Weighting composite endpoints in clinical trials: essential evidence for the heart team

Abstract

Background: Coronary revascularization trials often use a composite endpoint of major adverse cardiac and cerebrovascular events (MACCE). The usual practice in analyzing data with a composite endpoint is to assign equal weights to each of the individual MACCE elements. Noninferiority margins are used to offset effects of presumably less important components, but their magnitudes are subject to bias. This study describes the relative importance of MACCE elements from a patient perspective.

Methods: A discrete choice experiment was conducted. Survey respondents were presented with a scenario that would make them eligible for the Synergy Between Percutaneous Coronary Intervention With Taxus and Cardiac Surgery (SYNTAX) trial three-vessel disease cohort. Respondents chose among pairs of procedures that differed on the 3-year probability of MACCE, potential for increased longevity, and procedure/recovery time. Conjoint analysis derived relative weights for these attributes.

Results: In all, 224 respondents completed the survey. The attributes did not have equal weight. Risk of death was most important (relative weight 0.23), followed by stroke (0.18), potential increased longevity and recovery time (each 0.17), myocardial infarction (0.14), and risk of repeat revascularization (0.11). Applying these weights to the SYNTAX 3-year endpoints resulted in a persistent, but decreased margin of difference in MACCE favoring coronary artery bypass graft surgery compared to percutaneous coronary intervention. When labeled only as "procedure A" and "procedure B," 87% of respondents chose coronary artery bypass graft surgery over percutaneous coronary intervention. When procedures were labeled as "coronary stent" and "coronary bypass surgery," only 73% chose coronary artery bypass graft surgery. Procedural preference varied with demographics, sex, and familiarity with the procedures.

Conclusions: The MACCE elements do not carry equal weight in a composite endpoint, from a patient perspective. Using a weighted composite endpoint increases the validity of statistical analyses and trial conclusions. Patients are subject to bias by labels when considering coronary revascularization.