Infusions of solutions of magnesium sulfate for patients with acute myocardial infarction were shown by a meta-analysis of seven small studies and a larger study of 2316 patients (L1MIT-2) to have clinical efficacy. However, the ISIS-4 study of 58,050 patients found no improvement in short-term mortality rates with magnesium therapy in patients with acute myocardial infarction. In this article we explore the following four differences between the ISIS-4 study and the earlier studies: (1) Time of initiation of magnesium treatment after acute myocardial infarction and thrombolytic therapy; (2) dosage of magnesium in the first 24 hours after acute myocardial infarction; (3) duration of magnesium infusion after acute myocardial infarction; and (4) differences in patient risks in control and treatment groups. These four differences may explain the different outcomes among these studies and indicate the type of additional studies that are needed to define the clinical utility of magnesium infusion in the treatment of patients with acute myocardial infarction. (Am Heart J 1996;132:471-7.)
Published results of magnesium salt infusions for patients with suspected acute myocardial infarction (AMI)1-33 have ranged from little or no benefit and slightly increased risk19 to as much as an 89% reduction in the short-term mortality rate15 in small studies with up to 300 patients per study l-18, 20, 21 and a 25% lower short-term mortality rate in the Second Leicester Intravenous Magnesium Intervention trial (LIMIT-2), an intermediate-sized study of 2316 patients.22, 23 Magnesium infusion not only resulted in a lower mortality rate that persisted in long-term follow-up,4, 21, 23 but it improved left ventricular function in the 28-day phase of the LIMIT-2 study.22 The predominantly good results reported among the 1300 patients with AMI from the small studies in the meta-analysis24, 25 led to recommendations that magnesium therapy be instituted in the management of patients with AMI.24-28 Some investigators commented that more extensive studies were required for the results to be convincing. 29-31
The Fourth International Study of Infarct Survival (ISIS-4), an extensive mega-study of 58,050 patients,32 concluded that magnesium infusion achieved no lowering of the mortality rate and even presented some increased risk. This unexpected finding, combined with questions about the validity of the smaller studies (on the basis of statistical analysis that treated all findings as if they had been obtained from studies using the same protocol), evoked editorials with opposite points of view,33-36 commentaries,37-39 letters to editors,40-44 and more extensive discussions of the mechanisms of magnesium action that bear on the different outcomes of its use in myocardial infarction and reperfusion.16, 21, 45-48 Some of the activities of magnesium that are considered potentially protective against ischemia-induced cardiac dysfunction and tissue damage, thereby preventing extension of AMI-induced myocardial damage, include antiplatelet aggregation, vasodilating effects (mediated in part by platelet-derived and endothelium-derived factors), calcium-blocking effects, reduction of potassium loss, and protection against free radical-induced injury. Antiarrhythmic effects, which were also expected to exert protective effects, were encountered in the clinical studies by Rasmussen et al, 3 and Shechter et al,15, 16 but not by Woods et al,22
In his analysis of errors that resulted when data from heterogeneous studies were treated as if they were from homogeneous studies, Antman35 pointed out that "big numbers do not tell the whole story." Apart from differences in protocols of the smaller studies and the mega-study, the involvement of more than 1000 hospitals in the ISIS-4 trial must have resulted in differences in procedures. Four clinically important dissimilarities are found among the protocols used in the small studies, 1-21 LIMIT-2, 22-23 and ISIS-432 that affect comparative mortality rates: (1) time of initiation of magnesium treatment after AMI and thrombolytic therapy; (2) dosage of magnesium in the first 24 hours after AMI; (3) duration of post AMI magnesium infusion; and (4) differences in patient risks in control and treatment groups.
