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Is there a place for magnesium in the treatment of acute
myocardial infarction?
Mildred S. Seelig, MD, MPH,a and Ronald J. Elin,
MD, PhDb
Chapel Hill, N.C., and Bethesda, Md.
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.
TIME OF INITIATION OF MAGNESIUM TREATMENT AFTER AMI AND
THROMBOLYTIC THERAPY
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.
DOSAGE OF MAGNESIUM IN THE FIRST 24 HOURS AFTER AMI
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.
Table I. Short-term mortality rate compared with 24-hour
magnesium dosage
| Trial (reference) |
24-hour MG*
dosage (mmol) |
Short-term†
mortality (%) |
| Feldstedt et al.19 |
80 |
24 |
| ISIS-432 |
80 |
5.5 |
| 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.
.
DURATION OF MAGNESIUM INFUSION AFTER AMI
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].
DIFFERENCES IN PATIENT RISKS IN CONTROL AND TREATMENT
GROUPS
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).
RATIONALES FOR MAGNESIUM TREATMENT OF ACUTE MYOCARDIAL
INFARCTION
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.
WHAT HAVE WE LEARNED FROM THE CLINICAL STUDIES OF MAGNESIUM
TREATMENT OF AMI?
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
WHAT ADDITIONAL STUDIES ARE NEEDED?
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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