LETTER
Megatrials for Clinical Decision Making
Heather L. Horton, MD, PhD
1 October 1996 | Volume 125 Issue 7 | Page 621
TO THE EDITOR:
In their article on meta-analyses, Borzak and Ridker [1] comment on a perplexing issue. Why did a reasonably large trial (LIMIT-2 [Second Leicester Intravenous Magnesium Intervention Trial]) [2] show a therapeutic benefit for magnesium in patients who had had acute myocardial infarction when a megatrial (ISIS-4 [Fourth International Study of Infarct Survival]) [3] did not? If the difference is the timing with which the drug was given, another trial can be done. If the results of LIMIT-2 were wrong, however, and magnesium has no benefit in the treatment of acute myocardial infarction under any circumstances, some serious questions must be asked about the sample sizes needed to correctly determine therapeutic efficacy. All of the trials discussed by Borzak and Ridker are in the field of cardiology, where trials enrolling tens of thousands of patients are becoming increasingly common.
LIMIT-2 was a randomized, double-blind trial of 2316 patients. In any other specialty, this trial would be considered very large. If this sample size is inadequate, how are we to conduct trials to evaluate diseases less common than acute myocardial infarction? In many cases, it would be impossible to enroll 10 000 patients in a reasonable time frame. Should multiple trials be done for all therapies? If 10 000 patients are required to show a treatment effect, is this effect clinically relevant? If megatrials are required for every therapy or alteration in therapy, evidence-based medicine may be facing serious difficulties.
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Author and Article Information
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Lankenau Hospital, Wynnewood, PA 19086
1. Borzak S, Ridker PM. Discordance between meta-analyses and large-scale randomized, controlled trials. Examples from the management of acute myocardial infarction. Ann Intern Med. 1995; 123:873-7.
2. Woods KL, Fletcher S, Roffe C, Haider Y. Intravenous magnesium sulfate in suspected acute myocardial infarction: results of the second Leicester Intravenous Magnesium Intervention Trial (LIMIT-2). Lancet. 1992; 339:1553-8.
3. ISIS-4: a randomized factorial trial assessing early oral captopril, oral mononitrate, and intravenous magnesium sulfate in 58,050 patients with suspected acute myocardial infarction. ISIS-4 (Fourth International Study of Infarct Survival) Collaborative Group. Lancet. 1995; 345:669-85.
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