Current issues of ACP Journal Club are published in Annals of Internal Medicine


Therapeutics

Intravenous magnesium sulfate decreased long-term mortality after MI

ACP J Club. 1994 Sept-Oct;121:40. doi:10.7326/ACPJC-1994-121-2-040


Source Citation

Woods KL, Fletcher S. Long-term outcome after intravenous magnesium sulphate in suspected acute myocardial infarction: the second Leicester Intravenous Magnesium Intervention Trial (LIMIT-2). Lancet. 1994 Apr 2;343:816-9.


Abstract

Objective

To analyze long-term survival in patients with suspected acute myocardial infarction (MI) treated with intravenous magnesium sulfate compared with placebo.

Design

Randomized, double-blind, placebo-controlled trial.

Setting

Coronary care unit of Leicester Royal Infirmary, United Kingdom.

Patients

2316 patients {mean age, 62 y; 27% women} (data from Woods KL, et al. Lancet. 1992;339:1553-8) with suspected acute MI were recruited during a 5-year period. Exclusion criteria were complete heart block or renal failure (serum creatinine > 300 ┬Ámol/L). Patients were followed until death or 1-year after randomization (range, 1 to 5.5 y; mean, 2.7 y). 99.5% of patients were accounted for at study end.

Intervention

Patients were randomly assigned to receive either an immediate intravenous loading injection and 24-hour infusion of magnesium sulfate (8 mmol and 65 mmol, respectively) {n = 1159}* or placebo (equal volumes of saline) {n = 1157}*. (*Data from Woods.)

Main Outcome Measures

All-cause mortality and cause-specific mortality rates.

Main Results

All-cause mortality was reduced by 16% (relative risk reduction [RRR]) in the magnesium group compared with the placebo group (95% CI, 2% to 29%; P = 0.03). Mortality from ischemic heart disease was reduced by 21% (RRR) in the magnesium group compared with the placebo group (CI, 5% to 35%; P = 0.01). Mortality from other causes was similar in both groups.

Conclusion

Early intravenous administration of magnesium sulfate was effective in reducing all-cause mortality and mortality from ischemic heart disease in patients with acute myocardial infarction.

Sources of funding: Leicestershire Health Authority and the British Heart Foundation.

For article reprint: Dr. K.L. Woods, Division of Clinical Pharmacology, Department of Medicine and Therapeutics, University of Leicester, Clinical Sciences Building, Leicester Royal Infirmary, Leicester LE2 7LX, United Kingdom. FAX 44-533-523-108.


Commentary

The study by Woods and Fletcher extends the 28-day follow-up from the original LIMIT-2 report to a mean of 2.7 years with essentially similar findings. A clinically important reduction occurred in total and cardiovascular mortality. The authors also suggest that the positive results of this study, which conflict with the negative results observed by the ISIS-4 investigators in 58 000 patients receiving a similar magnesium dose (1), may be explained by study design. In the LIMIT-2 trial, patients received magnesium an average of 3 hours after the onset of symptoms and before thrombolytic therapy, whereas in ISIS-4, patients were randomly assigned an average of 8 hours after symptoms and usually received magnesium after completion of thrombolytic therapy. The authors of the LIMIT trial suggest it is critical to administer magnesium early and before thrombolytic therapy to mitigate reperfusion injury, the main proposed mechanism of benefit. Magnesium was not superior to placebo in any subgroup analysis of ISIS-4 (Woods KL and colleagues. Unpublished data); however, this included patients who received magnesium 0 to 3 hours after the onset of symptoms and included patients not treated with thrombolytic agents. Most clinically relevant subgroups of ISIS-4 were larger than the entire LIMIT-2 population.

An alternative interpretation of the LIMIT-2 report is that the positive results may have been caused by the play of chance because the lower limit of the 95% CI was close to 0. Even if magnesium tempers reperfusion injury, prompt thrombolytic therapy should not be preempted by magnesium infusion because thrombolytic agents are unequivocally beneficial and extremely sensitive to the timing of administration. Although magnesium is safe and inexpensive, LIMIT-2 is insufficiently persuasive, in light of ISIS-4, to recommend routine use in acute MI.

James McCord, MD
Steven Borzak, MD Henry Ford Hospital Detroit, Michigan, USA


Reference

1. ISIS Collaborative Group. Randomized study of intravenous magnesium in over 50 000 patients with suspected acute myocardial infarction. Circulation. 1993;88(Suppl 4):1559.


Author's Response

By protocol, ISIS-4 patients were randomly assigned after completion of thrombolysis. The time interval was not recorded. The minority who received no thrombolytic therapy were randomly assigned a median of 12 hours after symptom onset. An effect of magnesium on reperfusion injury, therefore, cannot be tested in any subgroup of ISIS-4.