Genetic considerations

Dual antiplatelet therapy with aspirin and a P2Y(12) receptor antagonist improves outcomes in patients with acute coronary syndrome and in those treated with percutaneous coronary intervention (PCI) and a coronary stent. Candidate gene and genome-wide association studies have found that common genetic polymorphisms of the cytochrome P450 (CYP) 2C19 isoenzyme that result in a loss of functional activity are associated with less exposure of clopidogrel active metabolite and a diminished antiplatelet effect. Meta-analyses of registries and genetic substudies of randomized clinical trials demonstrate that carriers of these polymorphisms who are treated with clopidogrel are at an increased risk of cardiovascular events, particularly stent thrombosis, compared with noncarriers. This deleterious effect appears to be attenuated in patients not treated with PCI. The influence of polymorphisms of other genes, such as ABCB1, is inconsistent across clinical studies. The clinical efficacy of the newer P2Y(12) antagonists prasugrel and ticagrelor do not appear to be affected by the CYP2C19 genotype, but these agents increase major bleeding not related to coronary artery bypass surgery. Although data from randomized clinical trials are currently lacking, these observations suggest that a pharmacogenomic-guided approach to antiplatelet therapy in acute coronary syndrome could potentially maximize ischemic benefit while minimizing bleeding risk.