Braunwald, E., Cannon, C. P., McCabe, C. H. Use of composite endpoints in thrombolysis trials of acute myocardial infarction American journal of cardiology. 1993;72(19):G3-G12.

Although preventing early mortality following acute myocardial infarction (MI) is the most important goal of thrombolytic therapy, insistence on its use as the only or principal endpoint in trials of acute MI will limit the number of new thrombolytic-antithrombotic regimens that can be tested, and thus may inhibit future progress of this important area of cardiovascular therapeutics. Trials of thrombolytic therapy over the past decade, as discussed in this article, have demonstrated that: (1) thrombolytic therapy improves both mortality and intermediate endpoints, and (2) intermediate nonfatal endpoints are strongly linked to long-term mortality. Taken together, these facts provide strong evidence that intermediate nonfatal events can be used as valid endpoints in future trials of thrombolytic therapy. The unsatisfactory outcome composite endpoint, which incorporates mortality and important intermediate endpoints, will make it possible to compare innovative new regimens in much smaller trials. Ultimately, both of these approaches (i.e., megatrials using a mortality endpoint and smaller trials utilizing a composite unsatisfactory outcome endpoint) can be used in a complementary fashion. A new regimen could first be tested using the unsatisfactory outcome endpoint; if it showed particular promise, it could then become a candidate for testing in a megatrial. Conversely, if it did not prove better than standard regimens, futile research in tens of thousands of patients might be prevented. Thus, the use of composite endpoints will expand the number of new thrombolytic-antithrombotic regimens that can be tested and, it is hoped, accelerate progress in the treatment of acute MI.

Trial: TIMI 4