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Intravenous magnesium sulphate in suspected acute myocardial infarction: results of the second Leicester Intravenous Magnesium Intervention Trial (LIMIT-2)
Saturday 27 June
No 8809
1992
ORIGINAL ARTICLES
magnesium sulphate in suspected acute myocardial infarction: results of the second Leicester Intravenous Magnesium Intervention Trial (LIMIT-2) Intravenous
The cardiovascular actions of the magnesium ion pharmacological concentrations include coronary and systemic vasodilatation, platelet inhibition, and antiarrhythmic effects. Magnesium has also been reported to protect myocardial tissue in experimental models of ischaemia and reperfusion. Several small clinical trials in suspected acute myocardial infarction have suggested that early mortality can be reduced by intravenous infusion of magnesium salts in the acute phase, but none has been of sufficient size to be conclusive. We therefore conducted a randomised, double blind, placebo controlled study in 2316 patients with suspected acute myocardial infarction who received either intravenous magnesium sulphate (8 mmol over 5 min followed by 65 mmol over 24 h) or physiological saline. The primary outcome measure was 28-day mortality, which was ascertained in 99·3% of patients. The groups were well balanced for prognostic factors. By intention-to-treat analysis mortality from all causes was 7·8% in the magnesium group and 10·3% in the placebo group (2p=0·04), a relative reduction of 24% (95% confidence interval 1-43%). Within the coronary care unit the incidence of left ventricular failure was reduced by 25% (7-39%) in the magnesium group (2p=0·009). There was no significant difference between the groups in the incidence of heart block or the use of antiarrhythmic drugs, direct-current cardioversion, or temporary pacing. Myocardial infarction was confirmed in 65% of each group, with closely similar rises in cardiac enzymes. The side-effects of at
magnesium treatment were transient flushing, related to speed of injection of the loading dose, and an increased incidence of sinus bradycardia (2p=0·02). Exploratory subgroup analyses of 28-day mortality did not indicate any effect modification by thrombolysis or aspirin, or by previous treatment with beta blockers, calcium antagonists, or diuretics. Intravenous magnesium sulphate is a simple, safe, and widely applicable treatment. Its efficacy in reducing early mortality of myocardial infarction is comparable to, but independent of, that of thrombolytic or antiplatelet therapy. Introduction Several clinical trials have examined the effects of intravenous magnesium salts in suspected acute myocardial infarction. Most have reported a lower mortalityl-4 and a lower incidence of arrhythmias1,5-7 in magnesium-treated patients, though none has been of sufficient statistical power to be conclusive. A pooled analysis of the results of all known randomised trials (seven studies including a total of 1300 patients) indicated that the odds of death were reduced by about half but the confidence interval was wide.8 The treatment regimens varied: 30-90 mmol of magnesium sulphate or chloride was given over 24-48 h, increasing the ADDRESSES: Department of Pharmacology and Therapeutics University of Leicester, Leicester, UK (K L. Woods, MD, S. Fletcher, BA); Coronary Care Unit, Leicester Royal Infirmary (C. Roffe, MRCP, Y. Haider, MRCP). Correspondence to Dr Kent L. Woods, Department of Pharmacology and Therapeutics, Clinical Sciences Building, Leicester Royal Infirmary, Leicester LE2 7LX, UK
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magnesium concentration by 30-100%. Few adverse effects were reported, the commonest being flushing. Magnesium has been described as a physiological calcium antagonist and there are several plausible mechanisms for a beneficial effect in acute myocardial infarction.9 At the concentrations achieved in the trials, magnesium reduces peripheral vascular resistance10 and dilates human coronary arteries both in vitro and in vivo. 11,12 Antiarrhythmic effects of various kinds have been observed clinically and in experimental models of myocardial ischaemia.13-15 The electrophysiological effects of magnesium on normal cardiac serum
concentrations reached in the trials; a slight prolongation of the atrium-His interval is consistent with antagonism of the slow calcium current.16,17 Magnesium inhibits platelet function, perhaps indirectly by release of prostacyclin. 18 The concentration-effect relation is not clearly defined but over the range 1 -45-2-3 mmol/1 there was inhibition of platelet aggregation and then rapid disaggregation of platelet thrombi in an in-vivo rabbit model of arterial endothelial injury. 19 Myocardial protection against ischaemic injury has been reported in laboratory animals but the magnesium concentrations were generally higher than those attainable clinically.2O The mechanism of protection may be inhibition of mitochondrial calcium overload2l and preservation of intracellular ATP and creatine phosphate reserves.22 The study reported here was started in response to the findings of earlier trials (one of them conducted in this unit1,2) and was designed to test, with adequate statistical power, the following hypotheses: (1) that intravenous magnesium reduces early mortality in suspected acute myocardial infarction; (2) that progression to acute myocardial infarction among patients with unstable coronary artery disease can be reduced by magnesium; (3) that intravenous magnesium reduces the frequency of clinically important early arrhythmias in patients presenting with suspected myocardial infarction.
function
are
minor at the
TABLE I-RANDOMISATION OF PATIENTS ADMITTED TO CCU,
SEPTEMBER, 1987, TO FEBRUARY, 1992 I
serum
Methods Power calculations The primary outcome of interest was defined as 28-day mortality in all patients as randomised. Initial power calculations indicated that about 2000 patients would be needed. After recruitment began in September, 1987, routine use of aspirin and thrombolysis was introduced when the ISIS-2 findings were published.23 The power calculations were revised to adjust for the anticipated reduction in placebo group mortality, without unblinding the data already collected. The assumptions made were: (i) that 60% of patients randomised would have acute myocardial infarction confirmed; (ii) that 28-day mortality would be 12-5% in these patients and zero in the remainder; (iii) that the study should be able to detect with 80% probability at the two-sided 5% level of significance a true reduction of one-third in 28-day mortality among patients given magnesium (this being the lower 95% confidence limit of a pooled analysis of the published trials at that time). Provision was made for up to twelve one-sided interim analyses for adverse outcome only, as a safety measure.’ Target trial size was 1500 patients with confirmed myocardial infarction, requiring a total recruitment of 2500 patients. Interim analyses of 28-day mortality to detect a clear adverse trend in the magnesium group (lp < 0-01) were made by a statistician independent of the study at intervals of 4-6 months. No such trend was seen at any interim analysis. Since the protocol did not permit early stopping of the trial in response to a favourable trend at interim analysis, no adjustment was made to the final two-sided p value (2p).
Recruitment The trial was conducted between September, 1987, and February, 1992, in the coronary care unit (CCU) of Leicester Royal
Infirmary. The unit admits 1000 patients a year, about 50% of whom have the discharge diagnosis of acute myocardial infarction and 25% angina. Patients were eligible for the study if they were judged likely to have acute myocardial infarction with onset in the preceding 24 h. No electrocardiographic (ECG) criteria were specified. Exclusion criteria were (i) inability or refusal to give verbal consent; (ii) complete heart block; (iii) trial entry on a previous admission; (iv) a clinical indication for therapeutic use of magnesium; (v) serum creatinine > 300 unol/1. Randomisation was not delayed for a serum creatinine measurement unless renal failure was known or suspected. If the serum creatinine was found to be > 300 ol/l after randomisation, the trial infusion was stopped to avoid possible accumulation of magnesium but the patient remained in the allocated treatment group for analysis. Treatments Identical treatment packs for active and placebo treatments were manufactured in the sterile production unit of the district pharmacy service and coded according to a computer-generated blocked randomisation schedule. Packs contained magnesium sulphate solution 8 mmol in 4 ml for injection over 5 min and 65 mmol in 50 ml for infusion over the following 24 h, or equal volumes of physiological saline. An adhesive numbered label, transferred from the pack cover to the patient’s notes, was the only identifier. During the trial the randomisation codes were held by the pharmacy department and the independent statistician only.
