Evaluation of CYP2C19 Genotype-Guided De-Escalation of P2Y12 Antiplatelet Agents in Patients After a Percutaneous Coronary Intervention in a Real-World Setting

The P2Y₁₂ inhibitor clopidogrel is a prodrug that is bioactivated by the hepatic CYP2C19 enzyme to form its active metabolite and exert its antiplatelet effects. Up to 30% of the US population carry a CYP2C19 nonfunctional genetic variant that reduces clopidogrel’s antiplatelet effects and clinical effectiveness in patients undergoing a percutaneous coronary intervention (PCI) procedure. Genotyping has become a useful strategy for prescribers to more precisely guide P2Y₁₂ inhibitor therapy choice after PCI. To lessen bleeding risk and cost, some patients may need to switch from the more potent prasugrel and ticagrelor after the early post-PCI period to the less potent clopidogrel, which is defined as de-escalation of P2Y₁₂ inhibitor therapy. However, use of CYP2C19 genotyping to guide de-escalation of P2Y₁₂ inhibitor therapy after PCI has not been studied extensively in a real-world population. In this observational study, we explored how genotype-guided de-escalation is performed in a real-world population and its effect on ischemic and bleeding outcomes. Among patients initiated on prasugrel/ticagrelor, approximately 23% were de-escalated to clopidogrel, and the majority of patients were ultrarapid metabolizers (UM), rapid metabolizers (RM), or normal metabolizers (NM). Compared to patients continued on prasugrel or ticagrelor, UM/RM/NM patients de-escalated to clopidogrel exhibited no significant difference in the composite of major atherothrombotic events (MAE) or major bleeding events (12.2 vs 15.2 events per 100 patient-years, respectively; adjusted HR 0.65, 95% CI 0.38-1.11, p=0.11). There was also no significant difference in either MAE (adjusted HR 0.69, 95% CI 0.37-1.28, p=0.23) or major bleeding (adjusted HR 0.57, 95% CI 0.23-1.43, p = 0.23) between patients continued on prasugrel or ticagrelor and UM/RM/NM patients de-escalated to clopidogrel. However, there was a statistically significant decrease in clinically significant bleeding events in UM/RM/NM patients de-escalated to clopidogrel compared to those continued on prasugrel/ticagrelor (6.2 vs 15.1 events per 100 patient-years, respectively; adjusted HR 0.37, 95% CI 0.18-0.75, p = 0.006).  Collectively, these data suggest that CYP2C19 genotype-guided de-escalation of P2Y₁₂ inhibitor therapy appears to be a feasible, safe, and effective strategy associated with lower clinically significant bleeding risk for PCI patients in a real-world clinical setting. Validation in a larger multicenter study is needed.