Review of research methodology used in clinical trials of magnesium and myocardial infarction - Why does controversy persist despite ISIS-4?

Coronary Artery Disease

Volumn 7, Issue 5, 1996, Pages 348-351

  Woods, Kent L ^a  

^a UNIVERSITY OF LEICESTER   (United Kingdom)

Author keywords

acute myocardial infarction; clinical trials; magnesium; mega trials; meta analysis

Indexed keywords

MAGNESIUM;

ACUTE HEART INFARCTION; ARTICLE; DRUG POTENCY; DRUG RESEARCH; HEART PROTECTION; HUMAN; HUMAN CELL; HUMAN TISSUE; PRIORITY JOURNAL; REPERFUSION INJURY; STATISTICAL ANALYSIS; VASODILATATION;

EID: 0029787666     PISSN: 09546928     EISSN: None     Source Type: Journal    
DOI: 10.1097/00019501-199605000-00003     Document Type: Article

References (24)

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2. Woods KL: Possible pharmacological actions of magnesium in acute myocardial infarction. Br J Clin Pharmacol 1991, 32:3-10.
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13. 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 1984, 343:816-819. Follow-up of the trial reported in [14] for a median of 2.7 years showed 16% (95% confidence interval 2-29%, P=0.03) reduction in all-cause mortality rate and 21% (5-35%, P=0.01) reduction in ischaemic heart disease mortality rate in the magnesium group.
14. 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. A hypothesis-testing conventionally powered trial in which 2316 patients were randomly allocated to receive either intravenous magnesium sulphate or placebo for 24 h, beginning with a loading dose at a median of 3 h from symptom onset and before the onset of action of any concurrent thrombolytic treatment. Mortality at 28 days was reduced by 24% (95% confidence interval 1-43%, P=0.04) in the magnesium group and the occurrence of early left ventricular failure by 25% (7-39%, P=0.009).
15. ISIS-4 (Fourth International Study of Infarct Survival) Collaborative Group: 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, 345:669-685. The factorial design of this mega-trial allowed three treatments to be assessed separately for their effect on mortality. The comparison group for magnesium was an open-control, rather than a placebo-treated, group. The assessments of endpoints other than mortality (e.g. heart failure) are therefore vulnerable to reporting bias. There was a small mortality reduction with captopril but none for magnesium or mononitrate. Of the patients entering the trial, 70% had had preceding thrombolytic treatment; the interval between thrombolysis and randomization was not recorded but is likely to have been typically 3 h or more from indirect evidence of time from symptom onset. The 30% of non-thrombolysed patients were randomly allocated at a median of 12 h from onset.
16. Yusuf S, Collins R, Peto R: Why do we need some large, simple randomized trials? Stat Med 1984, 3:409-420. This influential paper presents the case for large, simple randomized trials of the effects on mortality of widely practicable treatments of common conditions and the added benefits of a factorial design. The potential difficulty of generalizing the results to important clinical subgroups is raised in discussion by Ederer and Feinstein.
17. Shechter M, Hod H, Chouraqui P, Kaplinsky E, Rabinowitz B: Magnesium therapy in acute myocardial infarction when patients are not candidates for thrombolytic therapy. Am J Cardiol 1995, 75:321-323.
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19. Yusuf S, Peto R, Lewis J, Collins R, Sleight P: Beta blockade during and after myocardial infarction: an overview of the randomized trials. Prog Cardiovasc Dis 1985, 27:335-371. This important and widely cited review sets out the case for pooled analysis of all accessible trials that can be considered to address a single therapeutic question. The approach is used here to assess the efficacy of β-blockade in reducing mortality acutely and in the long term after myocardial infarction, drawing on evidence from some 50 trials.
20. Woods KL: Mega-trials and the management of acute myocardial infarction. Lancet 1995, 346:611-614.
21. du Toit EF, Opie LH: Modulation of severity of reperfusion stunning in the isolated rat heart by agents altering calcium flux at onset of reperfusion. Circ Res 1992, 70:960-967.
22. Herzog WR, Atar D: Magnesium and myocardial infarction. Lancet 1994, 343:1285-1286.
23. Atar D, Serebruany V, Poulton J, Godard J, Schneider A, Herzog WR: Effects of magnesium supplementation in a porcine model of myocardial ischemia and reperfusion. J Cardiovasc Pharmacol 1994, 24:603-611.
24. Herzog WR, Schlossberg ML, MacMurdy KS, Edenbaum LR, Gerber MJ, Vogel RA, et al.: Timing of magnesium therapy affects experimental infarct size. Circulation 1995, 92:2622-2626. This paper provides clear experimental evidence that myocardial protection by magnesium occurs during the narrow time-window of early reperfusion, using an in-vivo porcine model of temporary coronary occlusion.