Data collection and analysis A computerised CCU data system was developed into which was entered a standard record for every CCU admission. This held information on medical history, presenting symptoms, complications, management, laboratory data, and final diagnosis at the time of discharge from the CCU. Criteria for diagnosis of acute myocardial infarction were at least two of the following: a typical history; a rise in total serum creatine kinase to at least twice the laboratory normal upper limit, supported by a rise in hydroxybutyrate dehydrogenase; evolving ECG changes consistent with acute infarction. Definition of complications, as with the final diagnosis, was by clinical staff responsible for the patients’ routine care. Management decisions were guided by a comprehensive CCU policy document. Clinical data were recorded during the admission and not subsequently revised. All trial patients were "flagged" in the National Health Service Central Register for long-term ascertainment of deaths. Information on 28-day survival was also obtained from hospital, general practitioner, and health authority records. Sub-studies were performed in representative groups of randomised patients to obtain supplementary data: (1) 48 h profiles of serum magnesium (40 patients); (2) 24 h Holter monitoring for detailed analysis of arrhythmia frequency (70 patients), computer analysis of tapes being supplemented by visual verification of all abnormal rhythms; (3) measurement of haemodynamic response to trial treatment (44 patients). Cardiac output velocity was measured with a dedicated doppler machine (Digidop 220). The intra-subject
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coefficient of variation for the method was 7%. Simultaneous heart rate
and indirect blood pressure
were
TABLE II-BASELINE CHARACTERISTICS OF RANDOMISED
PATIENTS
measured automatically
(Dynamap). Significance
tests of proportions (including 28-day mortality) by means of the X2 statistic from 2 x 2 contingency tables, with stratification where indicated. For pooled analyses of mortality across published trials we used the Mantel-Haenszel weighted odds were done
ratio and X2 statistic.2s Parametric methods were used for continuous variables where appropriate--otherwise medians and interquartile ranges are given and non-parametric tests were used. Point estimates of treatment effects are shown with their 95% confidence intervals.
Ethical aspects The protocol of the study was approved by the Leicestershire Health Authority ethics committee. In addition to the one-sided interim analyses of 28-day mortality described above, surveillance of complication rates in all CCU patients was maintained during the study, the results being compared with a baseline period of 9 months between the installation of the data system and the start of the trial. An increased incidence of sinus bradycardia and use of atropine in the unit were noted but were judged not to require unblinding of the data in the absence of more serious adverse trends.
Results Randomisation and follow-up A total of 2316 patients entered the study in a 53-month period during which over half of CCU admissions were randomised. Reasons for non-randomisation of the remainder are shown in table I. The assumptions made for the power calculations proved to be slightly conservative. Acute myocardial infarction was confirmed in 65% of randomised patients (predicted 60%); placebo group 28-day mortality was 13 8% among those with infarction (predicted 12-5%) and 3.2% among those without (predicted 0%). Baseline characteristics of the patients in the magnesium and placebo groups were well matched for important prognostic variables apart from a minor imbalance of site of infarction (table 11). Follow-up was achieved to hospital discharge for 100% of trial patients and to 28 days for 99-3% of them. Survival to 28 days could not be positively confirmed for 9 patients in the magnesium group and 7 in the saline group, either because they left the country after discharge (6), were of no fixed abode (6), or were untraceable through their recorded address and general practitioner (4). These patients were excluded from the 28-day mortality analysis but were included in analyses
therefore averaged 12 h in length. The major separation between the trial groups occurred on the subsequent two days. This is reflected in the within-CCU mortality which was 3-6% in the magnesium group and 5-6% in the placebo group-a relative reduction of 36% (4-57%, 2p =0-03). Several exploratory subgroup analyses of the 28-day mortality data, not specified in the study design, are shown in fig 2. Within the limitations of statistical power none of the factors examined seems to influence the mortality
of in-hospital events. Mortality For all
patients
as
randomised, 28-day mortality
was
78% in the magnesium group and 10-3% in the placebo group (2p 0-04), a relative reduction of 24% (1-43%). The odds ratio of death (magnesium : placebo) was 0-74 =
(0.55-1-00)
and was virtually unchanged (0-76) by stratification for site of infarction, indicating lack of bias by this factor. The only pre-specified subgroup analysis was an examination of the effect of magnesium on 28-day mortality with and without concurrent thrombolysis, done in 35% of trial patients. Mortality odds ratios were 0-76 (0.46-1-27) in the thrombolysed patients and 0-72 (0-49-0-99) in the non-thrombolysed patients. There was no significant interaction between the effects of magnesium and of
thrombolytic treatment on 28-day mortality. Fig 1 shows mortality curves over 28 days for the two trial groups. ’Day 0’ was the calendar day of randomisation and
n IU"’"
Fig 1-Mortality
curves over
,t.u.ll wi
28 days from randomisation.
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TABLE IV-USE OF TREATMENTS WITHIN THE CCU FOR HEART FAILURE AND FOR RHYTHM DISTURBANCES, BY RANDOMISATION GROUP
Mortality odds ratio
1
Fig 2-Exploratory analysis of the mortality odds ratio (magnesium : placebo), shown with its 95% CL in subgroups of patients defined by stratification on the factors listed. reduction associated with magnesium therapy, with the possible exception of age. The cut point of 70 yr was chosen (rather than the mid-point of the age distribution of randomised patients) to give an approximate balance of deaths in the upper and lower strata since this determines the precision of the point estimate in each. The possibility of a lesser effect of magnesium in younger patients is no more than a hypothesis to be further examined. Of particular interest is the lack of any apparent effect modification by concurrent aspirin therapy or by regular beta blocker, diuretic, or calcium antagonist therapy preceding admission. Most of the non-aspirin subgroup entered the trial before use of aspirin became routine in September, 1988. Delay time (elapsed time from onset of symptoms to admission) was stratified around the median for all randomised patients and did not modify the magnesium effect; three-quarters of patients were admitted within 6 h
(table II). Morbidity and treatment in the CCU There was a lower incidence in the magnesium group of left ventricular failure as assessed clinically (11-2% vs
14-9%, 2p=0-009) or radiologically (17-2% vs 22-0%, 2p 0-004) and a trend towards lower incidence of oliguria =
I
I
and anuria (table ill). The prevalence of hypotension, defined as a systolic blood pressure < 100 mm Hg for an hour or longer, was the same in the two groups. Sinus bradycardia was commoner among magnesium-treated patients (10-8% vs 8-0%, 2p=0-02) but the incidence of atrioventricular block (any degree) did not differ. The morbidity data recorded in table III could not be rigorously standardised since they were based on the clinical judgments of a large number of clinicians. However, they are corroborated by separate data on treatments given in the coronary care unit (table iv). A lower use of loop diuretics (2p==0’03) and sodium nitroprusside infusions (2p = 0-03) and the greater use of atropine (2p 0-0004) in the patients receiving magnesium are consistent with their lower recorded incidence of left ventricular failure and higher incidence of sinus bradycardia. There was no significant excess of heart block in the magnesium group, and rates of temporary pacemaker insertion did not differ. There was no evidence of any difference in the frequency of tachyarrhythmias in the trial groups as judged by the recorded occurrence of specific abnormal rhythms, the use of direct-current cardioversion, or the administration of antiarrhythmic drugs. Detailed analysis of 24 h Holter monitoring records in a subgroup of 70 patients likewise revealed no statistically significant differences for any class of abnormal rhythm. Acute myocardial infarction was the discharge diagnosis in 754 patients in each group and the distributions of the =
TABLED—CUN!CALCOURSE, LABORATORY DATA, AND 28-DAY OUTCOME
LVF = Left ventncular failure.
