Genotyping: one piece of the puzzle to personalize antiplatelet therapy.
The loss-of-function hepatic cytochrome P450 (CYP) 2C19*2 allele has been associated with reduced clopidogrel active metabolite generation and higher ex vivo platelet reactivity to adenosine diphosphate. Independently, in post hoc analyses, CYP2C19*2 has been associated with worse clinical outcomes during clopidogrel therapy. The controversy surrounding the diminished effectiveness of clopidogrel in poor metabolizers, those having 2 loss-of-function alleles, has been recently highlighted in the "boxed warning" issued by the U.S. Food and Drug Administration. However, much of the variation in clopidogrel response is not explained by the CYP2C19*2 allele (the most frequent loss-of-function allele), and other factors, both genetic and nongenetic, are likely to be important contributors. High on-treatment platelet reactivity to adenosine diphosphate during clopidogrel therapy is a well-documented predictor of recurrent ischemic events in the percutaneous coronary intervention population. While platelet function is dynamic in individual patients because of the influence of variable external factors, the influence of the CYP2C19*2 allele is intrinsically constant. Thus, it may be reasonable to consider both genotyping and platelet function measurement to assess ischemic risk and to guide antiplatelet therapy. Prospective clinical trials to test new algorithms for optimal personalized antiplatelet therapy are needed to provide the evidence base required for the routine adoption of genotyping into clinical practice.
Gurbel
Paul A
PA
Sinai Center for Thrombosis Research, Cardiac Catheterization Laboratory, Sinai Hospital of Baltimore, Baltimore, Maryland 21215, USA. pgurbel@lifebridgehealth.org
Tantry
Udaya S
US
Shuldiner
Alan R
AR
Kereiakes
Dean J
DJ
D000077144:Clopidogrel; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D006801:Humans; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage*; D013988:Ticlopidine / Q000008:administration & dosage / Q000031:analogs & derivatives*
D010975:Platelet Aggregation Inhibitors; D003577:Cytochrome P-450 Enzyme System; D000077144:Clopidogrel; D013988:Ticlopidine