Lessons from “an effective, safe, simple” intervention that wasn't

A meta-analysis of treatments in myocardial infarction published in 1992 retrospectively showed that streptokinase was associated with a highly significant fall in mortality by 1977, after inclusion of 15 trials.1 Thrombolysis was, however, not widely recommended until 10 years later—after the effect was confirmed in two mega trials.1 2 3 In the case of magnesium, a substantial fall in mortality was evident by 1990, after inclusion of seven trials. In 1993, based on an updated meta-analysis it was argued that magnesium treatment represented an “effective, safe, simple and inexpensive” intervention that should be introduced into clinical practice without further delay.4 The negative results of ISIS 4 (the fourth international study of infarct survival), published in last week's Lancet,5 have dealt a blow to enthusiasm for both magnesium and meta-analysis.6 As the findings of meta-analyses and systematic reviews are generally not tested in mega trials the situation regarding magnesium represents an opportunity to examine a false positive meta-analysis.

The table compares the meta-analyses of trials of magnesium and streptokinase after myocardial infarction. Trials were cumulatively included until the treatment effect was significant at P<0.001. For magnesium, seven small trials whose results were published in the 1980s were sufficient to establish the effect. Although trials were larger in the case of fibrinolytic treatment, twice as many studies and two decades were necessary to reach the same level of significance. Until recently it could …