NS=2p>005 *Patients with confirmed AMII
Fig 3-Achieved serum magnesium concentrations (with SEM) in patients treated by the magnesium sulphate regimen (n=20). In the placebo group mean serum magnesium was within the laboratory reference range throughout.
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reperfusion injury, evidence was sought for greater efficacy of magnesium in patients receiving a thrombolytic drug but
their 95% Cis) in placebocontrolled randomised trials of intravenous magnesium in suspected AMI.I.
Fig 4-Mortality odds ratios (with
Follow-up was to hospital discharge in all studies apart from Rasmussen et al (30 days),3,29 Smith et al (28 days),1.2 and LIMIT-2 (28 days). Pooled estimates and their 95% CI are also shown for the 7 published trials and for these plus the LIM IT-2 data.
highest measured creatine kinase and hydroxybutyrate dehydrogenase were not significantly different. Serum magnesium concentrations Baseline mean serum magnesium was normal in both groups and remained in the normal range in the placebo group. Fig 3 shows the serum magnesium profile over 48 h in a sample from the magnesium-treated group. A value at the end of the infusion was available for 86% of trial patients, averaging 1 -55 mmol/1 (SD 0-44) in the magnesium group and 0-82 mmol/1 (SD 0-09) in the placebo group.
Haemodynamic changes and side-effects Flushing was a common but not universal symptom at the time of the initial magnesium injection and could be substantially reduced in frequency and intensity by giving the injection over 10 min. Doppler measurements in a sample of patients showed a 20% (SEM 5%, 2p < 0-001) rise in cardiac output by the end of the magnesium injection which subsided during the first 15 min of the infusion. Heart rate was unchanged (95% confidence interval - 1-8 to + 4-4 beats per min). Blood pressure fell transiently by a mean of 8 mm Hg (SEM 2-7 mm, 2p = 0-005) systolic and 5 mm Hg diastolic. A longer (SEM 18 mm, 2p <0-02) haemodynamic study was impractical because of extraneous factors such as concurrent drug treatment and rhythm changes. No important adverse effects of magnesium were identified.
+
Discussion The
primary outcome of interest, total 28-day mortality intention-to-treat by analysis, is not susceptible to bias provided good randomisation and a high rate of follow-up can be achieved. Both conditions were met. The measured effect of the magnesium regimen on mortality is consistent with the pooled data of the other published trials (fig 4) and is of similar magnitude to that achieved by thrombolytic an
drugs or aspirin.23,26 The benefit appears similar in all subgroups except for a possible age interaction noted above. &cause
this was not seen. The exploratory subgroup analyses of mortality were performed to generate hypotheses on the mechanism of the magnesium effect and were of low statistical power. Lack of effect modification by aspirin argues against an antiplatelet effect of magnesium, despite the experimental evidence to support it.19 Lack of effect modification by previous diuretic that therapy suggests magnesium is acting rather than pharmacologically by correcting a deficit. The second hypothesis tested in the study, that progression to acute myocardial infarction among patients with unstable coronary artery disease can be reduced by magnesium treatment, was suggested by the study of Rasmussen et al 29 and by subsequent observations on patients with coronary spasm.32 We observed identical rates of confirmed infarction in the magnesium and placebo groups. Peak cardiac enzyme levels were similar but since detailed cardiac enzyme profiles were not done we can make no inference on infarct size. Although the data on early morbidity could in theory be biased by "unblinding" of treatment allocation by the common occurrence of flushing, we think this unlikely because of their consistency and the corroborating evidence of drug use. These analyses were not central to the study but were performed to shed light on the way in which magnesium might reduce early mortality. The reduced incidence of left ventricular failure in patients given magnesium may have important implications for long-term outcome, since early left ventricular dysfunction is a strong predictor of poor outcome. Equally consistent is the evidence against an antiarrhythmic action of magnesium, the third hypothesis under test. Several earlier trials indicated reductions in frequency of various types of arrhythmia with magnesium in suspected myocardial infarction but the definitions of arrhythmias varied widely and numbers were small.8 The best unifying hypothesis for the reduction of mortality and left ventricular dysfunction by magnesium is a direct protective action on the myocardium. Afterload reduction is unlikely to have contributed because the haemodynamic effects of the magnesium regimen lasted only for a few minutes. Magnesium has been shown experimentally to protect myocardium from ischaemia/ reperfusion injury, increasing the speed and ultimate extent of recovery of cardiac output.2o Possible mechanisms include reduction of cytoplasmic calcium overload or mitigation of its adverse effects on mitochondrial function.9,21 Further research is needed to defme the concentration-effect relation at cellular level. In the main study sinus bradycardia was found to be associated with magnesium treatment. The mechanism may be related to Mgregulation of acetylcholine-activated K channels in pacemaker tissue or an effect on Ca2 + current.27 Sinus bradycardia in the magnesium-treated group did not seem to be commoner with inferior infarction or previous beta blockade. Several electrophysiological studies in patients with and without underlying heart disease have shown sinus node function to be unaffected by the serum magnesium concentrations attained here16,17 and we did not observe a fall in heart rate after the magnesium bolus in either the haemodynamic or the Holter monitoring substudy. Differences in statistical power could account for these apparent discrepancies, or there may have been a small group of patients more susceptible to sinus slowing whom
of the contribution of calcium overload
to
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could not identify. In a case report, an obstetric patient whose serum magnesium was inadvertently raised to 16 mmol/1 (ten times higher than in the present- study) developed sinus bradycardia and hypotension responding promptly to intravenous calcium chloride.31 Neuromuscular blockade necessitated ventilation for some hours but recovery was complete after rapid renal excretion of magnesium. Loss of tendon reflexes is the first sign of neuromuscular blockade by magnesium and is reported to occur at 4-5 mmol/l; it was not seen in any patient in the present study. Although atrium-His conduction has been shown to be slowed slightly by intravenous magnesium in man,16,17 we did not observe an increased risk of heart block. On present evidence we see no reason to withhold the magnesium regimen from patients with a pre-existing conduction abnormality. The protocol was designed to achieve the intended doubling of serum magnesium promptly, so that any benefit of treatment would be provided at the time of maximum risk (fig 3). Flushing and occasional nausea and local discomfort can be almost abolished by giving the injection over 10-15 min and ideally diluting it to a volume of 10 ml or more. Any such symptoms are transient despite the maintenance of the serum magnesium level by the 24 h infusion. Experience in a large and representative group of patients has shown that this is a simple and safe treatment which can be generally used for suspected acute myocardial infarction. The point estimate of benefit is a reduction over the first 4 weeks of about 25 deaths per 1000 patients treated. No contraindications have been identified, though in the presence of moderate to severe renal failure adjustment of the maintenance infusion will be necessary to avoid accumulation of magnesium. Additional information on the same regimen will come from the analysis of the ISIS-4 study33 and data on long-term outcome are being collected in the present trial.
we
The study was funded by projects grants from Leicestershire Health Authority and the British Heart Foundation. We thank the patients who agreed to participate. The study was made possible by the willing support of a large number of individuals, particularly the following:
University of Leicester-Department of Pharmacology and Therapeutics: D. B. Bamett, Ng. Department of Medicine: R. Bing, A. Heagerty, H. Thurston. Department of Epidemiology and Public Health: Carol Jagger. Computer Centre: Sylvia West. Leicester Royal Infirmary--Cûrorw,ry care unit: O. Browne, S. Collington, V. Gaynor, J. Hignett, J. Huggms, D. Ibbotson, D. Kyle, L. Wheat, T. Badger, G. Woollacott, K. Baldock, H. Bishop, J. Bonser, A. Jackson, S. Johnson, T. Patel, K. Stokes, J. Tranter, C. Brown, S. Jugon, D. Mayers; A. Al-Chalabi, M. Andrews, T. Blake, M. Boggttd, H. Brookes, E. Clarke, P. Coates, J. Coffey, A. Cooper, L. David, F. Dore-Green, J. Dyer, D. Ellison, A. Elouzi, I. Fraser, M. Gandi, K. Gilmore, W. Goddard, G. Good, S. Goodacre, L. L.
