In patients undergoing percutaneous coronary intervention (PCI), the standard of care is dual antiplatelet therapy with a P2Y 12 inhibitor (clopidogrel, prasugrel, or ticagrelor) and aspirin. Current clinical practice guidelines now recommend more potent P2Y 12 inhibitors (prasugrel or ticagrelor) over clopidogrel in acute coronary syndrome (ACS). However, clopidogrel remains the most commonly prescribed P2Y 12 inhibitor in the setting of PCI and is also the preferred agent in the treatment and secondary prevention of stroke. Clopidogrel is a prodrug that requires bioactivation by the CYP2C19 enzyme. It has been shown that clopidogrel use in patients who are CYP2C19 no function allele carriers are associated with impaired antiplatelet inhibition and a higher risk of major adverse cardiovascular and cerebrovascular events. Compared to clopidogrel, prasugrel and ticagrelor clinical response is not impacted by CYP2C19 genotype. Even with a demonstrated increased risk of adverse outcomes in CYP2C19 no function allele carriers treated with clopidogrel, routine implementation of CYP2C19 genotyping to guide antiplatelet therapy selection has remained controversial and has not been widely adopted. Recent results from multiple prospective randomized and nonrandomized clinical trials investigating the use of CYP2C19 genotypeguided antiplatelet therapy following PCI have advanced the evidence base demonstrating the clinical utility of this strategy. Multiple recent studies have examined the effects of CYP2C19 genotype on clopidogrel outcomes in the setting of stroke and neurointerventional procedures. In this review, we discern the clinical utility of using CYP2C19 genotype testing to guide antiplatelet therapy prescribing by evaluating the impact of CYP2C19 genotypeguided selection of antiplatelet therapy on clinical outcomes, summarizing emerging data from cardiovascular and neurology clinical studies, and discussing implications for clinical practice guidelines, remaining knowledge gaps and future research directions.

The Age, Body mass index, Chronic kidney disease, Diabetes mellitus, and CYP2C19 GENEtic variants (ABCD‐GENE) score was developed to identify patients at risk for diminished antiplatelet effects with clopidogrel after percutaneous coronary intervention (PCI). The objective of this study was to validate the ability of the ABCD‐GENE score to predict the risk for atherothrombotic events in a diverse, real‐world population of clopidogrel‐treated patients who underwent PCI and received clinical CYP2C19 genotyping to guide antiplatelet therapy. A total of 2,341 adult patients who underwent PCI, were genotyped for CYP2C19, and received treatment with clopidogrel across four institutions were included (mean age 64 ± 12 years, 35% women, and 20% Black). The primary outcome was major atherothrombotic events, defined as the composite of all‐cause death, myocardial infarction, ischemic stroke, stent thrombosis, or revascularization for unstable angina within 12 months following PCI. Major adverse cardiovascular events (MACE), defined as the composite of cardiovascular death, myocardial infarction, ischemic stroke, or stent thrombosis, was assessed as the secondary outcome. Outcomes were compared between patients with an ABCD‐GENE score ≥ 10 vs. < 10. The risk of major atherothrombotic events was higher in patients with an ABCD‐GENE score ≥ 10 (n = 505) vs. < 10 (n = 1,836; 24.6 vs. 14.7 events per 100 patient‐years, adjusted hazard ratio (HR) 1.66, 95% confidence interval (CI), 1.23–2.25, P < 0.001). The risk for MACE was also higher among patients with a score ≥ 10 vs. < 10 (16.7 vs. 10.1 events per 100 patient‐years, adjusted HR 1.59, 95% CI 1.11–2.30, P = 0.013). Our diverse, real‐world data demonstrate diminished clopidogrel effectiveness in post‐PCI patients with an ABCD‐GENE score ≥ 10.

Study Objective: To compare the clinical effectiveness of genotype-guided P2Y12 inhibitor selection following PCI in older patients (≥70 years) and younger patients (<70 years). Design and Setting: Single-center, retrospective, cohort study. Risk of major adverse cardiovascular or cerebrovascular events (MACCE), defined as stent thrombosis, ischemic stroke, transient ischemic attack, non-fatal acute coronary syndrome, or cardiovascular death during 12 months after PCI, was compared across genotype and antiplatelet therapy groups by proportional hazards regression in patients ≥70 years and <70 years. Patients: 1,469 patients who underwent PCI and had CYP2C19 genotype testing at a single academic medical center. Measurements and Main Results:The study population was comprised of 402 (27.4%) ≥70 years (older group) and 1067 (72.6%) <70 years (younger group). Alternative P2Y12 inhibitors (prasugrel or ticagrelor) were used less often in the older group than the younger group in patients with a CYP2C19 no function allele (55% vs. 67%; p = 0.02) and in patients without a no function allele (10% vs. 35%, p < 0.001). For patients treated with clopidogrel, MACCE was significantly higher in no function allele carriers compared to those without a no function allele in the older group (19.2% vs. 12.7%; adjusted HR 2.32; 95% CI 1.07-5.05; p = 0.03) and the younger group (17.4% vs. 10.4%; adjusted HR 2.01; 95% CI 1.17-3.46; p = 0.01). In patients without a no function allele, MACCE risk was similar with clopidogrel compared to prasugrel or ticagrelor in the older group (adjusted HR 0.99; 95% CI 0.44-2.21; p = 0.98) and the younger group (adjusted HR 1.12; 95% CI 0.72-1.74; p = 0.61). Conclusion:This study suggests important clinical benefits of CYP2C19 genotypeguided antiplatelet therapy after PCI in both younger and older patients.

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