reinfarction and ventricular fibrillation emerged gradually thereafter.

Adverse Events/Safety Data

Higher incidence of cardiogenic shock in the metoprolol group, especially in hemodynamically unstable patients.

Authors' Conclusions

Early β-blocker therapy in acute MI reduces the risks of reinfarction and ventricular fibrillation but increases the risk of cardiogenic shock, particularly within the first day after admission.

It is generally prudent to initiate β-blocker therapy in the hospital only after hemodynamic stabilization post-MI.

Critical Analysis

A. Strengths:

• Large sample size (45,852 patients) enhances the power and generalizability of the findings.
• Multicenter design across 1,250 hospitals increases external validity.
• Randomized controlled design minimizes selection bias.

B. Limitations:

• Lack of detailed information on inclusion/exclusion criteria.
• Potential variability in treatment administration across numerous hospitals.
• Limited data on long-term outcomes beyond the treatment period.

C. Literature Context:

Previous Studies and Meta-Analyses:

Previous randomized trials have examined the use of β-blockers in acute myocardial infarction, but their value in the context of standard treatments like aspirin and fibrinolytic therapy has been uncertain. While earlier studies suggested reductions in adverse events, these were conducted prior to the widespread use of modern therapies, leaving unanswered questions about the balance of benefits and risks.

Contrasting Methodological Quality:

This trial is notable for its large sample size (45,852 patients) and multicenter design, which enhances external validity compared to smaller, single-center studies. Its randomized, placebo-controlled design minimizes selection bias, offering a robust contribution to evidence on β-blocker use in AMI.

Comparisons with Guidelines:

At the time of the study, β-blockers were commonly recommended for acute MI, but the optimal timing of therapy initiation was not well established. The study helps refine these recommendations by emphasizing the importance of hemodynamic stability before starting β-blockers.

This Trial's Contribution: Clarifies the dual effects of β-blockers in acute MI, highlighting the need for careful timing based on hemodynamic stability.

Clinical Application

Impact on Current Practice: Suggests delaying the initiation of β-blocker therapy until after stabilization post-MI to mitigate the risk of cardiogenic shock while still gaining benefits in reducing reinfarction and ventricular fibrillation.

Applicable Patient Populations: Particularly beneficial for hemodynamically stable patients after the initial 24-hour period post-MI.

How to Use This Info in Practice

Recommendation: Initiate β-blocker therapy in acute MI patients once hemodynamic stability is achieved to balance benefits and risks effectively.