Important insight into the marginal effects of magnesium infusions in the ISIS-4 study is gained by considering the evidence that magnesium must be provided as soon as possible after AMI and before reperfusion. In the small studies and the LIMIT-2 study, magnesium infusion was begun as soon as possible after onset of symptoms and before, simultaneously with, almost immediately after, or without fibrinolytic therapy. In the ISIS-4 study, 70% of the patients received thrombolytic therapy several hours before magnesium infusion was begun. Woods et al,22 attributed the 24% reduction in the 28-day mortality rate in the LIMIT-2 study to prompt administration of magnesium, which had been shown in laboratory studies (see below) to lessen reperfusion injury, which begins immediately after blood flow is reestablished. In a recent report by Thogersen et al,21 of a 22-month follow-up of patients with suspected AMI, fibrinolysis had been induced within 20 minutes of admission in 59% of those who received magnesium infusion shortly thereafter. The in-hospital mortality rate was 2 of 118 (1.7%) in patients who received magnesium and 7 of 111 (6.3%) in those who received the placebo infusion. Patients with proven AMI had a 48% mortality risk reduction compared with placebo control subjects. After 22 months there were 23 deaths (3.1%) in the group treated with magnesium and 31 deaths (6.6%) in the group given placebo; the mortality rate had decreased by 54%. Thrombolysis, which was induced very shortly before the magnesium was administered, exerted no effect on the favorable response to magnesium.
Induced ischemia in isolated hearts and in vivo and comparative clinical studies have shown that the corrective effects of pharmacologic amounts of magnesium are diminished when the magnesium is administered as little as 1 hour after reperfusion has been initiated. Kirkels et al,49 demonstrated in an isolated heart model that loss of myocardial magnesium during ischemia and reperfusion did not greatly impair energy production but that high levels of magnesium before ischemia or during reperfusion may well be protective because of interactions of magnesium that affect calcium, potassium, and sodium fluxes. In evaluating the myocardial damage caused by ischemia, cardioplegia, and reperfusion, Shattock et al, 50 attributed some of the functional and antiarrhythmic effects of magnesium to its prevention of cellular Ca overload. DuToit and Opie51 showed in a working rat heart model that magnesium attenuated Ca influx only when it was administered within 15 minutes of reperfusion. Leor and Kloner52 demonstrated substantial diminution of infarct size when magnesium infusion was started in rats before coronary occlusion and sustained for 45 minutes after reperfusion was initiated. Similarly, Monteiro Barros et al,53 demonstrated in a dog model that early magnesium infusion (just after occlusion and at reperfusion) reduced infarct size. Pig models have also been used to show the protective effects of magnesium. Meus et al,54 found that a magnesium load immediately after coronary ligation followed by infusion of 1 gm/hr for 24 hours prevented the ventricular fibrillation seen in all control pigs given saline solution, even though the magnesium treatment only slightly reduced the size of the infarction compared with that of controls. Herzog and Atar and their coworkers42, 43, 55 studied infusions of MgSO4 at the time of transient coronary ischemia or after coronary occlusion and reperfusion. They found that magnesium, when given early enough, significantly attenuated stunning and reduced infarct size in pigs treated with magnesium compared with controls.
The need for early initiation of magnesium therapy raises the question of whether magnesium, an essential element and a pharmacologic agent when given in high doses, 56-58 might function to limit or replace myocardial magnesium loss caused by ischemia and reperfusion. Bloom59 and Chang et al,60 showed that magnesium-deficient dogs that were subjected to coronary occlusion, maintained for an hour, and then reperfused for 4 hours had larger infarcts than did similarly challenged magnesium-replete dogs. The work of Herzog et al, 61 has provided additional insight into a possible mechanism of the increase in vulnerability to myocardial ischemia with magnesium deficiency: Magnesium-deficient pigs subjected to ischemic stunning are protected by antioxidants.
Fewer instances of 28-day left ventricular failure (a strong predictor of subsequent mortality) in LIMIT-2 patients treated with magnesium might relate to their 21% greater survival rate during a mean follow-up of 2.7 years.23 This is in accord with protection provided by early magnesium therapy against ischemia-perfusion injury, with timing of magnesium treatment in relation to thrombolytic therapy being critical. This explanation of contrasting ISIS-4 results was refuted by Yusuf and Flather,33 who judged that recanalization of occluded arteries would have been almost simultaneous with magnesium infusion in a large proportion of ISIS-4 patients. However, in the complete report32 it was estimated that arterial patency of 50% to 60% was restored by 90 minutes in the 70% of patients who received fibrinolysis. Half of these patients were given magnesium within 2 hours after starting fibrinolysis. An additional 25% appear to have received magnesium between 2 and 6 hours after occlusion and subsequent fibrinolysis; this was too late for magnesium protection.
