Clinical Outcomes and Sustainability of Using CYP2C19 Genotype-Guided Antiplatelet Therapy After Percutaneous Coronary Intervention

Abstract

Background: CYP2C19 loss-of-function (LOF) alleles impair clopidogrel effectiveness after percutaneous coronary intervention. The feasibility, sustainability, and clinical impact of using CYP2C19 genotype-guided dual antiplatelet therapy (DAPT) selection in practice remains unclear.

Methods: A single-center observational study was conducted in 1193 patients who underwent percutaneous coronary intervention and received DAPT after implementation of an algorithm that recommends CYP2C19 testing in high-risk patients and alternative DAPT (prasugrel or ticagrelor) in LOF allele carriers. The frequency of genotype testing and alternative DAPT selection were the primary implementation end points. Risk of major adverse cardiovascular or cerebrovascular and clinically significant bleeding events over 12 months were compared across genotype and DAPT groups by proportional hazards regression.

Results: CYP2C19 genotype was obtained in 868 (72.8%) patients. Alternative DAPT was prescribed in 186 (70.7%) LOF allele carriers. CYP2C19 testing (P<0.001) and alternative DAPT use in LOF allele carriers (P=0.001) varied over time. Risk for major adverse cardiovascular or cerebrovascular was significantly higher in LOF carriers prescribed clopidogrel versus alternative DAPT (adjusted hazard ratio, 4.65; 95% confidence interval, 2.22-10.0; P<0.001), whereas no significant difference was observed in those without a LOF allele (adjusted hazard ratio, 1.37; 95% confidence interval, 0.72-2.85; P=0.347). Bleeding event rates were similar across groups (log-rank P=0.816).

Conclusions: Implementing CYP2C19 genotype-guided DAPT is feasible and sustainable in a real-world setting but challenging to maintain at a consistently high level of fidelity. The higher risk of major adverse cardiovascular or cerebrovascular associated with clopidogrel use in CYP2C19 LOF allele carriers suggests that use of genotype-guided DAPT in practice may improve clinical outcomes.

Keywords: acute coronary syndrome; clopidogrel; cytochrome P-450 CYP2C19; genetic testing; percutaneous coronary intervention; pharmacogenetics; precision medicine.

© 2018 American Heart Association, Inc.

Figures

Figure 1. P2Y12 inhibitor maintenance therapy by CYP2C19 status

(A) Study population summary by CYP2C19 genotype availability, loss-of-function (LOF) allele status, and maintenance therapy. (B) CYP2C19 phenotype distribution in genotyped patients: ultrarapid (UM: n=40; 4.6%), rapid (RM: n=196; 22.6%), normal (NM: n=369; 42.5%), intermediate (IM: n=239; 27.5%); poor (PM: n=24; 2.8%) metabolizers The IM [*1/*2=190 (21.9%), *1/*3=1 (0.1%), *2/*17=48 (5.5%), *3/*17=0 (0%)] and PM [*2/*2=24 (2.8%), *2/*3=0 (0%), *3/*3=0 (0%)] phenotypes included multiple genotypes. (C) Maintenance therapy distribution (clopidogrel, prasugrel, or ticagrelor) by CYP2C19 status (NG, not genotyped).

Figure 2. Prasugrel or ticagrelor selection by clinical factor and CYP2C19 phenotype status

The frequency of alternative therapy (prasugrel or ticagrelor) use as maintenance therapy (y-axis) in the strata of CYP2C19 intermediate or poor metabolizers (IM/PM) and ultrarapid, rapid or normal metabolizers (UM/RM/NM) is presented according to the absence (No) and presence (Yes) of the following clinical factors: (A) acute coronary syndrome (ACS) indication for PCI; (B) elevated bleeding risk; (C) left anterior descending (LAD) artery stent placement. The odds ratio (95% CI) for the association between presence of the clinical factor with prasugrel/ticagrelor selection within each CYP2C19 phenotype strata (IM/PM or UM/RM/NM), and the CYP2C19 phenotype*clinical factor interaction P-value is provided.

Figure 3. Cardiovascular and bleeding outcomes following PCI by CYP2C19 status and P2Y12 inhibitor therapy

Kaplan-Meier curves for (A) major adverse cardiovascular and cerebrovascular event (MACCE) and (B) clinically significant bleeding event incidence in patients that underwent CYP2C19 testing and had follow-up available after the index PCI admission (N=751). (C) Kaplan-Meier curve for MACCE in the strata of patients presenting with an ACS indication for PCI (n=459). Data are shown across four CYP2C19 genotype and antiplatelet therapy strata: intermediate or poor metabolizers carrying a loss-of-function allele prescribed clopidogrel (LOF-clop), LOF allele carriers prescribed alternative therapy (LOF-alt), ultrarapid, rapid or normal metabolizers without a LOF allele prescribed clopidogrel (No LOF-clop); patients without a LOF prescribed alternative therapy (No LOF-alt). The unadjusted log rank P-value for outcomes across the four groups, and the adjusted HR, 95% CI and P-value for the indicated between-group comparisons, are provided.

Figure 4. Frequency of CYP2C19 genotype testing and P2Y12 inhibitor maintenance therapy selection by CYP2C19 status over time

The index PCI date was categorized into 6-month intervals. The frequency of (A) CYP2C19 genotype testing and (B) alternative therapy (prasugrel or ticagrelor) use in the strata of CYP2C19 intermediate or poor metabolizers (IM/PM) and ultrarapid, rapid or normal metabolizers (UM/RM/NM) in each time interval was compared. The chi-squared P-value is provided.