Clopidogrel Pharmacogenetics

Abstract

Common genetic variation in CYP2C19 (cytochrome P450, family 2, subfamily C, polypeptide 19) *2 and *3 alleles leads to a loss of functional protein, and carriers of these loss-of-function alleles when treated with clopidogrel have significantly reduced clopidogrel active metabolite levels and high on-treatment platelet reactivity resulting in increased risk of major adverse cardiovascular events, especially after percutaneous coronary intervention. The Food and Drug Administration has issued a black box warning advising practitioners to consider alternative treatment in CYP2C19 poor metabolizers who might receive clopidogrel and to identify such patients by genotyping. However, routine clinical use of genotyping for CYP2C19 loss-of-function alleles in patients undergoing percutaneous coronary intervention is not recommended by clinical guidelines because of lack of prospective evidence. To address this critical gap, TAILOR-PCI (Tailored Antiplatelet Initiation to Lessen Outcomes due to Decreased Clopidogrel Response After Percutaneous Coronary Intervention) is a large, pragmatic, randomized trial comparing point-of-care genotype-guided antiplatelet therapy with routine care to determine whether identifying CYP2C19 loss-of-function allele patients prospectively and prescribing alternative antiplatelet therapy is beneficial.

Keywords: clinical trial; clopidogrel; cytochrome P450 CYP2C19; drug labeling; genetics; humans; pharmacogenetics.

Figure 1.

Genetic effects and pharmacokinetic response to clopidogrel. [Reproduced with permission from Massachusetts Medical Society]

Figure 2.

Platelet reactivity by CYP2C19 genotype after clopidogrel loading. [Reproduced with permission from American Medical Association]

Figure 3.

P2Y12 inhibitor use by quarter from January 2012 to January 2014 at 47 Michigan hospitals in the Blue Cross Blue Shield of Michigan Cardiovascular Consortium. [Reproduced with permission from Elsevier Publishing]

Figure 4.

TAILOR-PCI Study Design.

Figure 5.

Systems Medicine tools for CYP450 regulation in Precision Cardiovascular Medicine. Scheme attic representation of factors identified from various omic technologies that may regulate the pharmacogenomic impact of CYP450 variation on antiplatelet therapy. For example, in addition to CYPC219 genomic variants identified in genome-wide association studies, methylation of P2Y12 receptor in epigenomics, the action of miR-103/107 on CYP2C19 in microRNAomics, transferrin and peroxiredoxin-4 identified by proteomics, TMAO in metabolomics and microbiomics can impact cardiovascular outcomes. Beyond omics, incorporation of ‘big data’ and clinical variables from the electronic health record with heart rate and activity levels from mobile health technology, along with findings from imaging (such as high risk plaque, coronary calcium), may help predict individuals who may be at high risk for clinical events. (Abbreviations: CYP450: cytochrome P450; CYP2C19: cytochrome P450, family 2, subfamily C, polypeptide 19; P2Y12: the adenosine diphosphate receptor on the surface of platelets, to which clopidogrel binds; miR-103/107: microRNA-103 and microRNA-107; TMAO: trimethylene N-oxide). [Reproduced with permission from MDPI]