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Magnesium in acute myocardial infarction: Still an open question

Mildred S Seelig MD MPH, Ronald J Elin MD PhD, Elliott M Antman MD

MS Seelig, RJ Elin, EM Antman. Magnesium in acute myocardial infarction: Still an open question. Can J Cardiol 1998; 14(5):745-749.

Many activities of magnesium have justified randomized controlled trials of its role in acute myocardial infarction (AMI), which have shown reduction of short term mortality by 25% to over 50%. The Fourth International Study of Infarct Survival (ISIS-4) megastudy failed to confirm these findings, and, based on analysis of pooled findings, it was concluded that magnesium has no place in treatment of AMI. The fixed effects statistical model employed in ISIS-4 for evaluation of pooled data is inappropriate because the studies were not homogeneous. Among the differences between the earlier studies and the mega trial, the most significant was the time at which magnesium infusions were started relative to the time of reperfusion. Animal studies have shown that magnesium is protective only if present before or at the time of reperfusion. Unlike in earlier trials, in which magnesium infusions were started soon after the ischemic event or simultaneously with a lytic agent, in ISIS-4 magnesium treatment was withheld until after iatrogenic or spontaneous reperfusion occurred. This can explain poor therapeutic results in ISIS-4, but not the hypotension and bradycardia encountered in a minority of patients in that study. Dosage difference alone cannot explain this, even though the amounts given in the small studies were 40% to 25% less than that in ISIS-4, because the dose used in the Second Leicester Intravenous Magnesium Intervention Trial (LIMIT-2) was only slightly lower than that used in ISIS-4. Administration of high dose magnesium with an angiotensin-converting enzyme inhibitor (which spares magnesium) or the vasodilating oral nitrate in arms of ISIS-4 may have contributed to adverse effects of hypermagnesemia. Also, the very low mortality rate of controls in ISIS-4 suggests that the patients may have been at relatively low risk, and it is in high risk patients that magnesium has been shown to be most effective. A large scale study of magnesium in such patients is being started.

Key Words: Acute myocardial infarction, Magnesium, Meta-analysis, Reperfusion injury

Le magnésium dans l'infarctus aigu du myocarde : La question reste en suspens

RÉSUMÉ: Les nombreuses propriétés du magnésium ont été à l'origine de plusieurs essais randomisés contrôlés visant à déterminer son rôle dans l'infarctus aigu du myocarde (IAM) qui ont fait état de réductions de la mortalité à cout terme allant de 25 % à plus de 50 %. La quatrieme édition de la méga-étude International Study of Infarct Survival (ISIS-4) s'est révélée incapable de confirmer ces résultats et, sur la base de l'analyse des résultats regroupés, on à conclu que le magnésium n'a pas sa place dans le traitement de l'IAM. Le modele statistique a effets fixes utilisé lors de l'étude ISIS-4 pour l'évaluation des données regroupées ne convient pas parce que les études n'étaient pas homogènes. Parmi les différences notées entre les études antérieures et le méga-essai, la plus importante a été le moment auquel les perfusions de magnésium ont été débutées par rapport au moment de la reperfusion des coronaires. Des études chez l'animal ont démontré que le magnésium ne protegè que s'il est présent avant la survenue des lésions de reperfusion ou au moment de la reperfusion. Contrairement aux essais antérieurs, au cours desquels les perfusions de magnésium avaient été débutées peu après l'accident ischémique ou avec un agent lytique, dans l'essai ISIS-4, le traitement au magnésium a été retardé jusqu'à la survenue d'une lésion de reperfusion iatroèene ou spontanée. Cela pourrait expliquer les piètres résultats thérapeutiques observés lors de l'étude ISIS-4, mais non pas l'hypotension et la bradycardie notée chez une minorité de patients de cette étude. Les différences de posologie ne sauraient expliquer à elles seules ce phénoméne, même si les quantité administrées dans le cadre des études de moindre envergure étaient de 40 à 25 % inférieures à celles qui ont été utilisées lors de l'essai ISIS-4, parce que la dose utilisée dans le Second Leicester Intravenous Magnesium Intervention Trial (LIMIT-2) n'était que légèrement plus faible. L'administration de fortes doses de magnésium avec un inhibiteur de l'enzyme de conversion de l'angiotensine (qui épargne le magnésium) ou avec des dérivés nirrés vasodilatateurs par voie orale, dans différents volets d'ISIS-4, peut avoir contribué aux effets indésirables de l'hypermagnésemie. Également, le très faible taux de mortalité observé chez les témoins de l'étude ISIS-4 donne à penser que les patients peuvent avoir été exposés à un risque relativement faible et que ce n'est que chez les patients à risque éléve que le magnésium serait le plus efficace. Une étude de grande envergure sur le magnésium chez ce type de patient est sur le point de commencer.

