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

Abstract

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 aspirintreated (81 or 325 mg for Ն3 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 24.8Ϯ0.3 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 Ͻ65 seconds, was associated with major adverse cardiovascular events (Pϭ0.0149). After adjustment for covariables (including sex, aspirin dose, Thrombolysis in Myocardial Infarction risk score, clopidogrel use), both serum thromboxane B 2 Ͼ3.1 ng/mL and PFA-100 collagen-ADP CT Ͻ65 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 acidstimulated 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.)

Oxylipid Profile of Low‐Dose Aspirin Exposure: A Pharmacometabolomics Study

“…We also observed higher levels of 5‐LOX products (namely, the eicosapentaenoic acid–derived 5S‐HEPE, the LA‐derived 9‐HODE, the AA‐derived 5‐HETE, and the α‐linolenic acid–derived 9‐HOTrE) in women. This is in accordance with previous findings that androgens downregulate 5‐LOX product formation 9, 10, 37, 38. Most of these constitutive differences in oxylipid levels persisted after aspirin treatment and no sex‐specific effect of aspirin on oxylipid was observed, consistent with our previous findings in this population 4, 9, 11, 12, 39…”

“…The mechanisms underlying variability in aspirin response are poorly understood. Incomplete COX‐1 inhibition has been observed in several settings;9, 10 however, poor response despite complete COX‐1 inhibition has also been reported 9, 11…”

Impact of Platelet Reactivity on Long-term Clinical Outcomes and Bleeding Events in Japanese Patients Receiving Antiplatelet Therapy with Aspirin

“…In the present study, a low response to aspirin was not associated with MACCEs in the overall patient group; however, subgroup analysis showed that a low response to aspirin was an independent predictor of long-term MACCEs in patients less than 70 years old (RR, 2.58; 95% CI: 1.04-6.28; p = 0.041). In fact, the patients in previous studies [23][24][25][26][27][28] who had a low response to aspirin associated with a poor clinical outcome were younger than the patients in this study. It could be speculated that the low response to aspirin is a risk factor of MACCEs in patients in this age criteria.…”

“…Because in previous studies patients showing an association of a low response to aspirin with a poor clinical outcome were much younger (age of low responders; 59±15 years, 63.8±10.8 years, and 58.7 ±12.4 years) [23][24][25] than in this study (age of low responders; 69.2±8.0 years), we performed subgroup analyses of patients who were ＜70 years old and ≥ 70 years old at enrollment.…”

MiR‐21 role in aspirin‐dependent PPARα and multidrug resistance protein 4 upregulation

“…Importantly, emerging studies support an association between high on‐aspirin treatment residual platelet reactivity and adverse clinical outcomes in patients with cardiovascular and cerebrovascular disease 26, 27, 28, 29…”