TOWNSEND LETTER for DOCTORS & PATIENTS - APRIL 2003

Intravenous Magnesium for Acute Myocardial Infarction: The Controversy Continues

In the 1980s and early 1990s, at least seven small, randomized, placebo-controlled trials demonstrated that intravenous administration of magnesium within several hours of the onset of acute myocardial (AMI) infarction could significantly reduce mortality, in part by reducing the incidence of life-threatening arrhythmias. The reduction in mortality in most of these studies was approximately 50 to 70%, with a range of 24 to 88%.^1-3 An 80% decrease in mortality was also reported in a more recent, small-scale trial.⁴ Only one small trial failed to confirm the beneficial effect of magnesium.⁵

In addition to its anti-arrhythmic effect, magnesium inhibits platelet aggregation, promotes vaso-dilation, and plays a crucial role in myocardial energy production. Moreover, the cost of magnesium therapy is negligible in comparison with that of fibrinolytic agents and other conventional treatments for AMI. If the beneficial effect of magnesium could be confirmed in larger clinical trials, then this mineral would be considered an ideal treatment for AMI.

However, a multi-center trial (ISIS-4) reported in 1995, which enrolled more patients than all of the other trials combined, found no difference in mortality between patients given intravenous magnesium and those given a placebo.⁶ In addition, IV magnesium treatment resulted in significant increases in the incidence of hypotension and heart failure and higher frequencies of cardiogenic shock during or just after the infusion period. Another recently published large-scale trial (MAGIC), also failed to demonstrate any beneficial effect of magnesium.⁷ Based on their results, the investigators in this new study concluded "there is no indication for the routine administration of intravenous magnesium" in patients with AMI.

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Numerological chauvinists might argue that the two negative large-scale trials (which included a total of more
than 30,000 patients) outweigh the eight small double-blind trials (which included a total of only several thousand patients). Indeed, meta-analyses that pooled all of the studies have concluded that magnesium is ineffective. However, it is difficult to explain how an ineffective treatment could produce statistically significant positive results (in some cases, highly significant) in 8 of 11 trials. The probability of that occurring by chance is extremely remote.

A more likely explanation for the discrepant results is differences in methodology. One potentially important difference between the positive and negative studies was the dose of magnesium administered. In most of the studies that showed benefit, the amount of magnesium given during the first 24 hours ranged from 50 to 66.6 mmol. The positive study that found the least benefit (a 24% reduction in mortality), the so-called "LIMIT-2" trial, used a dose of 73 mmol during the first 24 hours. In the negative ISIS-4 and MAGIC studies, and in the one small negative trial, the doses of magnesium given during the first 24 hours were 80, 76, and 80 mmol, respectively.

Excessive intravenous doses of magnesium can cause potentially serious side effects, including hypotension and bradycardia. In patients suffering an AMI, these side effects could result in an extension of the infarct and an increased risk of heart failure and shock. These adverse effects of magnesium were, in fact, reported in some of the negative studies.

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One might reasonably conclude from the data that administering 50 to 66.6 mmol of magnesium over a 24-hour period can reduce mortality from AMI by approximately 50 to 80%. Larger doses are less effective, and a dose of 80 mmol given over 24 hours may be toxic for certain individuals, such as those who are older, those who have lower lean body mass, and those with compromised renal function. It might seem that the 76 mmol given in the negative MAGIC study was not significantly greater than the 73 mmol used in LIMIT-2, which was associated with a 24% reduction in mortality. However, the patients in MAGIC were older than those in LIMIT-2 (mean age, 70 vs. 62 years), and may therefore have been more susceptible to the adverse effects of high-dose magnesium.

Because of the enormous public health and economic implications, it is important that another large-scale trial be undertaken, in which safe doses of magnesium (perhaps 50 mmol in 24 hours) are given. If such a study is done, an attempt should be made to individualize the dose, based on factors such as age, lean body mass, and renal function. In the interim, intravenous administration of magnesium in the early stages of AMI remains a viable option.

Alan R. Gaby, MD

References:

1. Shechter M, et al. Beneficial effect of magnesium sulfate in acute myocardial infarction. Am J Cardiol 1990;66:271-274.

2. Woods KL, et al. Intravenous magnesium sulphate in suspected acute myocardial infarction: results of the second Leicester Intravenous Magnesium Intervention Trial (LIMIT-2). Lancet 1992;339:15531558.

3. Rasmussen HS, et al. Intravenous magnesium in acute myocardial infarction. Lancet 1986;1:234-236.

4. Gyamlani G, et al. Benefits of magnesium in acute myocardial infarction: timing is crucial. Am Heart J 2000;139:703.

5. Feldstedt M, et al. Magnesium substitution in acute ischaemic heart syndromes. Eur Heart J 1991;12:12151218.

6. ISIS-4 Collaborative Group. ISIS-4: a randomised factorial trial assessing early oral captopril, oral mononitrate, and intravenous magnesium sulphate in 58,050 patients with suspected acute myocardial infarction. Lancet 1995;345:669-685.

7. Antman EM. Early administration of intravenous magnesium to high-risk patients with acute myocardial infarction in the Magnesium in Coronaries (MAGIC) Trial: a randomised controlled trial. Lancet 2002;360:1189-1196.

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