Re-Thinking Composite Endpoints in Clinical Trials: Insights from Patients and Trialists
Background—Many clinical trials use composite endpoints to reduce sample size, but the relative importance of each individual endpoint within the composite may differ between patients and researchers.
Methods and Results—We asked 785 cardiovascular patients and 164 clinical trial authors to assign 25 "spending weights" across 5 common adverse events comprising composite endpoints in cardiovascular trials: death, myocardial infarction (MI), stroke, coronary revascularization, and hospitalization for angina. We then calculated endpoint ratios ("ratios") for each participant's ratings of each nonfatal endpoint relative to death. Whereas patients assigned an average weight of 5 to death, equal or greater weight was assigned to MI (mean ratio 1.12) and stroke (ratio 1.08). In contrast, clinical trialists were much more concerned about death (average weight of 8) than MI (ratio 0.63) or stroke (ratio 0.53). Both patients and trialists considered revascularization (ratios 0.48 and 0.20, respectively) and hospitalization (ratios 0.28 and 0.13, respectively) as substantially less severe than death. Differences between patient and trialist endpoint weights persisted after adjustment for demographic and clinical characteristics (p<0.001 for all comparisons).
Conclusions—Neither patients nor clinical trialists weigh individual components of a composite endpoint equally. While trialists are most concerned about avoiding death, patients place equal or greater importance on reducing MI or stroke. Both groups considered revascularization and hospitalization as substantially less severe. These findings suggest that equal weights in a composite clinical endpoint do not accurately reflect the preferences of either patients or trialists.
- Received September 30, 2013.
- Revision received July 19, 2014.
- Accepted August 6, 2014.