Why did the multicentre Fourth International Study of Infarct Survival (ISIS-4) (1), in which magnesium was infused in 58,050 patients from trials in close to 100 hospitals with suspected acute myocardial infarction (AMI), not confirm the 25% to 50% reduction in mortality reported in randomized, controlled trials (RCT) of 100 to 2356 patients from single institutions (2-21), with benefit persisting in long term follow-up (6,17,18)? The justification for treating AMI patients with magnesium was summarized by three of the investigators, who then undertook clinical studies of magnesium infusion as soon as possible after the ischemic event (22-24). The potential benefits included reduction of potassium loss, calcium channel blocking activity, antiplatelet aggregation, vasodilation (also mediated by platelet-derived and endothelial-derived factors), improvement of energy metabolism, protection against ischemia-induced cardiac dysfunction and tissue damage (directly or by protection against free radicals), and anti-arrhythmic effects. More recent evaluation of the mechanisms involved has shown that advantages afforded by magnesium therapy also include membrane stabilization, reduction of oxygen demand and improvement of collateral blood supply to the infarct zone (25).

Reviews and meta-analyses of results from RCTs that were available before or at about the time that the ISIS-4 study commenced concurred that magnesium had been shown to be of value in improving survival of AMI patients (26,27). Results of definitive animal model investigations of how long magnesium infusion can be delayed after infarction before it is likely to lose its protective effects against the tissue damage caused by myocardial ischemia were not available before the ISIS-4 trial was undertaken. However, findings from earlier studies of animal models of occluded coronary arteries illustrated several of the activities of magnesium that affect cardiac vulnerability and extent of damage following AMI.

Chang et al (28) showed in 1985 that magnesium-deficient dogs developed larger infarcts when subjected to coronary obstruction with subsequent reperfusion than did controls. In the same year, it was reported that when blood flow is restored to an ischemic area of the heart, the necrotic area enlarges and myocardial stunning occurs that is characterized by myocardial dysfunction and arrhythmias in association with diminished vasodilation (29). Several studies then attributed the benefit of magnesium in experimental myocardial ischemia followed by reperfusion in rats and swine predominantly to its anti-arrhythmic effect (30-33). Two of the mechanisms shown in animal studies to contribute to the protective effect of magnesium against effects of myocardial stunning are calcium channel blockade (25,32,34-38) (magnesium was first reported in 1984 to be a physiological calcium blocker [39]) and interference with free radical release (25,37,38). Ischemia has been shown to increase free radicals in swine myocardium (40), and in rats severe magnesium deficiency at the time of coronary occlusion enhances free radical release (41). Earlier work with anoxic or ischemic arrested hearts may be pertinent because it showed that the metabolic disruption is linked with loss of membrane integrity, resulting in egress of intracellular magnesium in the early minutes after ischemia, in association with increased protons (42). Additionally, it has been demonstrated in swine that mild hypomagnesemia of 0.65 mmol/L) extends the duration of postischemic stunning of the heart (43). More recently, it was demonstrated that magnesium infusions must be provided before or at the time of reperfusion for protection to be elicited, but not after reperfusion damage has developed (44-48).

The delay (after iatrogenic or spontaneous reperfusion) before magnesium was infused in the ISIS-4 trial has been implicated in failure to obtain the improvement shown in earlier studies (48-58). Those early, small RCTs did not employ thrombolytics but provided magnesium infusions early after the onset of ischemic symptoms. Similarly, in the second Leicester Intravenous Magnesium Intervention Trial (LIMIT-2), magnesium was given either at the same time as, or slightly before, thrombolysis was initiated in the 36% of patients who received reperfusion therapy (personal communication).

However, delay in providing magnesium does not explain entirely the slightly greater incidence of adverse effects in magnesium-treated patients, adverse effects not seen in any of the early RCTs except for one (59). In that study the same dose was used as in ISIS-4 (80 mmol magnesium over 24 h), and nitrates were given to one-third of the 150 magnesium-treated patients. In one of the arms of the ISIS-4 study nitrates were administered with and without magnesium (1). There was a significant increase in atrioventricular conduction disturbances, and short term mortality was increased over that in controls — adverse effects that the authors of the small study thought might have been avoided with a lower dose of magnesium (59). In ISIS-4, there were significantly more bradycardia events among patients given magnesium than in those not treated with magnesium, and hypotension severe enough to require termination of the magnesium infusion or heart failure in 11/1000 and 12/1000, respectively. The overall death rate was slightly higher in patients given magnesium than in others (7.64% of 29,000 patients versus 7.24% of 29,000 patients, respectively).

Because the adverse effects, both in the small study (59) and in the megastudy (1), are characteristic of hypermagnesemia, it is plausible to attribute them to high infusion magnesium dosage in combination with drugs that act synergistically with excess magnesium. In the case of oral nitrate therapy in many of the patients in both the small and the large studies, vasodilation caused by high serum magnesium, possibly intensified by nitrate, may have been responsible for some of the instances of hypotension and shock. When an angiotensin-converting enzyme (ACE) inhibitor was added to the nitrate and magnesium, or when it was provided with just magnesium, there were more deaths in the treated than in the control patients. ACE inhibition of magnesium excretion (60,61) may have sustained hypermagnesemia.

