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Clinical Trials

4. Endpoints

Composite Endpoints

While some guidelines—such as the guidance on trial design in the International Conference on Harmonization Guideline for Good Clinical Practice —generally prefer a primary endpoint based on a single outcome that will be defined before the study begins, many recent studies include multiple outcomes as part of a composite endpoint. Exploratory clinical investigations or early-phase studies are more likely to have multiple outcomes, with some of these being developed during the study.

An example of a clinical trial with a composite endpoint of multiple outcomes is the CURE (Clopidogrel in Unstable Angina to Prevent Recurrent Events) study (Yusuf, Zhao, Mehta et al., 2001). This study looked at the effects of clopidogrel in patients with acute coronary syndromes without ST-segment elevation. In this trial, the primary endpoint was a composite of the following clinical outcomes:

  • Death from cardiovascular causes;
  • Stroke; and
  • Nonfatal myocardial infarction.

When multiple outcomes can be experienced by any of the patients it is often best to present both the total number of outcomes per patient and hierarchical counts of outcomes. In the latter, only one outcome can be counted for each patient, and it is usually the most serious outcome that is recorded. The rules for the hierarchy of outcomes are usually established in advance of the trial, with a fatal outcome taking precedence over a nonfatal one. Another way of combining outcomes would be to compare the number of recurrences of identical outcomes, such as the number of seizures experienced by patients with epilepsy during a follow-up period.

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