Highlights from recent advances in antiplatelet pharmacogenomics.

Abstract

Pers. Med. (2014) 11(2), 135–138 ISSN 1741-0541 CYP2C19-guided antiplatelet therapy in coronary artery disease Coronary artery disease (CAD) is the leading cause of morbidity and mortality worldwide [1]. Clinical practice guidelines currently recommend dual antiplatelet therapy with aspirin and a P2Y12 inhibitor in patients experiencing an acute coronary syndrome, with or without a percutaneous coronary intervention (PCI), and in stable CAD patients undergoing an elective PCI [2]. Clopidogrel, a prodrug that requires hepatic biotransformation into its active thiol metabolite via CYP450 isoenzyme CYP2C19, remains the most commonly prescribed P2Y12 inhibitor. Importantly, CYP2C19 is highly polymorphic and includes common loss-offunction alleles (*2 or *3) and a common gain-of-function (GOF) allele (*17) in multiple populations [3]. It is now clear that individuals carrying one or two loss-of-function alleles exhibit a significantly lower capacity to metabolize clopidogrel into its active metabolite and inhibit platelet activation, compared with wild-type individuals, and are, therefore, at significantly higher risk of adverse cardiovascular events following acute coronary syndrome or PCI [4]. These data led the US FDA to place a black-box warning in the clopidogrel prescribing information in March 2010 to alert clinicians of these risks [5]. Moreover, carriers of the GOF *17 allele, which enhances CYP2C19 transcription, have been reported to exhibit enhanced inhibition of platelet function and increased bleeding risk; however, conflicting results in the literature exist regarding the association between the *17 allele and bleeding risk [6]. By contrast, CYP2C19 genotype does not influence the pharmacokinetics, pharmacodynamics or clinical response to the more recently approved P2Y12 inhibitors, prasugrel and ticagrelor, which are more expensive than clopidogrel and associated with higher bleeding risk. The rapid accumulation of these data has generated considerable debate surrounding the following question: should CYP2C19 genotyping be used to guide selection of a P2Y12 inhibitor following PCI? Expert insight into this question, including the Clinical Pharmacogenetics Implementation Consortium [6] and the American College of Cardiology Foundation/American Heart Association [2], has collectively concluded that this approach should be considered in certain circumstances and more data are needed. Three notable gaps in knowledge have served as a barrier to more widespread implementation of CYP2C19-guided antiplatelet therapy in practice. First, it remains unclear whether clinically relevant associations between CYP2C19 genotype and clinical outcomes exist in clopidogrel-treated stable CAD patients undergoing elective PCI. Second, it remains unclear whether a clinically relevant association between the GOF CYP2C19*17 allele, clopidogrel use and bleeding risk truly exists. The third, and most important, gap in knowledge remains to be the lack of prospective, randomized clinical studies evaluating the impact of a CYP2C19-guided dual antiplatelet therapy strategy on clinical outcomes in patients undergoing PCI. The three studies highlighted below collectively offer new insight into each of these gaps in evidence regarding the potential clinical utility of CYP2C19 genotype-directed antiplatelet therapy in patients with CAD, part of Research Highlights