In American Journal of Cardiology 76:172-173, 1995
ISIS-4 and LIMIT-2
Editorial: Reexamination of Magnesium Infusions in Myocardial
Infarction
Mildred S. Seelig, M.D., M.P.H.,
Department of Nutrition, University of North Carolina, Chapel
Hill, North Carolina
Ronald J. Elin, M.D., Ph.D.,
Clinical Pathology, National Institutes of Health, Bethesda,
MD
The disparity of published results of magnesium salt infusions
in treatment of suspected acute myocardial infarction, AMI(1-5),
has evoked controversy.(5-10) Important clinical questions need
resolution. Why did the Fourth International Study of Infarct
Survival (ISIS-4) of 58,050 suspected AMI patients find no
overall benefit from magnesium infusions, and even some increased
risk,(5) while the Second Leicester Intravenous Magnesium
Intervention Trial (LIMIT-2) in 2,316 suspected AMI patients
reported that magnesium infusion resulted in improved left
ventricular function, as well as lowered short-term mortality(1)
that persisted, in a long-term follow up(2)? Why did a
meta-analysis of the results of magnesium infusion given to
>1300 AMI patients with suspected AMI in small controlled
studies show a dramatic reduction in mortality(3) and also
decreased post-AMI arrhythmias that were not seen in either large
study? Do the negative findings of the mega-trial [ISIS-4] negate
the protective effects of magnesium, that were reported in the
earlier trials? The findings in LIMIT-2 led to the recommendation
that, because it is a safe, simple, inexpensive intervention,
magnesium should be entered into clinical practice without
delay.(4) Is it justified to conclude, as did authors of ISIS-4,
largely from statistical interpretation of pooled findings, that
there are no longer grounds for use of magnesium in AMI?(5-9) The
following 4 important dissimilarities among the protocols used in
ISIS-4,(5) LIMIT-2,(1-2) and in the meta-analyzed small
studies(3) deserve scrutiny: 1. time of initiation of magnesium
treatment in relation to thrombolytic therapy; 2. total dosage in
the first 24 hours; 3. duration of post-AMI magnesium infusions,
and 4. treatment of control groups, that affects comparative
mortality rates.
1. In the small studies and in LIMIT-2, magnesium infusion was
begun as soon as possible after onset of symptoms, and before or
without subsequent fibrinolysis. Since reperfusion injury begins
immediately on reestablishing blood flow, and magnesium is
protective,(1,2,6-2) Woods et al(1) attributed the 24% reduction
in 28-day mortality in LIMIT-2 to its prompt administration,
before thrombolysis, the timing of magnesium treatment in
relation to thrombolysis being critical.(2) Reduced 28-day left
ventricular failure - a strong predictor of subsequent mortality
- might explain the 21% reduction in mortality over a mean follow
up of 2.7 years, of the LIMIT-2 patients who had received early
magnesium treatment. Yusuf and Flather(9) denied that the failure
of ISIS-4 to confirm the earlier favorable findings was caused by
delay in providing magnesium. They commented that recanalisation
of occluded arteries would have been almost simultaneous with the
magnesium infusion in a large proportion of ISIS-4
magnesium-treated patients who underwent thrombolysis. However,
the report(5) indicates that magnesium was begun within two hours
of fibrinolytic therapy (which takes about 90 minutes for 50-60%
restoration of arterial patency) in about half of all randomized
patients. One fourth of the patients seem to have received
magnesium between two to six hours after onset of symptoms and
fibrinolysis; the remaining patients may have started treatment
up to 24 hours after symptom-onset. Because even slight delay may
lessen the beneficial effects of magnesium,(2) fibrinolysis,
given before magnesium, might have reduced or eliminated the
protection that could have been afforded by prompt magnesium
administration.
2. The amounts of magnesium infused over a 24-hour period
might account for differences in adverse effects. Galloe and
Graudal(7) analyzed the 24-hour magnesium dosages in the small
studies and showed the range to be 50-65 mM. They suggest that
the optimal amount of magnesium in the first 24 hours could be 55
mM, and that > 75mM may increase mortality. They referred to
the double-blind study of 298 patients with AMI studied by
Feldstedt et al,(11) who had reported that 24-hour magnesium
infusion of 80mM significantly increased bradyarrhythmias and led
to fatal pump failure. They observed that this could have been
avoided if lower infusion doses of magnesium had been given. In
LIMIT-2, the 24-hour dosage was 73 mM; 24-hour post-infusion
serum levels averaged 1.55 mM/L. In ISIS-4, 80 mM were given over
24 hours; serum magnesium levels were not reported.
Hypermagnesemia, by inducing generalized vasodilatation, can
cause profound hypotension, which could increase risk of shock
and of extension of myocardial necrosis. Hypermagnesemia was not
a problem in LIMIT-2;(1) it occurred significantly (p <0.001)
more often (sometimes severe enough to terminate magnesium
treatment) than in controls in magnesium treated patients in
ISIS-4.(5) Hypermagnesemia also causes blocks of conduction and
bradycardia. Magnesium treated patients in ISIS-4, when compared
to controls, had slightly increased second or third degree heart
block, small but significant increased heart failure (p
<0.001), and increased deaths due to cardiogenic shock (p
<0.001) that emerged during or just after the infusion. Thus,
the amount of magnesium over 24 hours may be a major factor in
morbidity and mortality.
3. Another difference between the small and large studies is
in duration of post-AMI magnesium treatment. Magnesium infusions
were continued after the first 24 hours, but at lower doses for
12 hours to two days longer or more, by groups reporting the
small trials,(12-14), a point that was raised in an earlier
editorial.(15) Because the anti-tachydysrhythmic effect of
magnesium(16) was seen only in the small studies, a longer
duration of post-AMI magnesium infusion might be required to
prevent tachydysrhythmias.
