Pharmacogenomics of Clopidogrel

Clopidogrel is an antiplatelet drug of the thienopyridine family whose mechanism of action is inhibition of one of the two platelet adenosine diphosphate receptors—P2Y12. It is indicated for prevention of vascular ischemic events in patients with symptomatic atherosclerosis, and acute coronary syndrome. It is also indicated, in association with acetyl salycilic acid, for the prevention of thrombosis after percutaneous coronary intervention with intracoronary stent implantation. A wide interindividual variability in response to clopidogrel has been reported. An inadequate response to clopidogrel, in terms of platelet function inhibition, was consistently associated in single studies and in large meta-analyses, with major adverse cardiovascular events. Genetic variants in genes involved in clopidogrel metabolism or platelet function have been associated with high on-treatment platelet reactivity and adverse outcomes in high-risk vascular patients. In particular, polymorphisms in the gene coding for one of the hepatic isoforms of the cytochrome P450, CYP2C19, have been associated with residual platelet reactivity and adverse outcomes. Pharmacogenetic tests of well-defined polymorphisms, used alone or in combination with platelet function tests, are widely recommended for the clinical practice to improve management of antiplatelet therapies tailored to individual patient characteristics, in this way amplifying the concept of “personalized medicine” and consequently reducing the occurrence of adverse events. Pharmacogenetic testing will allow cardiologists and primary physicians to obtain a rapid genetic profile of patients under treatment and to integrate this information in an accurate predictive algorithm to achieve truly personalized antiplatelet therapy.