The amount of magnesium infused during a 24 hour period might account for differences in adverse effects. Galloe and Graudal40 suggest that the optimal amount of magnesium in the first 24 hours might be 55 mmol/24 hr and that more than 75 mmol/24 hr might increase the mortality rate, on the basis of the dosage of magnesium infused during 24 hours after AMI ([Mg]) and the relative risk of death in 10 studies. We performed a similar analysis, selecting 10 trials in which the dosage of magnesium administered during the first 24 hours of therapy after AMI and the short-term mortality rate were defined (Table I). We treated each of these trials as an independent event, knowing that the number of patients per trial varied greatly. A graph of these 10 trials using a curve fitting algorithm (SAS Institute Inc., Cary, N.C.) produced a curve with the following equation: Mortality = -0.04[Mg] - 0.089[Mg]2 + 0.00115 [Mg]3 (Fig. 1). The curve was constrained to go through the origin because no magnesium therapy would have no effect on short-term mortality. This curve crosses the abscissa at 77.8 mmol/24 hr [Mg], which suggests that a magnesium concentration beyond this value exceeds the therapeutic window. The nadir is 52.2 mmol/24 hr [Mg], which suggests that this is the optimum dosage of magnesium at the time of AMI . However, a cluster of three studies that administered between 63 mmol/24 hr to 67 mmol/24 hr had the best improvement in short-term mortality rates.
Hypermagnesemia, by inducing generalized vasodilatation, can cause profound hypotension. This did not occur in the LIMIT-2 study, in which [Mg] was 73 mmol/24 hr. In the ISIS-4 study the [Mg] was 80 mmol/24 hr, and hypotension was significantly more frequent in patients treated with magnesium than in control subjects (2p < 0.001); hypotension was sometimes of sufficient severity to necessitate termination of magnesium infusion.32 This observation was made in 1991 by Feldstedt et al,19 who also provided infusions of 80 mmol/24 hr in the first 24 hours. This might increase the risk of shock and of myocardial necrosis extension. Hypermagnesemia also caused blocks of conduction and bradycardia. Patients treated with magnesium in the ISIS-4 study had a slightly increased incidence of second- or third-degree heart block, a small but a significant increase in heart failure (2p < 0.001), and an increased number of deaths as a result of cardiogenic shock (2p < 0.001) that emerged during or just after the infusion. The treatment group of the small study that used 80 mmol/24 hr magnesium19 had more atrioventricular conduction disturbances that were attributed to hypermagnesemia than did control subjects and had a slightly higher mortality rate. Thus the two studies that infused 80 mmol/24 hr magnesium in the first 24 hours19,32 found an increase in hypotension and conduction disturbances consistent with a dosage of magnesium in excess of the therapeutic threshold.
|Trial (reference)||24-hour MG*
|Feldstedt et al.19||80||24|
|Woods et al.22||73||-24|
|Shechter et al.17||67||-76|
|Smith et al.5||65||-71|
|Shechter et al.15||63.9||-89|
|Morton et al.1||60||-55|
|Rasmussen et al.2||49.8||-61|
|Ceremuzynski et al.13||32||-69|
|Abraham et al.17||10||-5|
*The amount of magnesium infused during the first 24 hours for treatment of AMI . Trials are listed in decreasing order by amount of magnesium infused per 24 hours.
†The short-term mortality rate (usually the 28 days after AMI) is the percentage difference between the mortality rate of the control group and the mortality rate of the group treated with magnesium divided by the mortality rate of the control group.
Another difference between the small and large studies was in the duration of magnesium treatment after AMI . In most of the small studies, infusions of a lower dose of magnesium were given after the first 24 hours, for a period of an additional 12 hours to 2 full days. Because the antitachydysrhythmic effect of magnesium62-64 was seen only in the small studies,1-17 continuation of magnesium infusion after the infarct might improve the ultimate outcome. In a comparison of a 3-day course of intravenous magnesium infusions with that of streptokinase, Ising et al,10 and Rebentisch et al,11 found that the requirement for antiarrhythmic treatment after the infarction was reduced more by magnesium than by streptokinase. A double-blind randomized trial of the effect of 20 hours of intravenously administered MgSO4 in patients with symptoms of acute myocardial infarction and results after a mean of 22 months follow-up,20, 21 disclosed not only a mortality rate that was approximately half that of patients who received an infusion of placebo but also a tendency toward reduction in ventricular premature contractions. Because neither the ISIS-432 nor LIMIT-223, 65studies verified the long-accepted antiarrhythmic action of magnesium that was shown in the smaller clinical trials of magnesium infusions without fibrinolytic agents, most of which were of longer duration, investigation to determine the optimum duration of treatment is indicated.