S. Grimes, R. Hammonds, S. Horsley, S. Jackson, N. Jenkins, K. Jones, A. Kenton, S. Keohane, C. Kneebone, S. Leno, T. S. Lim, C. Lord, M. Lumley, D. Mansfield, D. Markham, P. Martin, C. Millwater, S. Mullick, V. Pai, A. Palfreeman, S. Pavord, R. Peck, H. Phillips, F. Rawlinson, B. Rembacken, G. Saldanha, S. Shepherd, 1. Sharfuddin, A. Shiels, S. Smith, M. Speakman, V. Tan, D. Throssell, M. Tidmarsh, A. Turner, C. Udenzi, A. K. Vania, J. Van-Tam, A Weaver, P. Weston, S. Wharton, S. Wheatley, D. Wilkes, M. Wong. Pharmacy Department: A. Kollo, L. Ball, G. Bumphrey, B. Godfrey, P. White. Department of Chemical Pathology: J. Falconer-Smith, A. Jenkins, J. Mortimer. Letcester Polytechmc-Department of Mathematics and
Computing: C. Pindar, P. Shuttleworth. We also thank the staff of the Office of Population Censuses and Surveys and of many local general practices for their help with the provision of follow-up data.
REFERENCES 1. Smith LF, Heagerty AM, Bing RF, Barnett DB. Intravenous infusion of magnesium sulphate after acute myocardial infarction: effects on arrhythmias and mortality. Int J Cardiol 1986; 12: 175-80. 2. Woods KL, Fletcher S, Smith LFP. Intravenous magnesium in suspected acute myocardial infarction. Br Med J 1992; 304: 119. 3. Rasmussen HS, Gronbaek M, Cintin C, Balslev S, Norregard P, McNair P. One-year death rate in 270 patients with suspected acute myocardial infarction, initially treated with intravenous magnesium or placebo. Clin Cardiol 1988; 11: 377-81. 4. Shechter M, Hod H, Marks N, Kaplinsky E, Behar S, Rabinowitz B. Beneficial effect of magnesium sulfate in acute myocardial infarction.
Am J Cardiol 1990; 66: 271-74. 5. Rasmussen HS, Suenson M, McNair P, Norregard P, Balslev S. Magnesium infusion reduces the incidence of arrhythmias in acute myocardial infarction. A double-blind placebo-controlled study. Clin Cardiol 1987; 10: 351-56. 6. Abraham AS, Rosenmann D, Kramer M, et al. Magnesium in the prevention of lethal arrhythmias in acute myocardial infarction. Arch Intern Med 1987; 147: 753-55. 7. Ceremuzynski L, Jurgiel R, Kulakowski P, Gebalska J. Threatening arrhythmias in acute myocardial infarction are prevented by intravenous magnesium sulphate. Am Heart J 1989; 118: 1333-34. 8. Teo KK, Yusuf S, Collins R, Held PH, Peto R. Effects of intravenous magnesium in suspected acute myocardial infarction: overview of randomized trials. Br Med J 1991; 303: 1499-503. 9. Woods KL. Possible pharmacological actions of magnesium in acute myocardial infarction. Br J Clin Pharmacol 1991; 32: 3-10. 10. Mroczek WJ, Lee WR, Davidov ME. Effect of magnesium sulfate on cardiovascular hemodynamics. Angiology 1977; 28: 720-24. 11. Kimura T, Yasue H, Sakaino N, Rokutanda M, Jougasaki M, Araki H. Effects of magnesium on the tone of isolated human coronary arteries. Circulation 1989; 79: 1118-24. 12. Vigorito C, Giordano A, Ferraro P, et al. Hemodynamic effects of magnesium sulfate on the normal human heart. Am J Cardiol 1991; 67: 1435-37. 13. Tzivoni D, Keren A. Suppression of ventricular arrhythmias by magnesium. Am J Cardiol 1990; 65: 1387-99. 14. Iseri LT, Fairshter RD, Hardemann JL, Brodsky MA. Magnesium and potassium therapy in multifocal atrial tachycardia. Am Heart J 1985; 110: 789-94. 15. Haverkamp W, Hindricks G, Keteller T, Allberty D, Weithold D, Gulker H. Prophylactic antiarrhythmic and antifibrillatory effects of intravenous magnesium sulphate during acute myocardial ischaemia. Eur Heart J 1988; 9: 228. 16. Kulick DL, Hong R, Ryzen E, et al. Electrophysiological effects of intravenous magnesium in patients with normal conduction systems and no clinical evidence of significant cardiac disease. Am Heart J 1988; 115: 367-73. 17. Rogiers P, Vermeier W, Kesteloot H, Stroobandt R. Effect of the infusion of magnesium sulphate during atrial pacing on ECG intervals, serum electrolytes and blood pressure. Am Heart J 1989; 117: 1278-83. 18. Watson KV, Moldow CF, Ogburn PL, Jacob HS. Magnesium sulfate: rationale for its use in pre-eclampsia. Proc Natl Acad Sci USA 1986; 83: 1075-78. 19. Adams JH, Mitchell JRA. The effect of agents which modify platelet behaviour and of magnesium ions on thrombus formation in vivo. Thromb Haemostas 1979; 42: 603-10. 20. Hearse DJ, Stewart DA, Braimbridge MV. Myocardial protection during ischaemic cardic arrest: the importance of magnesium in cardioplegic solutions. J Thorac Cardiovasc Surg 1978; 75: 877-85. 21. Ferrari R, Albertini A, Curello S, et al. Myocardial recovery during post-ischaemic reperfusion: effects of nifedipine, calcium and magnesium. J Mol Cell Cardiol 1986; 18: 487-98. 22. Borchgrevink PC, Bergan AS, Bakoy OE, Jynge P. Magnesium and reperfusion of ischemic rat heart as assessed by 31P-NMR. Am J Physiol 1989; 256: H195-204. 23. ISIS-2 Collaborative Group. A randomised trial of intravenous streptokinase, oral aspirin, both, or neither among 17 187 cases of suspected acute myocardial infarction. Lancet 1988; ii: 349-60. 24. DeMets DL, Ware JH. Group sequential methods for clinical trials with a one-sided hypothesis. Biometrika 1980; 67: 651-60. 25. Mantel N, Haenszel W. Statistical aspects of the analysis of data from retrospective studies of disease. J Natl Cancer Inst 1959; 22: 719-48. 26. GISSI. Effectiveness of intravenous thrombolytic therapy in acute myocardial infarction. Lancet 1986; i: 397-402. 27. White RE, Hartzell HC. Magnesium ions in cardiac function. Regulator of ion channels and second messengers. Biochem Pharmacol 1989; 38: 859-67. 28. Morton BC, Nair RC, Smith FM, McKibbon TG, Poznanski WJ. Magnesium therapy in acute myocardial infarction—a double-blind study. Magnesium 1984; 3: 346-52. 29. Rasmussen HS, McNair P, Norregard P, Backer V, Lindeneg O, Balslev S. Intravenous magnesium in acute myocardial infarction. Lancet 1986; i: 234-36. 30. Feldstedt M, Bouchelouche P, Svenningsen A, et al. Failing effect of magnesium substitution in acute myocardial infarction. Eur HeartJ 31.
