Impact of the CYP2C19*17 Allele on Outcomes in Patients Receiving Genotype‐Guided Antiplatelet Therapy After Percutaneous Coronary Intervention

Abstract

Genotyping for CYP2C19 no function alleles to guide antiplatelet therapy after percutaneous coronary intervention (PCI) improves clinical outcomes. Although results for the increased function CYP2C19*17 allele are also reported, its clinical relevance in this setting remains unclear. A collaboration across nine sites examined antiplatelet therapy prescribing and clinical outcomes in 3,342 patients after implementation of CYP2C19‐guided antiplatelet therapy. Risk of major atherothrombotic and bleeding events over 12 months after PCI were compared across cytochrome P450 2C19 isozyme (CYP2C19) metabolizer phenotype and antiplatelet therapy groups by proportional hazards regression. Clopidogrel was prescribed to a similar proportion of CYP2C19 normal (84.5%), rapid (82.9%), and ultrarapid metabolizers (80.6%) (P = 0.360). Clopidogrel‐treated normal metabolizers (20.4 events/100 patient‐years; adjusted hazard ratio (HR) 1.00, 95% confidence interval (CI), 0.75–1.33, P = 0.993) and clopidogrel‐treated rapid or ultrarapid metabolizers (19.1 events/100 patient‐years; adjusted HR 0.95, 95% CI, 0.69–1.30, P = 0.734) exhibited no difference in major atherothrombotic events compared with patients treated with prasugrel or ticagrelor (17.6 events/100 patient‐years). In contrast, clopidogrel‐treated intermediate and poor metabolizers exhibited significantly higher atherothrombotic event risk compared with prasugrel/ticagrelor‐treated patients (adjusted HR 1.56, 95% CI, 1.12–2.16, P = 0.008). When comparing clopidogrel‐treated rapid or ultrarapid metabolizers to normal metabolizers, no difference in atherothrombotic (adjusted HR 0.97, 95% CI, 0.73–1.29, P = 0.808) or bleeding events (adjusted HR 1.34, 95% CI, 0.83–2.17, P = 0.224) were observed. In a real‐world setting of genotype‐guided antiplatelet therapy, the CYP2C19*17 allele did not significantly impact post‐PCI prescribing decisions or clinical outcomes. These results suggest the CYP2C19 *1/*17 and *17/*17 genotypes have limited clinical utility to guide antiplatelet therapy after PCI.

Translational Pharmacogenomics: Discovery, Evidence Synthesis and Delivery of Race‐Conscious Medicine

“…( b ) Racial/ancestral breakdown of participants included in the clinical trials leading to the approval of the antiplatelets, clopidogrel, prasugrel, and ticagrelor, and pharmacogenomic sub‐analysis conducted within these trials 86,91,115–120 . ( c ) Racial/ancestral breakdown of pharmacogenomic efforts evaluating the association between CYP2C19 and antiplatelet therapy 93,95,121–124 . ( d ) CPIC guidelines for CYP2C19 ‐guided antiplatelet therapy and breakdown of actionable CYP2C19 metabolizer phenotypes by race/ancestry 92 .…”

A physiologically based pharmacokinetic model of clopidogrel in populations of European and Japanese ancestry: An evaluation of CYP2C19 activity

“…However, in in the present analysis as well as previous reports, 8 the H4 metabolite AUC was similar in the UMs and EMs. Furthermore, Lee et al 53 reported that the risk of atherothrombotic events was not significantly different between CYP2C19 UMs and CYP2C19 EMs, indicating that the clinical utility of CYP2C19*17 to guide clopidogrel antiplatelet therapy is limited.…”

Genotype-Guided Use of P2Y12 Inhibitors: A Review of Current State of the Art

“…Tiroch et al reported a protective role of CYP2C19 gain of function alleles as carriers of CYP2C19-17 had a lower risk of target-lesion revascularization and MACE when compared to non-carriers ( 21 ). However, Lee et al reported a similar risk of MACE between carriers of CYP2C19-17and non-carrier ( 22 ). In terms of bleeding risk, Sibbing et al reported increased bleeding risk in carriers of CYP2C19-17 ( 23 ), while Lee et al reported similar bleeding risk between carriers and non-carriers ( 22 ).…”

“…However, Lee et al reported a similar risk of MACE between carriers of CYP2C19-17and non-carrier ( 22 ). In terms of bleeding risk, Sibbing et al reported increased bleeding risk in carriers of CYP2C19-17 ( 23 ), while Lee et al reported similar bleeding risk between carriers and non-carriers ( 22 ).…”