4. The treatment and mortality rates of control groups affect
rates of improvement in the test group. The higher control
mortality rate in LIMIT-2, than that in ISIS-4, might reflect the
fact that fewer LIMIT-2 controls underwent thrombolysis or
received anti-platelet therapy than did ISIS-4 controls: 35%
versus 70%, and 66% versus 94%, respectively. The >50%
reduction in mortality in magnesium-treated patients versus
controls in the small studies reflects high mortality rates in
controls, possibly because anti-platelet and fibrinolytic therapy
was not customary in the 1980s, when the small studies were
performed.
In the ISIS-4 discussion,(5) the benefit that was
conventionally significant (p=0.04)(8,9) in LIMIT-2 was
reevaluated and deemed uncertain, being statistically compatible
with both halving of mortality and there being no benefit. The
possibility that negative findings were not published, and that
this might have biased statistical interpretation of the
meta-analysis, has been suggested.(10) However, an important
negative clinical study, that dealt with increased mortality of
post-AMI magnesium infusions providing 80mM in the first 24 hours
was published in 1991.(11)
Some of the activities of magnesium, that should protect
against extension of AMI-induced myocardial damage, were
considered by Rasmussen(13,17) and by Woods(12) in their
rationales for use of magnesium in AMI. Antiarrhythmic and
calcium-blocking effects, reduction of potassium loss,
antiplatelet aggregation and vasodilating effects (mediated in
part by platelet-derived and endothelium-derived factors), and
protection against free radical-induced injury were cited as
activities of magnesium that should protect against
ischemia-induced cardiac dysfunction and tissue damage. The
administration of magnesium promptly after development of signs
and symptoms of AMI, and before other therapies, should maximize
protective effects of magnesium. Adverse effects, that increase
morbidity and mortality, might be minimized by excluding patients
with sinoatrial atrioventricular blocks, and by not exceeding the
24-hour optimal dosage of magnesium infusions (range 50-65 mM):
however this requires further study, as does the optimum duration
of magnesium therapy.
REFERENCES
1. Woods KL, Fletcher S, Roffe C, Haider Y. Intravenous
magnesium sulphate in suspected acute myocardial infarction:
results of the second Leicester Intravenous Magnesium
Intervention Trial (LIMIT-2). Lancet 1992;339:1553-1558.
2. Woods KL, Fletcher S: Long-term outcome after intravenous
magnesium sulphate in suspected acute myocardial infarction: the
second Leicester Intravenous Magnesium Intervention Trial
(LIMIT-2). Lancet 1994;243:816- 819.
3. Teo KK, Yusuf S, Collins R, Held PH, Peto R: Effects of
intravenous magnesium in suspected acute myocardial infarction:
overview of randomized trials. Brit Med J 1991;303:1499-1503.
4. Teo KK, Yusuf S: Role of magnesium in reducing mortality in
acute myocardial infarction. A review of the evidence. Drugs
1993;46:347-359.
5. ISIS-4: A randomized factorial trial assessing early oral
captopril, oral mononitrate, and intravenous magnesium sulphate
in 58,050 patients with suspected acute myocardial infarction.
Lancet 1995;345:669-682.
6. Casscells W: Magnesium and myocardial infarction
(commentary). Lancet 1994;343:807-809.
7. Galloe A, Graudal N (letter to editor): Magnesium and
myocardial infarction. Lancet 1994;343:1286-1287.
8. Unsigned: Teething problems for two innovations. Science
1994;265:1540.
9. Yusuf S, Flather M: Magnesium in acute myocardial
infarction. ISIS-4 provides no grounds for its use. (Editorial)
Brit Med J 1995;310:750-752.
10. Egger M, Smith GD: Misleading meta-analysis. Lessons from
"as effective, safe, simple" intervention that wasn't.
(Editorial) Brit Med J 1995; 310:752-754.
11. Feldstedt M, Boesgaard S, Bouchelouche P, Svenningsen A,
Brooks L, Lech Y, Aldershvile J, Skagen K, Godtfredsen J:
Magnesium substitution in acute ischaemic heart syndromes. Eur
Hear J 1991;12:1215-1218.
12. Morton BC, Nair RC, Smith FM, McKibbon TG, Poznanski WJ:
Magnesium therapy in acute myocardial infarction - a double-blind
study. Magnesium 1984; 3:346-352.
13. Rasmussen HS, Suenson M, McNair P, Norregard P, Balsey S:
Magnesium infusion reduces the incidence of arrhythmias in acute
myocardial infarction. A double-blind placebo-controlled study.
Clin Cardiol 1987; 10:351-356.
14. Ceremuzynski L, Jurgiel R, Kulakowski P, Gebalska J:
Threatening arrhythmias in acute myocardial infarction are
prevented by intravenous magnesium sulfate. Am Heart J
1989;118:1333-1334.
15. Seelig MS. Editorial: Magnesium in acute myocardial
infarction. (International Study of Infarct Survival 4). Am J
Cardiol 1991;68:1221- 1222.
16. Iseri LT: Magnesium and Dysrhythmias. Magnesium Bul
1986;8:223-229.
17. Rasmussen HS: Justification for intravenous magnesium
therapy in acute myocardial infarction. Magnesium Res
1988;1:59-73.
18. Woods KL: Possible pharmacological actions of magnesium in
acute myocardial infarction. Br J Clin Pharmacol
1991;32:3-10.
Address for reprints: Ronald J. Elin M.D., Ph.D., Chief,
Clinical Pathology Department, National Institutes of Health,
Building 10, Room 2C-306, 10 Center Drive-MSC 1508 Bethesda, MD
20892-1508
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