VIEWPOINT
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 eantman@bustoff.bwh.harvard.edu
Received for publication September 11, 1997. Accepted
February 26, 1998
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