My concern with this study lies with a noninferiority comparison using a composite primary endpoint that combines both efficacy (ischemic event) and safety (bleeding event) measures. Although this type of endpoint is selected to enhance power, it is problematic because of a lack of actual or expected concordance among its components. When concordant differences are present, the individual components lack power to determine if clinically meaningful differences exist.
In OPTIMIZE, a 10%-14% relative increase in ischemic events with 3 months of DAPT is counterbalanced by a 12% relative decrease in major bleeding. A counterbalance in relationship is graphically depicted in the analysis of stent thrombosis and major bleeding, with a 90-day landmark. Beyond 90 days, the absolute increase in events is 0.2% for both, which represents a fourfold relative increase in stent thrombosis with 3 months of DAPT and a twofold relative increase in major bleeding with longer therapy.
Indeed, the upper boundaries of the confidence intervals allow for a 35-fold increase in stent thrombosis with short treatment and an eightfold increase in major bleeding with longer therapy. This observation must be viewed in the context that OPTIMIZE excluded biomarker-positive acute coronary syndrome (ACS) within 30 days – those patients at greatest risk for stent thrombosis – and included subjects with an average age of 61 years – patients with a lower risk of bleeding events.
The exclusion of biomarker-positive ACS represents a significant portion of contemporary clinical practice, particularly in the context of relative efficacy for PCI and ACS vs. stable ischemic heart disease. Although the choice of clopidogrel vs. novel agents may be justified by exclusion of biomarker-positive ACS, the loading dose was not standardized by protocol. Finally, the Endeavor stent platform is problematic and difficult to extrapolate to other drug-eluting stents. Endeavor has largely been replaced by Resolute, which has a different polymer and drug-release kinetics.
More definitive conclusions about optimal DAPT duration still await the results of adequately powered, more inclusive, and contemporary randomized controlled trials.
Dean J. Kereiakes, M.D., is an interventional cardiologist at the Ohio Heart and Vascular Center, Cincinnati. These are excerpts of his remarks as discussant of the study at the meeting. Dr. Kereiakes reported financial associations with Medpace, HCRI, and other companies.
