Abstract 2129: Polymorphisms Associated With in vitro Aspirin Resistance Are Not Associated With Clinical Outcomes During Regular Aspirin Use
BACKGROUND Numerous genetic variants are associated with heightened in vitro platelet function on aspirin, but their association with future clinical events in patients who regularly use aspirin is unknown. We hypothesized that among patients with CAD who regularly use aspirin, those who carry such variants would be at higher risk for a composite outcome of death, MI, or stroke compared with noncarriers.
METHODS Consecutive patients (n=3,682) with significant CAD (>50% stenosis) at angiography who had DNA banked at the time of angiography as part of an ongoing biorepository at Duke University were followed at six months, then annually after angiography for death, MI, and stroke and for self-reported medication use including, “regular aspirin”. Only events that occurred during periods of reported aspirin use qualified for further analysis. Candidate SNPs (number in parentheses) were selected from the literature from the 9p21 (1) locus and from the following genes: GNB3 (1), HTR2A (1), SELP (1), VAMP8 (1), PEAR1 (1), ITGB3 (1), VAV3 (1), P2RY12 (1), ITGA2 (1), PECAM1 (1), GPVI (1), and GP1BA (1) (average call rate >99%, all in Hardy Weinberg equilibrium). The minor allele for each SNP was tested for its association with the composite outcome in dominant and additive models in a 2:1 test:validation fashion, with adjustment for relevant nongenetic covariates (including race) using Cox proportional hazards modeling.
RESULTS Median follow-up for the 3,682 patients (2,446, test; 1,216, validation) was 5.2 years. During this time 981 (27%) had the composite outcome during a period of reported aspirin use. None of the genotyped SNPs were significantly associated with the primary outcome in either the test cohort (p >0.2) or the combined test and validation cohorts (p >0.3) in any of the models. A post-hoc power analysis demonstrated 80 – 88% power to detect a relative risk of 1.3 or greater for carriers of the minor allele in the combined cohorts.
CONCLUSIONS In this cohort of patients with angiographically significant CAD who reported regular aspirin use, carriers of candidate SNPs associated with in vitro aspirin resistance were not at higher risk for future death, MI, or stroke. Use of these SNPs to guide more aggressive antiplatelet therapy is not justified by these results.