title: 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.
  
  
  RESULTS
  Blood was collected before percutaneous coronary intervention from 700 consecutive aspirin-treated (81 or 325 mg for > or =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.
authors.affiliation: Division of Hematology/Oncology, Children's Hospital Boston, 300 Longwood Ave., Boston, MA 02115-5737, USA. andrew.frelinger@childrens.harvard.edu
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Frelinger
authors.forename: YouFu
authors.initials: Y
authors.lastname: Li
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Linden
authors.forename: Marc R
authors.initials: MR
authors.lastname: Barnard
authors.forename: Marsha L
authors.initials: ML
authors.lastname: Fox
authors.forename: Douglas J
authors.initials: DJ
authors.lastname: Christie
authors.forename: Mark I
authors.initials: MI
authors.lastname: Furman
authors.forename: Alan D
authors.initials: AD
authors.lastname: Michelson
mesh_terms: D000328:Adult; D001241:Aspirin / Q000627:therapeutic use*; D001792:Blood Platelets / Q000201:enzymology*; D006328:Cardiac Catheterization; D003094:Collagen / Q000097:blood; D003324:Coronary Artery Disease / Q000097:blood / Q000188:drug therapy* / Q000503:physiopathology; D051545:Cyclooxygenase 1 / Q000378:metabolism*; D004351:Drug Resistance / Q000502:physiology; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D019007:P-Selectin / Q000097:blood; D010975:Platelet Aggregation Inhibitors / Q000627:therapeutic use*; D011237:Predictive Value of Tests; D011446:Prospective Studies; D013929:Thromboxane B2 / Q000097:blood; D016896:Treatment Outcome
chemical_list: D019007:P-Selectin; D010975:Platelet Aggregation Inhibitors; D013929:Thromboxane B2; D003094:Collagen; D051545:Cyclooxygenase 1; D001241:Aspirin