Author + information
- Received April 20, 2013
- Revision received June 7, 2013
- Accepted June 20, 2013
- Published online November 1, 2013.
- Chiara Viviani Anselmi, PhD∗,
- Carlo Briguori, MD, PhD†∗ (, )
- Roberta Roncarati, PhD∗,‡,
- Laura Papa, PhD∗,
- Gabriella Visconti, MD†,
- Amelia Focaccio, MD†,
- Francesca De Micco, PhD†,
- Michael V.G. Latronico§,
- Paolo Pagnotta, MD§ and
- Gianluigi Condorelli, MD, PhD§,‖∗ ()
- ∗Istituto di Ricovero e Cura a Carattere Scientifico Multimedica, Milan, Italy
- †Laboratory of Interventional Cardiology and Department of Cardiology, Clinica Mediterranea, Naples, Italy
- ‡Istituto Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche, Milan, Italy
- §Humanitas Clinical and Research Center, Rozzano, Milan, Italy
- ‖University of Milan, Milan, Italy
Objectives This study sought to assess the usefulness of clopidogrel-pathway genotyping and on-treatment platelet reactivity (OTR) testing in predicting major adverse cardiac events (MACE) in stable coronary artery disease (CAD) patients receiving drug-eluting stents (DES) under dual antiplatelet (clopidogrel plus aspirin) therapy.
Background The role of pharmacogenetics and OTR in predicting MACE—death, myocardial infarction, or stent thrombosis—in stable CAD patients scheduled for DES implantation is still debated.
Methods Patients with stable CAD treated by DES implantation (n = 1,432) were genotyped with a TaqMan OpenArray (Applied Biosystems, Carlsbad, California) and assessed for OTR with the VerifyNow P2Y12 test (Accumetrics Inc., San Diego, California). Genes tested were ABCB1, CYP1A2, CYP2B6*9, CYP2C8*3, CYP2C9*2, CYP2C19, CYP3A4, CYP3A5*3, P2RY12, and PON1CYP2C19. High OTR was defined as P2Y12 reaction units ≥230. The endpoint at 12-month follow-up was MACE occurring during antiplatelet therapy.
Results All groups that were stratified for loss-of-function variants of the cytochrome P450 gene CYP2C19 had significant hazard ratios (HR) for MACE (genotypic HR: 1.41, 95% confidence interval [CI]: 1.06 to 1.89, p = 0.01; allelic HR: 1.56, 95% CI: 2.26 to 1.2, p = 0.01). Variants of other clopidogrel-pathway genes were not significantly associated with MACE. When OTR was assessed, clinical significance was found only in high-risk diabetic (HR: 2.11, 95% CI: 1.29 to 3.45, p < 0.001) and chronic kidney disease (HR: 2.03, 95% CI: 1.03 to 4.02, p = 0.04) patients.
Conclusions CYP2C19 metabolizer status is an independent predictor of MACE after DES implantation and can be used for prognostication in all stable CAD patients. High OTR, as assessed by the VerifyNow P2Y12 test, is an independent predictor of MACE only for high-risk subsets, that is, patients with diabetes or chronic kidney disease.
Prof. Condorelli has received research grants from the National Research Council of Italy and the Italian Ministry of Health (Progetto “Apice”). All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Received April 20, 2013.
- Revision received June 7, 2013.
- Accepted June 20, 2013.
- American College of Cardiology Foundation