First Analysis of the Relation Between CYP2C19 Genotype and Pharmacodynamics in Patients Treated With Ticagrelor Versus ClopidogrelClinical Perspective: The ONSET/OFFSET and RESPOND Genotype Studies

Background— The influence of cytochrome P450 (CYP) 2C19 genotype on platelet function in patients treated with ticagrelor versus clopidogrel is unknown. Methods and Results— CYP2C19 (*1, *2, *3, *4, *5, *6, *7, *8, *17) genotyping was performed in patients with coronary artery disease treated with ticagrelor (180-mg load, 90 mg BID) (n=92) or clopidogrel (600-mg load, 75 mg/d) (n=82). All patients received 75 to 100 mg/d aspirin. Platelet function was measured by aggregometry, VerifyNow P2Y12 assay, and vasodilator-stimulated phosphoprotein-phosphorylation assay at predose, 8 hours postloading, and maintenance. In each treatment group, patients were categorized according to 2C19 genotype carrier status (loss-of-function, gain-of-function) and metabolizer status. Kruskal-Wallis test was used to compare platelet function among these categories for each treatment, and Wilcoxon rank sum test was used to compare platelet function between the clopidogrel and ticagrelor groups for each category. There was no statistically significant influence of genotype on platelet function during aspirin therapy alone. Ticagrelor exhibited lower platelet reactivity than clopidogrel by all assays irrespective of 2C19 genotype or metabolizer status ( P Conclusions— This report is the first to demonstrate the superior pharmacodynamic effect of ticagrelor compared with clopidogrel irrespective of CYP2C19 genotype. Whereas CYP2C19 genotype influenced the antiplatelet effect of clopidogrel, there was no effect of CYP2C19 genotype during ticagrelor therapy. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifiers: NCT00642811 and NCT00528411.