Variability in on-treatment platelet reactivity explained by CYP2C192 genotype is modest in clopidogrel pretreated patients undergoing coronary stenting

• Published in: Heart (British Cardiac Society) Vol. 97; no. 15; pp. 1239 - 1244
• Main Authors: Bouman, Heleen J, Harmsze, Ankie M, van Werkum, Jochem W, Breet, Nicoline J, Bergmeijer, Th O, ten Cate, Hugo, Hackeng, Christian M, Deneer, Vera H M, ten Berg, Jurriën M
• Format: Journal Article
• Language: English
• Published: England BMJ Publishing Group Ltd and British Cardiovascular Society 01.08.2011; BMJ Publishing Group LTD
• Subjects: Aged; Angioplasty, Balloon, Coronary - methods; antiplatelet treatment; Aryl Hydrocarbon Hydroxylases - genetics; Aryl Hydrocarbon Hydroxylases - metabolism; Blood platelets; Cardiovascular disease; Circulatory system; Clopidogrel; Coronary Artery Disease - blood; Coronary Artery Disease - genetics; Coronary Artery Disease - therapy; Coronary Restenosis - blood; Coronary Restenosis - genetics; Coronary Restenosis - prevention & control; CYP2C19; CYP2C192; Cytochrome P-450 CYP2C19; Diabetes; DNA - genetics; Dose-Response Relationship, Drug; Drug dosages; Female; Follow-Up Studies; genetics; Genotype; Genotype & phenotype; high on-treatment platelet reactivity; Humans; Hypertension; Laboratories; Male; Middle Aged; Platelet Activation - drug effects; Platelet Activation - genetics; Platelet Aggregation Inhibitors - administration & dosage; Platelet Aggregation Inhibitors - therapeutic use; platelet function testing; platelets; Polymerase Chain Reaction; Polymorphism, Genetic; Preoperative Period; Prognosis; Prospective Studies; Regression analysis; Stents; Ticlopidine - administration & dosage; Ticlopidine - analogs & derivatives; Ticlopidine - therapeutic use; Variables; Variance analysis
• ISSN: 1355-6037; 1468-201X
• DOI: 10.1136/hrt.2010.220509

BackgroundAn inadequate response to clopidogrel is mainly attributable to the variable formation of its active metabolite. The CYP2C19*2 loss-of-function polymorphism leads to reduced generation of the active metabolite and is, similarly to high on-treatment platelet reactivity (HPR), associated with recurrent atherothrombotic events following coronary stent implantation.AimTo determine the relative contribution of CYP2C19*2 genotype to HPR.Methods and resultsCYP2C19*2 genotyping and platelet function testing using 5 and 20 μmol/l ADP-induced light transmittance aggregometry (LTA), the PlateletWorks assay and the VerifyNow P2Y12 assay, were performed in 1069 clopidogrel pretreated patients undergoing elective coronary stenting (POPular study, http://clinicalTrials.gov/ NCT00352014). The relative contributions of CYP2C19*2 genotype and clinical variables to the interindividual variability of on-treatment platelet reactivity and the occurrence of HPR were established using multivariate regression models. CYP2C19*2 carrier status was associated with a more frequent occurrence of HPR. CYP2C19*2 genotype alone could explain 5.0%, 6.2%, 4.4% and 3.7% of the variability in 5 and 20 μmol/l ADP-induced LTA, the PlateletWorks assay and the VerifyNow P2Y12 assay, respectively, which increased to 13.0%, 15.2%, 5.6% and 20.6% when clinical variables were considered as well. Besides the CYP2C19*2 genotype, multiple clinical variables could be identified as independent predictors of HPR, including age, gender, body mass index, diabetes mellitus, clopidogrel loading dose regimen, use of amlodipine and platelet count.ConclusionThe CYP2C19*2 loss-of-function polymorphism is associated with a more frequent occurrence of HPR. However, the part of the interindividual variability in on-treatment platelet reactivity explained by CYP2C19*2 genotype is modest.