1988; 9: 226. Bohman VR, Cotton DB. Supralethal magnesemia with patient survival.
Obstet Gynecol 1990; 76: 984-86. Kugiyama K, Yasue H, Okumura K, et al. Suppression of exerciseinduced angina by magnesium sulphate in patients with variant angina. J Am Coll Cardiol 1988; 12: 1177-83. 33. Editorial. Magnesium for acute myocardial infarction? Lancet 1991; 338: 32.
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No 8809
1992
ORIGINAL ARTICLES
magnesium sulphate in suspected acute myocardial infarction: results of the second Leicester Intravenous Magnesium Intervention Trial (LIMIT-2) Intravenous
The cardiovascular actions of the magnesium ion pharmacological concentrations include coronary and systemic vasodilatation, platelet inhibition, and antiarrhythmic effects. Magnesium has also been reported to protect myocardial tissue in experimental models of ischaemia and reperfusion. Several small clinical trials in suspected acute myocardial infarction have suggested that early mortality can be reduced by intravenous infusion of magnesium salts in the acute phase, but none has been of sufficient size to be conclusive. We therefore conducted a randomised, double blind, placebo controlled study in 2316 patients with suspected acute myocardial infarction who received either intravenous magnesium sulphate (8 mmol over 5 min followed by 65 mmol over 24 h) or physiological saline. The primary outcome measure was 28-day mortality, which was ascertained in 99·3% of patients. The groups were well balanced for prognostic factors. By intention-to-treat analysis mortality from all causes was 7·8% in the magnesium group and 10·3% in the placebo group (2p=0·04), a relative reduction of 24% (95% confidence interval 1-43%). Within the coronary care unit the incidence of left ventricular failure was reduced by 25% (7-39%) in the magnesium group (2p=0·009). There was no significant difference between the groups in the incidence of heart block or the use of antiarrhythmic drugs, direct-current cardioversion, or temporary pacing. Myocardial infarction was confirmed in 65% of each group, with closely similar rises in cardiac enzymes. The side-effects of at
magnesium treatment were transient flushing, related to speed of injection of the loading dose, and an increased incidence of sinus bradycardia (2p=0·02). Exploratory subgroup analyses of 28-day mortality did not indicate any effect modification by thrombolysis or aspirin, or by previous treatment with beta blockers, calcium antagonists, or diuretics. Intravenous magnesium sulphate is a simple, safe, and widely applicable treatment. Its efficacy in reducing early mortality of myocardial infarction is comparable to, but independent of, that of thrombolytic or antiplatelet therapy. Introduction Several clinical trials have examined the effects of intravenous magnesium salts in suspected acute myocardial infarction. Most have reported a lower mortalityl-4 and a lower incidence of arrhythmias1,5-7 in magnesium-treated patients, though none has been of sufficient statistical power to be conclusive. A pooled analysis of the results of all known randomised trials (seven studies including a total of 1300 patients) indicated that the odds of death were reduced by about half but the confidence interval was wide.8 The treatment regimens varied: 30-90 mmol of magnesium sulphate or chloride was given over 24-48 h, increasing the ADDRESSES: Department of Pharmacology and Therapeutics University of Leicester, Leicester, UK (K L. Woods, MD, S. Fletcher, BA); Coronary Care Unit, Leicester Royal Infirmary (C. Roffe, MRCP, Y. Haider, MRCP). Correspondence to Dr Kent L. Woods, Department of Pharmacology and Therapeutics, Clinical Sciences Building, Leicester Royal Infirmary, Leicester LE2 7LX, UK
1554
magnesium concentration by 30-100%. Few adverse effects were reported, the commonest being flushing. Magnesium has been described as a physiological calcium antagonist and there are several plausible mechanisms for a beneficial effect in acute myocardial infarction.9 At the concentrations achieved in the trials, magnesium reduces peripheral vascular resistance10 and dilates human coronary arteries both in vitro and in vivo. 11,12 Antiarrhythmic effects of various kinds have been observed clinically and in experimental models of myocardial ischaemia.13-15 The electrophysiological effects of magnesium on normal cardiac serum
concentrations reached in the trials; a slight prolongation of the atrium-His interval is consistent with antagonism of the slow calcium current.16,17 Magnesium inhibits platelet function, perhaps indirectly by release of prostacyclin. 18 The concentration-effect relation is not clearly defined but over the range 1 -45-2-3 mmol/1 there was inhibition of platelet aggregation and then rapid disaggregation of platelet thrombi in an in-vivo rabbit model of arterial endothelial injury. 19 Myocardial protection against ischaemic injury has been reported in laboratory animals but the magnesium concentrations were generally higher than those attainable clinically.2O The mechanism of protection may be inhibition of mitochondrial calcium overload2l and preservation of intracellular ATP and creatine phosphate reserves.22 The study reported here was started in response to the findings of earlier trials (one of them conducted in this unit1,2) and was designed to test, with adequate statistical power, the following hypotheses: (1) that intravenous magnesium reduces early mortality in suspected acute myocardial infarction; (2) that progression to acute myocardial infarction among patients with unstable coronary artery disease can be reduced by magnesium; (3) that intravenous magnesium reduces the frequency of clinically important early arrhythmias in patients presenting with suspected myocardial infarction.
function
are
minor at the
TABLE I-RANDOMISATION OF PATIENTS ADMITTED TO CCU,
SEPTEMBER, 1987, TO FEBRUARY, 1992 I
serum
Methods Power calculations The primary outcome of interest was defined as 28-day mortality in all patients as randomised. Initial power calculations indicated that about 2000 patients would be needed. After recruitment began in September, 1987, routine use of aspirin and thrombolysis was introduced when the ISIS-2 findings were published.23 The power calculations were revised to adjust for the anticipated reduction in placebo group mortality, without unblinding the data already collected. The assumptions made were: (i) that 60% of patients randomised would have acute myocardial infarction confirmed; (ii) that 28-day mortality would be 12-5% in these patients and zero in the remainder; (iii) that the study should be able to detect with 80% probability at the two-sided 5% level of significance a true reduction of one-third in 28-day mortality among patients given magnesium (this being the lower 95% confidence limit of a pooled analysis of the published trials at that time). Provision was made for up to twelve one-sided interim analyses for adverse outcome only, as a safety measure.’ Target trial size was 1500 patients with confirmed myocardial infarction, requiring a total recruitment of 2500 patients. Interim analyses of 28-day mortality to detect a clear adverse trend in the magnesium group (lp < 0-01) were made by a statistician independent of the study at intervals of 4-6 months. No such trend was seen at any interim analysis. Since the protocol did not permit early stopping of the trial in response to a favourable trend at interim analysis, no adjustment was made to the final two-sided p value (2p).
Recruitment The trial was conducted between September, 1987, and February, 1992, in the coronary care unit (CCU) of Leicester Royal
Infirmary. The unit admits 1000 patients a year, about 50% of whom have the discharge diagnosis of acute myocardial infarction and 25% angina. Patients were eligible for the study if they were judged likely to have acute myocardial infarction with onset in the preceding 24 h. No electrocardiographic (ECG) criteria were specified. Exclusion criteria were (i) inability or refusal to give verbal consent; (ii) complete heart block; (iii) trial entry on a previous admission; (iv) a clinical indication for therapeutic use of magnesium; (v) serum creatinine > 300 unol/1. Randomisation was not delayed for a serum creatinine measurement unless renal failure was known or suspected. If the serum creatinine was found to be > 300 ol/l after randomisation, the trial infusion was stopped to avoid possible accumulation of magnesium but the patient remained in the allocated treatment group for analysis. Treatments Identical treatment packs for active and placebo treatments were manufactured in the sterile production unit of the district pharmacy service and coded according to a computer-generated blocked randomisation schedule. Packs contained magnesium sulphate solution 8 mmol in 4 ml for injection over 5 min and 65 mmol in 50 ml for infusion over the following 24 h, or equal volumes of physiological saline. An adhesive numbered label, transferred from the pack cover to the patient’s notes, was the only identifier. During the trial the randomisation codes were held by the pharmacy department and the independent statistician only.