Fig. 1. Plot of the data in Table I with the percentage short-term mortality on the ordinate and the dosage of magnesium infused over 24 hours after AMI ([Mg]) on the abscissa. Each trial constituted an in dependent event. The curve was constrained to pass through the origin. The equation for the curve is as follows: Short-term mortality <0.04[Mg] < 0.089[Mg]2 + 0.00115[Mg]3. The curve crosses the abscissa at 77.8 mmol/24 hr [Mg], and the nadir is 52.2 mmol/24 hr [Mg].
The mortality rates of control groups inevitably influence the improvement rates of treatment groups that receive effective therapy. It is possible that control subjects in the LIMIT-2 study had higher mortality rates than did control subjects in the ISIS-4 study because fewer LIMIT-2 control subjects underwent thrombolysis or received antiplatelet therapy than did ISIS-4 control subjects (35% versus 70% and 66% versus 94%, respectively). The greater than 50% reduction in mortality rate of patients treated with magnesium compared with control subjects in the small studies reflects high mortality rates for the control subjects, possibly because antiplatelet and fibrinolytic therapy was not customary in the 1980s when these small studies were done. In addition, the selection of high-risk patients (the elderly [older than 70 years] and/or patients unsuitable for thrombolytic therapy) explains the very high mortality rate for the control group in the study by 8hechter et al,15, 17 versus the impressive reduction in mortality rate of those treated with magnesium infusions (4% in patients with magnesium infusions compared with 17% in patients who received placebo infusions).
Rasmussen46 considered many of the actions of magnesium as justification for instituting his magnesium infusion research trial in patients with AMI . He and his colleagues demonstrated that patients with ischemic heart disease with and without infarction had magnesium deficiency by showing that they retained magnesium when an intravenous magnesium challenge test was used.66 Rasmussen46,47 commented that mechanisms of beneficial effects of magnesium therapy are multifactorial: (1) it has a direct depressive effect on the cardiac conduction system, thus decreasing risk of tachydysrhythmia; (2) it has an arterial dilatory effect, increasing coronary blood flow and reducing afterload on the myocardium; (3) it results in decreased infarct size; (4) it has an ion stabilizing effect, maintaining stable intracellular and extracellular potassium, sodium, and calcium concentrations with decreased myocardial calcium overload; (5) it improves energy generation in myocardium; and (6) it inhibits platelet aggregation. In his doctoral thesis, Rasmussen47 considers predisposing factors of magnesium deficiency in cardiovascular patients and mechanisms by which the repletion and pharmacologic use of magnesium exert beneficial effects.
In planning LIMIT-2, Woods48 considered some of the aforementioned activities of magnesium that should protect against extension of AMI -induced myocardial damage, as well as calcium blocking, favorable effects on platelet-derived and endothelium derived platelet-aggregating and vasoactive factors, and protection against free radical-induced injury.
Predisposing factors of magnesium deficiency in patients with AMI include inadequate dietary magnesium intake, use of diuretics, and secondary hyperaldosteronism. In addition, the stress of AMI increases catecholamine release and magnesium shift out of myocardial cells and increases calcium uptake.67 The therapeutic effects of pharmacologic doses of magnesium include coronary dilation with increased coronary blood flow and decreased peripheral resistance; increased myocardial magnesium and inhibition of myocardial calcium overload, which improve mitochondrial ATP synthesis; decreased catecholamine-induced magnesium/calcium shifts; suppression of arrhythmias; and inhibition of platelet aggregation and of the blood coagulation cascade that is enhanced by a high calcium/magnesium ratio, directly, and is mediated by endothelial-derived factors that are favorably affected by increased levels of magnesium.67
Providing magnesium promptly after development of signs and symptoms of AMI and before initiation of other therapies should maximize the protective effects of magnesium. Adverse effects that might increase morbidity and mortality might be minimized by excluding patients with conduction blocks from magnesium study groups and by not exceeding the 24-hour optimal dosage of magnesium infusions, which might be 50 to 65 mmol/24 hr, but which requires further study.
