Impact of CYP2C19 and CYP3A4 Inhibitor Use on Clopidogrel Clinical Effectiveness in CYP2C19 Genotyped Patients Undergoing Percutaneous Coronary Intervention

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  Figure 1. Summary of CYP2C19 or CYP3A4 inhibitor use in the study population. (a) The study population was stratified by P2Y12 inhibitor antiplatelet therapy and CYP2C19 genotype‐predicted phenotype. Patients in each subgroup were further categorized based on inhibitor use (yes vs. no) status. CYP2C19, cytochrome P450 2C19 enzyme. IM, intermediate metabolizer; NM, normal metabolizer; PM, poor metabolizer; RM, rapid metabolizer; UM, ultrarapid metabolizer. (b) Frequency of CYP2C19 or CYP3A4 moderate/strong inhibitor co‐prescribing with a P2Y12 inhibitor. Less commonly prescribed inhibitors (frequency <0.5%) aggregated in Other* include erythromycin (0.4%), verapamil (0.3%), imatinib (0.1%), clarithromycin (0.09%), ritonavir (0.09%), dronedarone (0.06%), fluvoxamine (0.06%), cobicistat (0.03%), and nefazodone (0.03%). The enzyme inhibited by each is summarized in Table S2 .

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  Figure 2. Time‐to‐cardiovascular clinical outcomes by CYP2C19/CYP3A4 Inhibitor Use Status. Kaplan–Meier curve for (a) major atherothrombotic events (MAE) and (b) major adverse cardiovascular events (MACE) over 12 months after the index percutaneous coronary intervention (PCI) among clopidogrel‐treated CYP2C19 normal, rapid, and ultrarapid metabolizers (NM/RM/UM) by inhibitor use status: CYP2C19 or CYP3A4 Inhibitor vs. No Inhibitor. The unadjusted log‐rank P‐value for each curve is presented. The tails of the Kaplan–Meier curves in panels (a) and (b) were truncated at 360 days after the index PCI. The Inhibitor group (red) had no events that occurred after day 360, when 19 patients were still in follow‐up. The No Inhibitor group (black) had n = 4 events that occurred after day 360, when 264 patients were still in follow‐up.

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  Figure 3. Time‐to‐major atherothrombotic events (MAE) by CYP2C19 inhibitor or CYP3A4 inhibitor use status. Kaplan–Meier curve for MAE over 12 months after the index percutaneous coronary intervention (PCI) among clopidogrel‐treated CYP2C19 normal, rapid, and ultrarapid metabolizers (NM/RM/UMs) by inhibitor use status: CYP2C19 Inhibitor vs. CYP3A4 Inhibitor vs. No Inhibitor. The tails of the Kaplan–Meier curves were truncated at 360 days after the index PCI. The CYP2C19 Inhibitor and CYP3A4 Inhibitor groups had no events that occurred after day 360, with 4 and 15 patients still in follow‐up, respectively. In the No inhibitor group, n = 4 events occurred after day 360, when 264 patients were still in follow‐up. The multivariable model was stratified by site and ACS indication for PCI, and were adjusted for age, sex, self‐reported Black or African American race, obesity, dyslipidemia, stroke/TIA, and β‐blocker use. Baseline characteristics are described in Table S4 .

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  Figure 4. Time‐to‐major atherothrombotic events (MAE) by Proton Pump Inhibitor (PPI) Use Status. Kaplan–Meier curve for MAE over 12 months after the index percutaneous coronary intervention (PCI) among clopidogrel and PPI‐treated CYP2C19 normal, rapid, and ultrarapid metabolizers (NM/RM/UMs) by PPI use status: Omeprazole/esomeprazole vs. Other PPIs vs. No PPI. The tails of the Kaplan–Meier curves were truncated at 360 days after the index PCI. The Omeprazole/esomeprazole and Other PPIs groups had no events that occurred after day 360, when 49 and 50 patients were still in follow‐up, respectively. In the No PPI group, n = 4 events occurred after day 360, when 184 patients were still in follow‐up. The multivariable model was stratified by site and ACS indication for PCI, and was adjusted for age, sex, self‐reported Black or African American race, current smoker, Hispanic ethnicity, dyslipidemia, diabetes, prior MI, prior revascularization, stroke/TIA, heart failure, atrial fibrillation, history of GI bleeding or ICH, and CKD. Baseline characteristics were described in Table S5 .