Data collection and analysis A computerised CCU data system was developed into which was entered a standard record for every CCU admission. This held information on medical history, presenting symptoms, complications, management, laboratory data, and final diagnosis at the time of discharge from the CCU. Criteria for diagnosis of acute myocardial infarction were at least two of the following: a typical history; a rise in total serum creatine kinase to at least twice the laboratory normal upper limit, supported by a rise in hydroxybutyrate dehydrogenase; evolving ECG changes consistent with acute infarction. Definition of complications, as with the final diagnosis, was by clinical staff responsible for the patients’ routine care. Management decisions were guided by a comprehensive CCU policy document. Clinical data were recorded during the admission and not subsequently revised. All trial patients were "flagged" in the National Health Service Central Register for long-term ascertainment of deaths. Information on 28-day survival was also obtained from hospital, general practitioner, and health authority records. Sub-studies were performed in representative groups of randomised patients to obtain supplementary data: (1) 48 h profiles of serum magnesium (40 patients); (2) 24 h Holter monitoring for detailed analysis of arrhythmia frequency (70 patients), computer analysis of tapes being supplemented by visual verification of all abnormal rhythms; (3) measurement of haemodynamic response to trial treatment (44 patients). Cardiac output velocity was measured with a dedicated doppler machine (Digidop 220). The intra-subject
1555
coefficient of variation for the method was 7%. Simultaneous heart rate
and indirect blood pressure
were
TABLE II-BASELINE CHARACTERISTICS OF RANDOMISED
PATIENTS
measured automatically
(Dynamap). Significance
tests of proportions (including 28-day mortality) by means of the X2 statistic from 2 x 2 contingency tables, with stratification where indicated. For pooled analyses of mortality across published trials we used the Mantel-Haenszel weighted odds were done
ratio and X2 statistic.2s Parametric methods were used for continuous variables where appropriate--otherwise medians and interquartile ranges are given and non-parametric tests were used. Point estimates of treatment effects are shown with their 95% confidence intervals.
Ethical aspects The protocol of the study was approved by the Leicestershire Health Authority ethics committee. In addition to the one-sided interim analyses of 28-day mortality described above, surveillance of complication rates in all CCU patients was maintained during the study, the results being compared with a baseline period of 9 months between the installation of the data system and the start of the trial. An increased incidence of sinus bradycardia and use of atropine in the unit were noted but were judged not to require unblinding of the data in the absence of more serious adverse trends.
Results Randomisation and follow-up A total of 2316 patients entered the study in a 53-month period during which over half of CCU admissions were randomised. Reasons for non-randomisation of the remainder are shown in table I. The assumptions made for the power calculations proved to be slightly conservative. Acute myocardial infarction was confirmed in 65% of randomised patients (predicted 60%); placebo group 28-day mortality was 13 8% among those with infarction (predicted 12-5%) and 3.2% among those without (predicted 0%). Baseline characteristics of the patients in the magnesium and placebo groups were well matched for important prognostic variables apart from a minor imbalance of site of infarction (table 11). Follow-up was achieved to hospital discharge for 100% of trial patients and to 28 days for 99-3% of them. Survival to 28 days could not be positively confirmed for 9 patients in the magnesium group and 7 in the saline group, either because they left the country after discharge (6), were of no fixed abode (6), or were untraceable through their recorded address and general practitioner (4). These patients were excluded from the 28-day mortality analysis but were included in analyses
therefore averaged 12 h in length. The major separation between the trial groups occurred on the subsequent two days. This is reflected in the within-CCU mortality which was 3-6% in the magnesium group and 5-6% in the placebo group-a relative reduction of 36% (4-57%, 2p =0-03). Several exploratory subgroup analyses of the 28-day mortality data, not specified in the study design, are shown in fig 2. Within the limitations of statistical power none of the factors examined seems to influence the mortality
of in-hospital events. Mortality For all
patients
as
randomised, 28-day mortality
was
78% in the magnesium group and 10-3% in the placebo group (2p 0-04), a relative reduction of 24% (1-43%). The odds ratio of death (magnesium : placebo) was 0-74 =
(0.55-1-00)
and was virtually unchanged (0-76) by stratification for site of infarction, indicating lack of bias by this factor. The only pre-specified subgroup analysis was an examination of the effect of magnesium on 28-day mortality with and without concurrent thrombolysis, done in 35% of trial patients. Mortality odds ratios were 0-76 (0.46-1-27) in the thrombolysed patients and 0-72 (0-49-0-99) in the non-thrombolysed patients. There was no significant interaction between the effects of magnesium and of
thrombolytic treatment on 28-day mortality. Fig 1 shows mortality curves over 28 days for the two trial groups. ’Day 0’ was the calendar day of randomisation and
n IU"’"
Fig 1-Mortality
curves over
,t.u.ll wi
28 days from randomisation.
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TABLE IV-USE OF TREATMENTS WITHIN THE CCU FOR HEART FAILURE AND FOR RHYTHM DISTURBANCES, BY RANDOMISATION GROUP
Mortality odds ratio
1
Fig 2-Exploratory analysis of the mortality odds ratio (magnesium : placebo), shown with its 95% CL in subgroups of patients defined by stratification on the factors listed. reduction associated with magnesium therapy, with the possible exception of age. The cut point of 70 yr was chosen (rather than the mid-point of the age distribution of randomised patients) to give an approximate balance of deaths in the upper and lower strata since this determines the precision of the point estimate in each. The possibility of a lesser effect of magnesium in younger patients is no more than a hypothesis to be further examined. Of particular interest is the lack of any apparent effect modification by concurrent aspirin therapy or by regular beta blocker, diuretic, or calcium antagonist therapy preceding admission. Most of the non-aspirin subgroup entered the trial before use of aspirin became routine in September, 1988. Delay time (elapsed time from onset of symptoms to admission) was stratified around the median for all randomised patients and did not modify the magnesium effect; three-quarters of patients were admitted within 6 h
(table II). Morbidity and treatment in the CCU There was a lower incidence in the magnesium group of left ventricular failure as assessed clinically (11-2% vs
14-9%, 2p=0-009) or radiologically (17-2% vs 22-0%, 2p 0-004) and a trend towards lower incidence of oliguria =
I
I
and anuria (table ill). The prevalence of hypotension, defined as a systolic blood pressure < 100 mm Hg for an hour or longer, was the same in the two groups. Sinus bradycardia was commoner among magnesium-treated patients (10-8% vs 8-0%, 2p=0-02) but the incidence of atrioventricular block (any degree) did not differ. The morbidity data recorded in table III could not be rigorously standardised since they were based on the clinical judgments of a large number of clinicians. However, they are corroborated by separate data on treatments given in the coronary care unit (table iv). A lower use of loop diuretics (2p==0’03) and sodium nitroprusside infusions (2p = 0-03) and the greater use of atropine (2p 0-0004) in the patients receiving magnesium are consistent with their lower recorded incidence of left ventricular failure and higher incidence of sinus bradycardia. There was no significant excess of heart block in the magnesium group, and rates of temporary pacemaker insertion did not differ. There was no evidence of any difference in the frequency of tachyarrhythmias in the trial groups as judged by the recorded occurrence of specific abnormal rhythms, the use of direct-current cardioversion, or the administration of antiarrhythmic drugs. Detailed analysis of 24 h Holter monitoring records in a subgroup of 70 patients likewise revealed no statistically significant differences for any class of abnormal rhythm. Acute myocardial infarction was the discharge diagnosis in 754 patients in each group and the distributions of the =
TABLED—CUN!CALCOURSE, LABORATORY DATA, AND 28-DAY OUTCOME
LVF = Left ventncular failure.
