Abstract 37: Secondary Stroke Prevention With Aspirin and Clopidogrel in CYP2C19 *17 Carriers Increases Risk of Major Non-CNS Bleeding

Combination aspirin and clopidogrel reduces risk of recurrent ischemic stroke, but was also associated with risk of non-central nervous system (CNS) major bleeding in the Platelet-Oriented Inhibition in New TIA or minor stroke clinical trial. The loss-of-function CYP2C19*2 allele potentially reduces clopidogrel efficacy, while the gain-of-function CYP2C19*17 allele may increase bleeding risk. The clinical application of these alleles is unclear. SNP genotyping of CYP2C19*2 and CYP2C19*17 are available in the Secondary Prevention of Small Subcortical Strokes clinical trial, a 2x2 factorial study in patients with lacunar infarcts where one arm tested the efficacy of secondary stroke prevention with aspirin plus clopidogrel versus aspirin alone. We hypothesized that patients carrying CYP2C19*2 would have more clopidogrel failure events (defined as a composite of ischemic stroke, transient ischemic attack, and cognitive decline), while patients carrying at least one CYP2C19*17 allele, would have more major bleeding, including sub-analysis of CNS and non-CNS major bleeding. The associations of CYP2C19*2 with treatment failure and CYP2C19*17 with major bleeding were assessed through logistic regression, adjusting for age, gender, race, and excluding CYP2C19*2/*17 carriers. The mean age of the cohort (n=522) was 62 (62% male). There were no significant differences in treatment failure events between *2 carriers and *2 non-carriers (Odds ratio (OR) [95% confidence interval (CI)] = 1.60 [0.66-3.87], p-value=0.29), adjusting for *17. Patients with a *17 allele had a significantly higher odds of a non-CNS hemorrhage (OR [95% CI] =2.50 [1.03-6.09], p-value=0.043), and a trend for significance after adjusting for *2, p-value=0.06. Only two CNS hemorrhages occurred in the total cohort; both occurred in normal CYP2C19 metabolizers. Although limited by sample size, the study suggests that CYP2C19 carrier status may contribute to non-CNS major bleeding risks seen in dual antiplatelet therapy secondary stroke prevention trials. Further studies are needed to confirm whether the presence of CYP2C19*17 or absence of *2 increases the risk of bleeding complications, which could have implications for treatment decisions in a precision medicine approach.