In contrast, low preinfarct magnesium levels in the patient population under study might increase tolerance of high magnesium dosage therapy as elevated magnesium in serum is taken up by deficient tissues. Support for this premise is derived from a substudy of ISIS-4, which was carried out in England and Poland (62) — two geographic areas reported to have soft water associated with low soil and ground water magnesium (63,64), and from the LIMIT-2 study, done in Leicester, England (15). In the ISIS-4 substudy, which used high magnesium dosage combined with drugs that maintain magnesium levels or that also have vasodilatory effects, patients receiving magnesium had slightly lower mean systolic blood pressure just after the initial 15 min bolus injection (of 126 mmol) and some facial flushing, but no other complications (62). The LIMIT-2 study, which provided 72 mmol of magnesium in 24 h — not significantly less than the dose in the trials that encountered adverse effects reported 25% lowered mortality and improvement in ventricular function without adverse effects (15).

The change in treatment patterns of the control populations might explain the percentage reduction of mortalities by magnesium infusion, from about 50% in the studies undertaken in the 1980s, which had high control mortalities, to 25% in the LIMIT-2 trial, which had lower control death rates. At the time of the small trials, adjunctive therapy, such as antiplatelet aggregation agents, was uncommon and thus the control mortality rates were high. Among the highest control mortalities were those recently reported in a study of magnesium infusions for 48 h in elderly AMI patients who were not eligible for thrombolytic therapy (20,21). The control group mortality rate in ISIS-4 was actually lower than that achieved in LIMIT-2 by magnesium therapy (7.8% in magnesium-treated patients in LIMIT-2 versus 7.2% in the control group of ISIS-4). There is little likelihood of demonstrating a beneficial effect of magnesium when control mortality is so low. It is important to note that only one-third of hospitalized AMI patients receive thrombolytic agents despite its proven benefits on outcomes (21). The elderly, for example, have a greater risk of postinfarct fatality than do younger patients and are less likely to be given thrombolytic therapy.

An inappropriate statistical model, which has been critiqued in detail elsewhere (48,54,55,58), was used in combining the results of the ISIS-4 study with those of the studies reporting favourable results. A fixed effects model was used in ISIS-4, and it was assumed that all the trials of magnesium to be pooled were homogeneous. When trials employ patient populations that differ in age, sex, risk factors and control group therapy, and when there are substantial differences in the protocol for administration of study drug, there is heterogeneity, which demands a random effects model for statistical validity. The random effects model includes terms for both within-trial and between-trial variability when estimating the treatment effect and calculating confidence intervals. As a result of using the fixed model, driven by the large sample size of ISIS-4, favourable results achieved in smaller trials (which, by administering magnesium early, were more likely to show blunting of reperfusion injury) were obscured. A meta-analysis using the random effects model finds the odds ratio for mortality (magnesium to control) to be 0.59 (0.39 to 0.90, P=0.014), indicating that magnesium is beneficial in AMI patients.

Given the large sample size of ISIS-4, the failure of the study to confirm the value of magnesium and the investigators' statement that the negative results proved that magnesium plays no role in improving the life expectancy of AMI patients (1,65) resulted in abandonment of magnesium in treatment of AMI in most American medical centres (48,54). Further study of early magnesium infusion in high risk AMI patients is needed before prematurely discarding this inexpensive therapy, which has significantly reduced mortality from AMI in high risk patients (20,21). Apart from the potential lifesaving value of magnesium in patients unsuitable for thrombolysis, the low cost of magnesium therapy (48) makes it attractive. In this cost conscious era of health care delivery, the possible benefits of magnesium should not be prematurely discarded. A well designed study is needed of early magnesium infusions in patients who are at high risk because they are ineligible for thrombolysis or because they are older. For such patients to receive perfusion therapy, the magnesium should be given before or at the time of initiation of treatment. In others, magnesium infusion should be started before spontaneous reperfusion is likely to occur.

The National Heart, Lung, and Blood Institute is initiating a double-blind, placebo controlled, multicentre study, termed MAGIC (MAGnesium In Coronaries), the primary objective of which is to determine whether early intravenous magnesium infusion to high risk patients with suspected AMI reduces all-cause, 30-day mortality.


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Department of Nutrition, School of Public Health, University of North Carolina, Chapel Hill, North Carolina; Department of Pathology and Laboratory Medicine, University of Louisville Hospital, Louisville, Kentucky; and Cardiovascular Division, Brigham and Women's Hospital, Boston, Massachusetts, USA

Correspondence and reprints: Dr Elliott M Antman, Cardiovascular Division, Brigham and Women's Hospital, 75 Francis Street, Boston, MA 02115, USA. Telephone 617-732-7143, fax 617-975-0990, e-mail

Received for publication September 11, 1997. Accepted February 26, 1998

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