NS=2p>005 *Patients with confirmed AMII
Fig 3-Achieved serum magnesium concentrations (with SEM) in patients treated by the magnesium sulphate regimen (n=20). In the placebo group mean serum magnesium was within the laboratory reference range throughout.
1557
reperfusion injury, evidence was sought for greater efficacy of magnesium in patients receiving a thrombolytic drug but
their 95% Cis) in placebocontrolled randomised trials of intravenous magnesium in suspected AMI.I.
Fig 4-Mortality odds ratios (with
Follow-up was to hospital discharge in all studies apart from Rasmussen et al (30 days),3,29 Smith et al (28 days),1.2 and LIMIT-2 (28 days). Pooled estimates and their 95% CI are also shown for the 7 published trials and for these plus the LIM IT-2 data.
highest measured creatine kinase and hydroxybutyrate dehydrogenase were not significantly different. Serum magnesium concentrations Baseline mean serum magnesium was normal in both groups and remained in the normal range in the placebo group. Fig 3 shows the serum magnesium profile over 48 h in a sample from the magnesium-treated group. A value at the end of the infusion was available for 86% of trial patients, averaging 1 -55 mmol/1 (SD 0-44) in the magnesium group and 0-82 mmol/1 (SD 0-09) in the placebo group.
Haemodynamic changes and side-effects Flushing was a common but not universal symptom at the time of the initial magnesium injection and could be substantially reduced in frequency and intensity by giving the injection over 10 min. Doppler measurements in a sample of patients showed a 20% (SEM 5%, 2p < 0-001) rise in cardiac output by the end of the magnesium injection which subsided during the first 15 min of the infusion. Heart rate was unchanged (95% confidence interval - 1-8 to + 4-4 beats per min). Blood pressure fell transiently by a mean of 8 mm Hg (SEM 2-7 mm, 2p = 0-005) systolic and 5 mm Hg diastolic. A longer (SEM 18 mm, 2p <0-02) haemodynamic study was impractical because of extraneous factors such as concurrent drug treatment and rhythm changes. No important adverse effects of magnesium were identified.
+
Discussion The
primary outcome of interest, total 28-day mortality intention-to-treat by analysis, is not susceptible to bias provided good randomisation and a high rate of follow-up can be achieved. Both conditions were met. The measured effect of the magnesium regimen on mortality is consistent with the pooled data of the other published trials (fig 4) and is of similar magnitude to that achieved by thrombolytic an
drugs or aspirin.23,26 The benefit appears similar in all subgroups except for a possible age interaction noted above. &cause
this was not seen. The exploratory subgroup analyses of mortality were performed to generate hypotheses on the mechanism of the magnesium effect and were of low statistical power. Lack of effect modification by aspirin argues against an antiplatelet effect of magnesium, despite the experimental evidence to support it.19 Lack of effect modification by previous diuretic that therapy suggests magnesium is acting rather than pharmacologically by correcting a deficit. The second hypothesis tested in the study, that progression to acute myocardial infarction among patients with unstable coronary artery disease can be reduced by magnesium treatment, was suggested by the study of Rasmussen et al 29 and by subsequent observations on patients with coronary spasm.32 We observed identical rates of confirmed infarction in the magnesium and placebo groups. Peak cardiac enzyme levels were similar but since detailed cardiac enzyme profiles were not done we can make no inference on infarct size. Although the data on early morbidity could in theory be biased by "unblinding" of treatment allocation by the common occurrence of flushing, we think this unlikely because of their consistency and the corroborating evidence of drug use. These analyses were not central to the study but were performed to shed light on the way in which magnesium might reduce early mortality. The reduced incidence of left ventricular failure in patients given magnesium may have important implications for long-term outcome, since early left ventricular dysfunction is a strong predictor of poor outcome. Equally consistent is the evidence against an antiarrhythmic action of magnesium, the third hypothesis under test. Several earlier trials indicated reductions in frequency of various types of arrhythmia with magnesium in suspected myocardial infarction but the definitions of arrhythmias varied widely and numbers were small.8 The best unifying hypothesis for the reduction of mortality and left ventricular dysfunction by magnesium is a direct protective action on the myocardium. Afterload reduction is unlikely to have contributed because the haemodynamic effects of the magnesium regimen lasted only for a few minutes. Magnesium has been shown experimentally to protect myocardium from ischaemia/ reperfusion injury, increasing the speed and ultimate extent of recovery of cardiac output.2o Possible mechanisms include reduction of cytoplasmic calcium overload or mitigation of its adverse effects on mitochondrial function.9,21 Further research is needed to defme the concentration-effect relation at cellular level. In the main study sinus bradycardia was found to be associated with magnesium treatment. The mechanism may be related to Mgregulation of acetylcholine-activated K channels in pacemaker tissue or an effect on Ca2 + current.27 Sinus bradycardia in the magnesium-treated group did not seem to be commoner with inferior infarction or previous beta blockade. Several electrophysiological studies in patients with and without underlying heart disease have shown sinus node function to be unaffected by the serum magnesium concentrations attained here16,17 and we did not observe a fall in heart rate after the magnesium bolus in either the haemodynamic or the Holter monitoring substudy. Differences in statistical power could account for these apparent discrepancies, or there may have been a small group of patients more susceptible to sinus slowing whom
of the contribution of calcium overload
to
1558
could not identify. In a case report, an obstetric patient whose serum magnesium was inadvertently raised to 16 mmol/1 (ten times higher than in the present- study) developed sinus bradycardia and hypotension responding promptly to intravenous calcium chloride.31 Neuromuscular blockade necessitated ventilation for some hours but recovery was complete after rapid renal excretion of magnesium. Loss of tendon reflexes is the first sign of neuromuscular blockade by magnesium and is reported to occur at 4-5 mmol/l; it was not seen in any patient in the present study. Although atrium-His conduction has been shown to be slowed slightly by intravenous magnesium in man,16,17 we did not observe an increased risk of heart block. On present evidence we see no reason to withhold the magnesium regimen from patients with a pre-existing conduction abnormality. The protocol was designed to achieve the intended doubling of serum magnesium promptly, so that any benefit of treatment would be provided at the time of maximum risk (fig 3). Flushing and occasional nausea and local discomfort can be almost abolished by giving the injection over 10-15 min and ideally diluting it to a volume of 10 ml or more. Any such symptoms are transient despite the maintenance of the serum magnesium level by the 24 h infusion. Experience in a large and representative group of patients has shown that this is a simple and safe treatment which can be generally used for suspected acute myocardial infarction. The point estimate of benefit is a reduction over the first 4 weeks of about 25 deaths per 1000 patients treated. No contraindications have been identified, though in the presence of moderate to severe renal failure adjustment of the maintenance infusion will be necessary to avoid accumulation of magnesium. Additional information on the same regimen will come from the analysis of the ISIS-4 study33 and data on long-term outcome are being collected in the present trial.
we
The study was funded by projects grants from Leicestershire Health Authority and the British Heart Foundation. We thank the patients who agreed to participate. The study was made possible by the willing support of a large number of individuals, particularly the following:
University of Leicester-Department of Pharmacology and Therapeutics: D. B. Bamett, Ng. Department of Medicine: R. Bing, A. Heagerty, H. Thurston. Department of Epidemiology and Public Health: Carol Jagger. Computer Centre: Sylvia West. Leicester Royal Infirmary--Cûrorw,ry care unit: O. Browne, S. Collington, V. Gaynor, J. Hignett, J. Huggms, D. Ibbotson, D. Kyle, L. Wheat, T. Badger, G. Woollacott, K. Baldock, H. Bishop, J. Bonser, A. Jackson, S. Johnson, T. Patel, K. Stokes, J. Tranter, C. Brown, S. Jugon, D. Mayers; A. Al-Chalabi, M. Andrews, T. Blake, M. Boggttd, H. Brookes, E. Clarke, P. Coates, J. Coffey, A. Cooper, L. David, F. Dore-Green, J. Dyer, D. Ellison, A. Elouzi, I. Fraser, M. Gandi, K. Gilmore, W. Goddard, G. Good, S. Goodacre, L. L.