Prompt initiation of magnesium infusion, either before or at the same time as thrombolytic agents, is necessary to achieve benefit. The favorable findings of the small trials and of LIMIT-2 indicated that magnesium is a safe, simple, inexpensive treatment for AMI.24-28 The negative findings of the ISIS-4 mega-trial, in which magnesium was provided late, do not negate the protective effects of magnesium shown in the studies in which magnesium was given without delay. It is not justifiable to conclude, largely from statistical analysis of pooled findings from studies with dissimilar protocols, that there are no longer grounds for use of magnesium in treating patients with AMI.32, 33 In the ISIS-4 discussion,32 the benefit shown in LIMIT-2 that is considered conventionally significant (2p = 0.04) was deemed uncertain.
As Antman pointed out in aneditorial35 and at this symposium,68 drawing broad clinical conclusions from a statistical analysis in which the database is derived from studies with different protocols can lead to fallacious conclusions. In a recent criticism of mega-trials that have unrestrictive protocols, limited data collection, effective randomization, and intention-to-treat analysis of deaths (a design adopted to increase statistical power maximally), Woods69 commented that such studies tend to generate effect estimates that are near null compared with those of conventional trials or meta-analysis. He observed that mechanism of action of the test substance, dose dependence, and time dependence must be taken into account to increase the true treatment effect to a maximum.
We have seen that there is a window for intravenous magnesium therapy in patients with AMI above which toxicity can develop. Why, then, was the amount of magnesium (73 mmol/24 hr) infused over 24 hours in the LIMIT-2 study not associated with adverse effects, whereas the 24-hour dosage of magnesium (80 mmol/24 hr) in the ISIS-4 study resulted in adverse findings (supra vide)? It is possible that the LIMIT-2 patients who received the relatively high magnesium dosage had suboptimal myocardial magnesium levels because they lived in Leicester, where the water is soft and the magnesium content is low,70, 71 and that this might have played a role in their tolerance of high magnesium dosage. It is plausible that, although magnesium deficiency has been shown to increase the size of the infarct resulting from coronary occlusion,59-61 vulnerability to ad verse effects of hypermagnesemia might be less in patients in whom magnesium deficiency is prevalent. It is possible that patients with low magnesium stores might use the elevated serum magnesium levels to correct the deficiency. Even though the hard water in England tends to be richer in calcium than in magnesium, myocardial magnesium levels were higher in London, where the water is hard, than they were in Glasgow, where the water is soft.71 It is noteworthy that investigators in Poland and England, countries reported to have soft water and/or low soil magnesium contents,72 did not report side effects from the high dosage magnesium in their portion of the ISIS-4 study.73
Multi-institution studies of the effects of magnesium infusions in patients with AMI who are at high risk (the elderly and/or those unsuitable for thrombolytic therapy) and in others with AMI before or with fibrinolysis should be undertaken. The magnesium infusion should be initiated immediately after admission to the hospital. Such a study is to be undertaken in the near future in the United States with the support of the National Institutes of Health (E. M. Antman, personal communication). These studies should (1) determine the optimal 24-hour dose, based on the amounts found efficacious and safe in the small studies (possibly 50 to 65 mmol/24 hr); (2) determine if the use of nitrates, with the aforementioned suggested lower doses of magnesium, will increase the risk of hypotension; (3) determine serum magnesium concentrations before and after magnesium infusions; and (4) sustain magnesium infusion at a lower dosage than that used in the first 24 hours to determine if antiarrhythmic effects will be demonstrable. In the secondary prevention phase, it should be ascertained if provision of a suitable oral magnesium preparation with and without an antioxidant will reduce occurrence of new events.
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From the School of Public Health, University of North Carolina, Chapel Hill,a and the Clinical Pathology Department, Warren Grant Magnuson Clinical Center, National Institutes of Health.b
Presented in part at the Fifth European Magnesium Congress, Vienna , Austria , June 15-18, 1995 .
Reprint requests: Ronald J. Elin, MD, PhD, Clinical Pathology Department, National Institutes of Health, Building 10, Room 2C306, 10 Center Dr., 14.0pt;MSC 14.0pt; 1508, Bethesda, MD 20892-1508.
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