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Variability in on-treatment platelet reactivity explained by CYP2C19*2 genotype is modest in clopidogrel pretreated patients undergoing coronary stenting
  1. Heleen J Bouman1,2,3,
  2. Ankie M Harmsze2,4,5,
  3. Jochem W van Werkum1,2,
  4. Nicoline J Breet1,2,
  5. Th O Bergmeijer1,2,
  6. Hugo ten Cate3,
  7. Christian M Hackeng2,6,
  8. Vera H M Deneer2,4,
  9. Jurriën M ten Berg1,2
  1. 1Department of Cardiology, St Antonius Hospital, Nieuwegein, The Netherlands
  2. 2St Antonius Center for Platelet Function Research, St Antonius Hospital, Nieuwegein, The Netherlands
  3. 3Department of Internal Medicine, Cardiovascular Research Institute Maastricht, Maastricht University Medical Center, Maastricht, The Netherlands
  4. 4Department of Clinical Pharmacy, St Antonius Hospital, Nieuwegein, The Netherlands
  5. 5Division of Pharmacoepidemiology and Pharmacotherapy, Utrecht Institute for Pharmaceutical Sciences (UIPS), Utrecht University, Utrecht, The Netherlands
  6. 6Department of Clinical Chemistry, St Antonius Hospital, Nieuwegein, The Netherlands
  1. Correspondence to Jurriën M ten Berg, Department of Cardiology, St Antonius Hospital, PO Box 2500, 3435 CM Nieuwegein, The Netherlands; jurtenberg{at}gmail.com

Abstract

Background An 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.

Aim To determine the relative contribution of CYP2C19*2 genotype to HPR.

Methods and results CYP2C19*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.

Conclusion The 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.

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Footnotes

  • HJB and AMH contributed equally to this study.

  • Competing interests JWvW reported speakers fees from Accumetrics and Siemens, The Medicines Company; NJB reported speakers fees from Siemens; JMtB reported speakers fees from Sanofi-Aventis, Eli Lilly, BMS and MSD, Sanofi-Aventis, Eli Lilly, Schering-Plough and GlaxoSmithKline. None of the other authors reported disclosures.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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