S. Grimes, R. Hammonds, S. Horsley, S. Jackson, N. Jenkins, K. Jones, A. Kenton, S. Keohane, C. Kneebone, S. Leno, T. S. Lim, C. Lord, M. Lumley, D. Mansfield, D. Markham, P. Martin, C. Millwater, S. Mullick, V. Pai, A. Palfreeman, S. Pavord, R. Peck, H. Phillips, F. Rawlinson, B. Rembacken, G. Saldanha, S. Shepherd, 1. Sharfuddin, A. Shiels, S. Smith, M. Speakman, V. Tan, D. Throssell, M. Tidmarsh, A. Turner, C. Udenzi, A. K. Vania, J. Van-Tam, A Weaver, P. Weston, S. Wharton, S. Wheatley, D. Wilkes, M. Wong. Pharmacy Department: A. Kollo, L. Ball, G. Bumphrey, B. Godfrey, P. White. Department of Chemical Pathology: J. Falconer-Smith, A. Jenkins, J. Mortimer. Letcester Polytechmc-Department of Mathematics and
Computing: C. Pindar, P. Shuttleworth. We also thank the staff of the Office of Population Censuses and Surveys and of many local general practices for their help with the provision of follow-up data.
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Am J Cardiol 1990; 66: 271-74. 5. Rasmussen HS, Suenson M, McNair P, Norregard P, Balslev S. Magnesium infusion reduces the incidence of arrhythmias in acute myocardial infarction. A double-blind placebo-controlled study. Clin Cardiol 1987; 10: 351-56. 6. Abraham AS, Rosenmann D, Kramer M, et al. Magnesium in the prevention of lethal arrhythmias in acute myocardial infarction. Arch Intern Med 1987; 147: 753-55. 7. Ceremuzynski L, Jurgiel R, Kulakowski P, Gebalska J. Threatening arrhythmias in acute myocardial infarction are prevented by intravenous magnesium sulphate. Am Heart J 1989; 118: 1333-34. 8. Teo KK, Yusuf S, Collins R, Held PH, Peto R. Effects of intravenous magnesium in suspected acute myocardial infarction: overview of randomized trials. Br Med J 1991; 303: 1499-503. 9. Woods KL. Possible pharmacological actions of magnesium in acute myocardial infarction. Br J Clin Pharmacol 1991; 32: 3-10. 10. Mroczek WJ, Lee WR, Davidov ME. Effect of magnesium sulfate on cardiovascular hemodynamics. Angiology 1977; 28: 720-24. 11. Kimura T, Yasue H, Sakaino N, Rokutanda M, Jougasaki M, Araki H. Effects of magnesium on the tone of isolated human coronary arteries. Circulation 1989; 79: 1118-24. 12. Vigorito C, Giordano A, Ferraro P, et al. Hemodynamic effects of magnesium sulfate on the normal human heart. Am J Cardiol 1991; 67: 1435-37. 13. Tzivoni D, Keren A. Suppression of ventricular arrhythmias by magnesium. Am J Cardiol 1990; 65: 1387-99. 14. Iseri LT, Fairshter RD, Hardemann JL, Brodsky MA. Magnesium and potassium therapy in multifocal atrial tachycardia. Am Heart J 1985; 110: 789-94. 15. Haverkamp W, Hindricks G, Keteller T, Allberty D, Weithold D, Gulker H. Prophylactic antiarrhythmic and antifibrillatory effects of intravenous magnesium sulphate during acute myocardial ischaemia. Eur Heart J 1988; 9: 228. 16. Kulick DL, Hong R, Ryzen E, et al. Electrophysiological effects of intravenous magnesium in patients with normal conduction systems and no clinical evidence of significant cardiac disease. Am Heart J 1988; 115: 367-73. 17. Rogiers P, Vermeier W, Kesteloot H, Stroobandt R. Effect of the infusion of magnesium sulphate during atrial pacing on ECG intervals, serum electrolytes and blood pressure. Am Heart J 1989; 117: 1278-83. 18. Watson KV, Moldow CF, Ogburn PL, Jacob HS. Magnesium sulfate: rationale for its use in pre-eclampsia. Proc Natl Acad Sci USA 1986; 83: 1075-78. 19. Adams JH, Mitchell JRA. The effect of agents which modify platelet behaviour and of magnesium ions on thrombus formation in vivo. Thromb Haemostas 1979; 42: 603-10. 20. Hearse DJ, Stewart DA, Braimbridge MV. Myocardial protection during ischaemic cardic arrest: the importance of magnesium in cardioplegic solutions. J Thorac Cardiovasc Surg 1978; 75: 877-85. 21. Ferrari R, Albertini A, Curello S, et al. Myocardial recovery during post-ischaemic reperfusion: effects of nifedipine, calcium and magnesium. J Mol Cell Cardiol 1986; 18: 487-98. 22. Borchgrevink PC, Bergan AS, Bakoy OE, Jynge P. Magnesium and reperfusion of ischemic rat heart as assessed by 31P-NMR. Am J Physiol 1989; 256: H195-204. 23. ISIS-2 Collaborative Group. A randomised trial of intravenous streptokinase, oral aspirin, both, or neither among 17 187 cases of suspected acute myocardial infarction. Lancet 1988; ii: 349-60. 24. DeMets DL, Ware JH. Group sequential methods for clinical trials with a one-sided hypothesis. Biometrika 1980; 67: 651-60. 25. Mantel N, Haenszel W. Statistical aspects of the analysis of data from retrospective studies of disease. J Natl Cancer Inst 1959; 22: 719-48. 26. GISSI. Effectiveness of intravenous thrombolytic therapy in acute myocardial infarction. Lancet 1986; i: 397-402. 27. White RE, Hartzell HC. Magnesium ions in cardiac function. Regulator of ion channels and second messengers. Biochem Pharmacol 1989; 38: 859-67. 28. Morton BC, Nair RC, Smith FM, McKibbon TG, Poznanski WJ. Magnesium therapy in acute myocardial infarction—a double-blind study. Magnesium 1984; 3: 346-52. 29. Rasmussen HS, McNair P, Norregard P, Backer V, Lindeneg O, Balslev S. Intravenous magnesium in acute myocardial infarction. Lancet 1986; i: 234-36. 30. Feldstedt M, Bouchelouche P, Svenningsen A, et al. Failing effect of magnesium substitution in acute myocardial infarction. Eur HeartJ 31.
1988; 9: 226. Bohman VR, Cotton DB. Supralethal magnesemia with patient survival.
Obstet Gynecol 1990; 76: 984-86. Kugiyama K, Yasue H, Okumura K, et al. Suppression of exerciseinduced angina by magnesium sulphate in patients with variant angina. J Am Coll Cardiol 1988; 12: 1177-83. 33. Editorial. Magnesium for acute myocardial infarction? Lancet 1991; 338: 32.
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