Program

Lecture Abstract：
CYP2C19 pharmacogenomics is a major determinant of interindividual response to clopidogrel, an oral P2Y12 inhibitor requiring hepatic bioactivation. Loss-of-function alleles, particularly CYP2C19*2 and *3, reduce active-metabolite exposure, increase on-treatment platelet reactivity, and attenuate protection against ischemic events. Their high prevalence in East Asian populations makes genotype-guided treatment especially relevant to stroke practice. Ticagrelor directly inhibits P2Y12, whereas prasugrel undergoes more efficient activation; neither is meaningfully dependent on CYP2C19, although prasugrel is contraindicated after stroke or transient ischemic attack and ticagrelor increases minor bleeding and dyspnea. In CHANCE-2, ticagrelor-aspirin reduced 90-day stroke compared with clopidogrel-aspirin among Chinese loss-of-function carriers with minor stroke or high-risk transient ischemic attack (6.0% versus 7.6%; hazard ratio, 0.77), without increasing moderate or severe bleeding, although overall bleeding increased. A prespecified 2025 INSPIRES analysis extended this concept to delayed presentation: among 5,003 patients treated 24 to 72 hours after onset, clopidogrel-aspirin reduced new stroke in noncarriers (hazard ratio, 0.67) but not carriers (hazard ratio, 0.96); however, the genotype-treatment interaction was not statistically significant. Coronary evidence similarly supports alternative P2Y12 inhibition for intermediate and poor metabolizers after acute coronary syndrome or percutaneous coronary intervention, while preserving clopidogrel for noncarriers may limit bleeding and cost. Guidance is evolving: the 2024 American Heart Association statement most strongly supports testing in acute coronary syndrome or percutaneous coronary intervention and considers testing potentially beneficial in selected East Asian stroke populations, whereas the 2026 UK CERSI-PGx guideline recommends testing all patients considered for clopidogrel where available and avoiding clopidogrel in intermediate or poor metabolizers. Successful implementation requires rapid turnaround, multidisciplinary ownership, clinician education, and electronic health-record decision support. CYP2C19-guided P2Y12 selection therefore offers a rational precision strategy, but broader validation across ancestries, stroke mechanisms, severities, and treatment windows remains essential. Clinical significance of CYP2C19*17, rare variants, drug interactions, cost-effectiveness, and access remains uncertain.