Elsevier

The Lancet

Volume 366, Issue 9497, 5–11 November 2005, Pages 1622-1632
The Lancet

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

https://doi.org/10.1016/S0140-6736(05)67661-1Get rights and content

Summary

Background

Despite previous randomised trials of early β-blocker therapy in the emergency treatment of myocardial infarction (MI), uncertainty has persisted about the value of adding it to current standard interventions (eg, aspirin and fibrinolytic therapy), and the balance of potential benefits and hazards is still unclear in high-risk patients.

Methods

45 852 patients admitted to 1250 hospitals within 24 h of suspected acute MI onset were randomly allocated metoprolol (up to 15 mg intravenous then 200 mg oral daily; n=22 929) or matching placebo (n=22 923). 93% had ST-segment elevation or bundle branch block, and 7% had ST-segment depression. Treatment was to continue until discharge or up to 4 weeks in hospital (mean 15 days in survivors) and 89% completed it. The two prespecified co-primary outcomes were: (1) composite of death, reinfarction, or cardiac arrest; and (2) death from any cause during the scheduled treatment period. Comparisons were by intention to treat, and used the log-rank method. This study is registered with ClinicalTrials.gov, number NCT 00222573.

Findings

Neither of the co-primary outcomes was significantly reduced by allocation to metoprolol. For death, reinfarction, or cardiac arrest, 2166 (9·4%) patients allocated metoprolol had at least one such event compared with 2261 (9·9%) allocated placebo (odds ratio [OR] 0·96, 95% CI 0·90–1·01; p=0·1). For death alone, there were 1774 (7·7%) deaths in the metoprolol group versus 1797 (7·8%) in the placebo group (OR 0·99, 0·92–1·05; p=0·69). Allocation to metoprolol was associated with five fewer people having reinfarction (464 [2·0%] metoprolol vs 568 [2·5%] placebo; OR 0·82, 0·72–0·92; p=0·001) and five fewer having ventricular fibrillation (581 [2·5%] vs 698 [3·0%]; OR 0·83, 0·75–0·93; p=0·001) per 1000 treated. Overall, these reductions were counterbalanced by 11 more per 1000 developing cardiogenic shock (1141 [5·0%] vs 885 [3·9%]; OR 1·30, 1·19–1·41; p<0·00001). This excess of cardiogenic shock was mainly during days 0–1 after admission, whereas the reductions in reinfarction and ventricular fibrillation emerged more gradually. Consequently, the overall effect on death, reinfarction, arrest, or shock was significantly adverse during days 0–1 and significantly beneficial thereafter. There was substantial net hazard in haemodynamically unstable patients, and moderate net benefit in those who were relatively stable (particularly after days 0–1).

Interpretation

The use of early β-blocker therapy in acute MI reduces the risks of reinfarction and ventricular fibrillation, but increases the risk of cardiogenic shock, especially during the first day or so after admission. Consequently, it might generally be prudent to consider starting β-blocker therapy in hospital only when the haemodynamic condition after MI has stabilised.

Introduction

β-blocker therapy is of proven value in the treatment of arrhythmias and hypertension, as well as for long-term secondary prevention after unstable angina and myocardial infarction (MI).1, 2, 3, 4 More recently, despite having previously been considered contraindicated, the use of β blockers has been shown to be beneficial in chronic heart failure.5, 6 The emergency treatment of suspected acute MI with intravenous then oral β-blocker therapy has also been studied in more than two dozen randomised trials.1, 7, 8, 9 Overall, those trials included more than 27 000 patients, but nearly all were done before fibrinolytic and antiplatelet therapy had become routine, and they mainly involved fairly low-risk patients (average control mortality was 4%). Collectively, though not separately, their results indicated that this treatment was safe and moderately effective in such low-risk patients, preventing six (SE 3) deaths per 1000.9 Moreover, results of retrospective analyses suggested that there might be somewhat greater benefits in higher-risk patients with ST-segment elevation9 or congestive heart failure.7, 8 Despite these findings, however, substantial uncertainty has persisted about the value of adding early β-blocker therapy to current standard interventions (eg, aspirin and fibrinolytic therapy) in acute MI,10, 11 and its use is limited and varies widely.12, 13, 14

In the previous trials, mortality during the first day or two after suspected acute MI seemed to be reduced by about a quarter with early β-blocker therapy,9 and this has been tentatively attributed to the prevention of life-threatening arrhythmias and cardiac rupture.9, 15 By contrast, fibrinolytic therapy has been shown to be associated with a small increase in mortality during this early period, perhaps at least in part due to an excess of cardiac rupture.16 Consequently, use of early β-blocker therapy in conjunction with fibrinolytic therapy might be particularly effective.10, 15, 16, 17 A few trials have attempted to assess this combination, but none was big enough to be reliably informative.17, 18, 19 Moreover, concerns have been raised about the potential hazards of intravenous rather than oral β-blocker therapy in acute MI.11 The aim of this study was to assess the balance of risks and benefits of adding early intravenous then oral metoprolol to current standard therapies in a wide range of patients.

Section snippets

Methods

COMMIT (ClOpidogrel and Metoprolol in Myocardial Infarction Trial; also Second Chinese Cardiac Study [CCS-2]) is a randomised placebo-controlled trial with a 2×2 factorial design, which separately assessed the efficacy and safety of early β-blocker therapy (intravenous then oral metoprolol) and of antiplatelet therapy (adding clopidogrel to aspirin) in suspected acute MI. Details of the study objectives, design, and methods have been reported previously20 and in the accompanying paper,21 and

Results

45 852 patients with suspected acute MI were randomised from 1250 Chinese hospitals to receive either intravenous then oral metoprolol (n=22 929) or matching placebo (n=22 923) for up to 28 days in hospital.21 Follow-up to first discharge or day 28 was available for all but two patients (figure 1). At discharge, the diagnosis was confirmed as MI in 95·8% (n=21 993 metoprolol and n=21 955 placebo) of randomised patients, possible MI in 1·8% (405 and 409), unstable angina in 1·3% (294 and 302),

Discussion

This large randomised trial of intravenous then oral β-blocker therapy for the emergency treatment of acute MI involved nearly twice as many patients and more than three times as many deaths as all previous such trials combined. Nevertheless, its results do not show that such treatment significantly reduced in-hospital mortality, either overall or in a wide range of different circumstances (including patients at high or low risk of death). Allocation to the metoprolol regimen studied did

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    Collaborators and participating hospitals listed at end of reference 21

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