Implementation of Genotype-Guided Antiplatelet Therapy
Feasible but Not Without Obstacles
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See Article by Lee et al
Dual antiplatelet therapy with aspirin and a P2Y12 receptor inhibitor is a cornerstone for prevention of recurrent cardiovascular events in patients with acute coronary syndromes or undergoing percutaneous coronary intervention (PCI). Although clopidogrel remains the most commonly used P2Y12 receptor inhibitor and is generally effective, a large body of retrospective evidence suggests that a subset of patients do not respond adequately to this medication resulting in increased on-treatment platelet reactivity and rates of atherothrombotic events. A major determinant of variable clopidogrel efficacy includes loss-of-function (LOF) genetic variation in the CYP2C19 gene, most notably CYP2C19*2 and *3. CYP2C19 is responsible, in part, for converting the clopidogrel prodrug into a biologically active thiol metabolite that irreversibly binds to the P2Y12 receptor thus inhibiting ADP-induced platelet aggregation.
In recent years, alternative P2Y12 receptor inhibitors (ie, prasugrel and ticagrelor) have been developed and are approved for use for most clinical indications in which clopidogrel is prescribed. Although large-scale trials have shown that these agents are superior to clopidogrel in terms of platelet inhibition and reduction of major adverse cardiovascular events, clopidogrel continues to be the most widely used agent because of its cost and lower propensity to cause pathological bleeding.1,2 Importantly, however, genetic variation in CYP2C19 does not alter the pharmacokinetics or antiplatelet potential of prasugrel and ticagrelor thereby providing a modality for more personalized antiplatelet therapy approaches. Indeed, the US Food and Drug Administration updated the clopidogrel label in 2010 advising clinicians to be aware that poor metabolizers of clopidogrel (eg, those that carry CYP2C19 LOF alleles) exhibit high cardiovascular event rates and that alternative therapy should be considered in these individuals. In addition, current American College of Cardiology Foundation/American Heart Association PCI guidelines state that genetic testing and …