Elsevier

The Lancet

Volume 360, Issue 9341, 19 October 2002, Pages 1189-1196
The Lancet

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Early administration of intravenous magnesium to high-risk patients with acute myocardial infarction in the Magnesium in Coronaries (MAGIC) Trial: a randomised controlled trial

https://doi.org/10.1016/S0140-6736(02)11278-5Get rights and content

Summary

Background

The benefits of supplemental administration of intravenous magnesium in patients with ST-elevation myocardial infarction (STEMI) are controversial. Despite promising results from work in animals and the ready availability of this simple, inexpensive treatment, conflicting results have been reported in clinical trials. Our aim was to compare short-term mortality in patients with STEMI who received either intravenous magnesium sulphate or placebo.

Methods

We did a randomised, double-blind trial in 6213 patients with acute STEMI who were assigned a 2 g intravenous bolus of magnesium sulphate administered over 15 min, followed by a 17 g infusion of magnesium sulphate over 24 h (n=3113), or matching placebo (n=3100). Our primary endpoint was 30-day all-cause mortality. At randomisation, patients were stratified by their eligibility for reperfusion therapy. The first stratum included patients who were aged 65 years or older and eligible for reperfusion therapy, and the second stratum included patients of any age who were not eligible for reperfusion therapy. Analysis was by intention-to-treat.

Findings

At 30 days, 475 (15·3%) patients in the magnesium group and 472 (15·2%) in the placebo group had died (odds ratio 1·0, 95% Cl 0·9–1·2, p=0·96). No benefit or harm of magnesium was observed in eight prespecified subgroup analyses of patients and in 15 additional exploratory subgroup analyses. After adjustment for factors shown to effect mortality risk in a multivariate regression model, no benefit of magnesium was observed (1·0, 0·8–1·1, p=0·53).

Interpretation

Early administration of magnesium in high-risk patients with STEMI has no effect on 30-day mortality. In view of the totality of the available evidence, in current coronary care practice there is no indication for the routine administration of intravenous magnesium in patients with STEMI.

Introduction

Despite reductions in the mortality of patients with ST-elevation myocardial infarction (STEMI) over the past several decades, the short-term mortality rate remains high in two subgroups of patients: those who are not eligible for reperfusion therapy and those older than 65 years who receive reperfusion therapy.1, 3 Adjunctive pharmacological treatments that might reduce mortality, especially in high-risk patients, are therefore of interest. Among such adjunctive therapies, supplemental intravenous magnesium is especially attractive, since it is readily available in all hospitals, easily administered, does not require special expertise, is familiar to doctors, carries little risk of toxicity, and is inexpensive.4, 5 Patients with STEMI might have a deficiency in total-body magnesium through a combination of dietary inadequacy, disease-induced loss, treatment-induced loss, increased age, and previous stressful conditions that could precipitate magnesium loss.5, 6 An analysis of the results of eight animal studies in four different species, in which magnesium was administered at various times before, during, and after release of coronary occlusion, suggested that magnesium has a cardioprotective effect. This cardioprotective effect, however, diminishes rapidly the later the treatment is given after reperfusion, and no benefit is seen if 1 h has elapsed after reperfusion.7

A meta-analysis of seven randomised controlled trials of magnesium that collectively enrolled 1266 patients between 1980 and 1990 indicated a benefit of magnesium with an odds ratio for mortality of 0·44 (0·27–0·71) by the fixed effects model and 0·45 (0·23–0·86) by the random effects model.8, 9 The second Leicester Intravenous Magnesium Intervention Trial (LIMIT-2) enrolled 2316 patients between 1987 and 1992 and reported an odds ratio of 0·74 (0·55–1·00) in favour of magnesium.10 However, the ISIS-4 collaborative group reported an odds ratio of 1·6 (0·99–1·13) for mortality, suggesting that magnesium was not helpful and might even be slightly harmful in the 58 050 patients studied in their open-label trial between 1991 and 1993.11 Critiques of ISIS-4 raised the possibility that the null effect of magnesium resulted from late administration of treatment to patients who were predominantly at low risk.5, 9, 12 Four other small trials13, 14, 15, 16 that collectively enrolled 896 patients reported mixed results, ranging from a trend toward an 8% mortality reduction to more than a 50% mortality reduction with magnesium.

In view of the potentially cost-effective nature of magnesium administration and the controversy that surrounds its effectiveness, the Magnesium in Coronaries (MAGIC) trial was designed as a large, simple trial to test the hypothesis that the early administration of intravenous magnesium would reduce the short-term mortality of high-risk patients with STEMI.

Section snippets

Patients

Between April, 1999, and March, 2002, the MAGIC trial investigators enrolled patients from 278 sites in 14 countries. A description of the trial design has been published.17 In brief, patients were included if they had ischaemic discomfort and showed ST elevation of 0·1 mV or more in two or more limb leads, or 0·2 mV or more in two or more contiguous precordial leads, or new or presumably new left bundle branch block. All patients had to be able to receive the blinded study drug within 6 h of

Results

Figure 1 shows the trial profile, and table 1 the baseline characteristics of the patients, organised by stratum and also by treatment group. Patients in stratum 1 were older than those in stratum 2 (by protocol design) and were more often women. The two treatment groups were well matched. Notable baseline characteristics of the entire trial population indicative of the high-risk nature of the patients include: median age 70 years; female sex 45%; anterior infarction 56%; and pulmonary

Discussion

In this study of high-risk patients with STEMI, neither benefit nor harm was associated with the early administration of intravenous magnesium. Extensive univariate analyses did not identify any subgroup that benefited from magnesium, nor was there evidence of benefit of magnesium in a multivariate model that adjusted for factors shown to effect the risk of mortality. There was also no evidence of benefit or harm of magnesium for the major secondary endpoints of treatment for heart failure or

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