Author(s): John Andrew Lee aff1 , Craig R Lee aff1 aff2 aff3 , Brent N Reed aff4 , David C Plitt aff5 , Melissa J Polasek aff1 , Lucius A Howell aff5 , Jonathan D Cicci aff6 , Kristen E Tasca aff6 , Karen E Weck aff2 aff7 , Joseph S Rossi aff8 , George A Stouffer [*] aff3 aff5
clopidogrel; pharmacogenomics; prasugrel; stent; ticagrelor
Dual antiplatelet therapy with aspirin and a P2Y12 inhibitor is standard of care following percutaneous coronary intervention (PCI) with intracoronary stent placement in stable and unstable coronary artery disease (CAD) patients [1,2 ]. The choice of P2Y12 inhibitor is based on patient-specific clinical factors and economic considerations, with clopidogrel being the most commonly prescribed [ 3 ].
Bioactivation of clopidogrel to its active thiol metabolite is dependent on CYP2C19 [4 ]. Loss-of-function (LOF) polymorphisms in CYP2C19 are common and confer a reduced capacity for clopidogrel bioactivation and platelet inhibition compared with wild-type [5 ]. Although the relationship between CYP2C19 genotype, clopidogrel use and clinical outcomes remains controversial, multiple studies have shown higher rates of stent thrombosis and myocardial infarction (MI) in CYP2C19 LOF (*2 or *3 ) allele carriers following acute coronary syndrome (ACS) or PCI [ 4-7 ], prompting the US FDA to require a black box warning in the clopidogrel labeling [8 ]. By contrast, CYP2C19 genotype does not influence the pharmacokinetics, antiplatelet effects or clinical response to either prasugrel or ticagrelor [9,10 ]. However, these recently approved P2Y12 inhibitors are more expensive than clopidogrel and associated with higher bleeding risk, particularly in patients predisposed to high risk of bleeding [2,3,11 ].
Although these data have generated considerable interest surrounding the potential utility of a CYP2C19 genotype-guided strategy to optimize P2Y12 inhibitor use following PCI, the impact of this strategy on clinical outcomes remains unclear. Consequently, there is debate and uncertainty surrounding whether CYP2C19 genotype should be used to guide antiplatelet therapy [8,12,13 ]. Guidelines promulgated by the American College of Cardiology Foundation/American Heart Association state that a genotype-guided approach 'might be considered' in high-risk patients (Class IIb, Level of Evidence: C), but more data are needed [1,8 ].
Our institution developed and implemented a treatment algorithm for the management of high-risk PCI patients that integrates CYP2C19 genotype with clinical factors to guide P2Y12 inhibitor selection. The objective of this study was to retrospectively evaluate the implementation of a CYP2C19 genotype-guided antiplatelet algorithm in clinical practice, and identify what factors influenced P2Y12 inhibitor selection in patients undergoing PCI.
Patients & methods
A CYP2C19 genotype-guided treatment algorithm for selection of a P2Y12 inhibitor in high-risk patients undergoing PCI was developed and implemented at the University of North Carolina (UNC) in April 2012 (Figure 1). High risk is defined as either an ACS or stable CAD with high-risk anatomic findings (revascularization in either a saphenous vein graft or the following locations in the coronary arteries: left main, proximal left anterior descending, proximal portion of a dominant circumflex or proximal right coronary artery). In a retrospective cohort study, 286 consecutive...