title: Effect of CYP2C19 Polymorphisms on the Platelet Response to Clopidogrel and Influence on the Effect of High Versus Standard Dose Clopidogrel in Carotid Artery Stenting.
abstract: OBJECTIVE
  Genetic background has been identified to be a major predictor of post-clopidogrel platelet inhibition in patients undergoing coronary stenting. However, there is a lack of data on clopidogrel response regarding genotype in patients undergoing carotid artery stenting (CAS). The influence of the most common allelic variants of CYP2C19 phenotypes and genotypes on response to baseline clopidogrel and on the pharmacodynamic effect of dose adjustment (high or standard dose of clopidogrel) in patients with high on-treatment reactivity after CAS was investigated.
  
  
  METHODS
  Platelet reactivity was assessed before and 30 days after carotid stenting using the VerifyNow P2Y12 assay to obtain P2Y12 reactivity unit (PRU) values.
  
  
  RESULTS
  A total of 209 patients (79.4% male, 44.1% currents smokers) were treated by CAS. Smokers improved responsiveness to clopidogrel (p = .034). With respect to CYP2C19 enzymatic function, 61 subjects (29.1%) were ultra-rapid metabolizers, 95 patients (45.5%) were extensive metabolizers, 51 (24.4%) were intermediate metabolizers, and two (0.96%) were poor metabolizers. Baseline PRU was significantly higher among intermediate-poor metabolizers compared with ultra-rapid (p = .001) or extensive metabolizers (p = .005). At 30 days follow up, in non-responding patients with the intermediate-poor metabolizer phenotype, the PRU value and inhibition percentage were significantly reduced with standard dose (p = .008; p = .0029) and high dose of clopidogrel (p = .00 0; p = .000). However, high dose clopidogrel did not achieve a more intense pharmacodynamic effect at 30 days (p = .994) compared with standard dose.
  
  
  CONCLUSIONS
  In patients undergoing carotid stenting, those with the CYP2C19*2 allele had increased basal PRU values and in fact clopidogrel non-responders increased significantly among intermediate-poor metabolizers. Although high dose and standard dose clopidogrel therapy was effective in lowering the 30 day PRU values in patients with high on-treatment reactivity who are intermediate-poor metabolizers, the use of high dose clopidogrel did not result in statistically significantly greater reductions in reactivity compared with the standard dose.
authors.affiliation: Department of Radiology, Interventional Neuroradiology, Virgen del Rocío University Hospital, Seville, Spain. Electronic address: ggjandro@gmail.com.
authors.forename: A
authors.initials: A
authors.lastname: González
authors.affiliation: Department of Neurology, Virgen del Rocío University Hospital, Seville, Spain.
authors.forename: F
authors.initials: F
authors.lastname: Moniche
authors.affiliation: Public Health Unit, Health Management Area South of Seville, Seville, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Cayuela
authors.affiliation: Department of Immunology, IBiS, Virgen del Rocío University Hospital, Seville, Spain.
authors.forename: J R
authors.initials: JR
authors.lastname: García-Lozano
authors.affiliation: Department of Immunology, IBiS, Virgen del Rocío University Hospital, Seville, Spain.
authors.forename: F
authors.initials: F
authors.lastname: Torrecillas
authors.affiliation: Department of Neurology, Virgen del Rocío University Hospital, Seville, Spain.
authors.forename: I
authors.initials: I
authors.lastname: Escudero-Martínez
authors.affiliation: Department of Neurology, Virgen del Rocío University Hospital, Seville, Spain.
authors.forename: J R
authors.initials: JR
authors.lastname: Gonzalez-Marcos
authors.affiliation: Department of Radiology, Interventional Neuroradiology, Virgen del Rocío University Hospital, Seville, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Mayol
authors.affiliation: Neurovascular Research Group, Stroke Program, IBiS, Virgen del Rocío University Hospital, Seville, Spain.
authors.forename: J
authors.initials: J
authors.lastname: Montaner
mesh_terms: D000368:Aged; D017130:Angioplasty / Q000009:adverse effects / Q000295:instrumentation*; D001792:Blood Platelets / Q000187:drug effects* / Q000378:metabolism; D002340:Carotid Artery Diseases / Q000097:blood / Q000175:diagnosis / Q000628:therapy*; D000077144:Clopidogrel; D065731:Cytochrome P-450 CYP2C19 / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D010597:Pharmacogenetics; D010641:Phenotype; D015539:Platelet Activation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage* / Q000378:metabolism; D011110:Polymorphism, Genetic; D058921:Purinergic P2Y Receptor Antagonists / Q000008:administration & dosage* / Q000378:metabolism; D058925:Receptors, Purinergic P2Y12 / Q000097:blood / Q000187:drug effects; D015607:Stents; D013988:Ticlopidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000378:metabolism; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: C548576:P2RY12 protein, human; D010975:Platelet Aggregation Inhibitors; D058921:Purinergic P2Y Receptor Antagonists; D058925:Receptors, Purinergic P2Y12; D000077144:Clopidogrel; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D013988:Ticlopidine
keywords: CYP2C19; Carotid artery stenting; Clopidogrel