Shift from surrogate end point to outcome trials: implications for cardiovascular safety assessment in development programs for antidiabetic drugs.

We assessed the effect of extending the range of cardiovascular (CV) end points to include hospitalization for unstable angina and hospitalization for coronary revascularization (Extended Major Adverse Cardiac Event criteria (MACE)) in addition to the standard ones, namely, CV-related death, nonfatal stroke, and nonfatal myocardial infarction (Core MACE). The trials selected for the analysis had a duration/follow-up period of ≥1 year and involved more than 1,000 subjects. Annual event rates (AERs) for Core MACE in patients with type 2 diabetes were estimated, and the duration of an event-driven CV outcome trial necessary to exclude ≥80% risk increase was modeled. All the studies revealed hazard ratios ≤1.0 for Core MACE end points whereas in 21% of the studies, the hazard ratio for hospitalization for unstable angina or coronary revascularization (Extended MACE) was >1 and was therefore discordant with Core MACE. The AERs for Core MACE ranged from 0.5% (recent clinical programs) to 6% (epidemiological studies); these low rates observed in recent programs would have the effect of increasing the duration required for a CV outcome trial. The addition of Extended MACE end points to the primary composite outcome in antidiabetic clinical trials is unlikely to obscure CV-related risk and may improve the feasibility of CV outcome trials.