Association of Cyclooxygenase-1-Dependent and -Independent Platelet Function Assays With Adverse Clinical Outcomes in Aspirin-Treated Patients Presenting for Cardiac Catheterization

Background-Poor clinical outcome in aspirin-treated patients has been termed aspirin resistance and may result from inadequate inhibition of platelet cyclooxygenase-1 (COX-1) by aspirin. The objectives of this study were to determine prospectively whether COX-1-dependent and other platelet function assays correlate with clinical outcomes in aspirin-treated patients. Methods and Results-Blood was collected before percutaneous coronary intervention from 700 consecutive aspirin-treated (81 or 325 mg for >= 3 days) patients. Platelet function was tested by (1) serum thromboxane B(2); (2) arachidonic acid-stimulated platelet surface P-selectin and activated glycoprotein IIb/IIIa and leukocyte-platelet aggregates; and (3) platelet function analyzer (PFA)-100 collagen-epinephrine and collagen-ADP closure time (CT). Adverse clinical outcomes of all-cause death, cardiovascular death, and major adverse cardiovascular events (cardiovascular death, myocardial infarction, hospitalization for revascularization, or acute coronary syndrome) were assessed by telephone interview and/or medical record review. Clinical outcomes information was obtained at 24.8 +/- 0.3 months after platelet function testing. By univariate analysis, COX-1-dependent assays, including serum thromboxane B(2) level, were not associated with adverse clinical outcomes, whereas the COX-1-independent assay, PFA-100 collagen-ADP CT < 65 seconds, was associated with major adverse cardiovascular events (P = 0.0149). After adjustment for covariables (including sex, aspirin dose, Thrombolysis in Myocardial Infarction risk score, clopidogrel use), both serum thromboxane B(2) > 3.1 ng/mL and PFA-100 collagen-ADP CT < 65 seconds were associated with major adverse cardiovascular events. In contrast, indirect measures of platelet COX-1 (arachidonic acid-stimulated platelet markers, shortened PFA-100 collagen-epinephrine CT) were not significantly associated with adverse clinical outcomes even after adjustment for covariables. Conclusions-In this prospective study of 700 aspirin-treated patients presenting for angiographic evaluation of coronary artery disease, residual platelet COX-1 function measured by serum thromboxane B(2) and COX-1-independent platelet function measured by PFA-100 collagen-ADP CT, but not indirect COX-1-dependent assays (arachidonic acid-stimulated platelet markers, shortened PFA-100 collagen-epinephrine CT), correlate with subsequent major adverse cardiovascular events. This study suggests that multiple mechanisms, including but not confined to inadequate inhibition of COX-1, are responsible for poor clinical outcomes in aspirin-treated patients, and therefore the term aspirin resistance is inappropriate. (Circulation. 2009;120:2586-2596.)