title: Combined influence of proton-pump inhibitors, calcium-channel blockers and CYP2C19*2 on on-treatment platelet reactivity and on the occurrence of atherothrombotic events after percutaneous coronary intervention.
abstract: BACKGROUND
  The carriage of CYP2C19*2 and the use of proton-pump inhibitors (PPIs) and calcium-channel blockers (CCBs) has been associated with the diminished efficacy of clopidogrel. However, previous studies have only assessed the isolated impact of these risk factors for clopidogrel poor response.
  
  
  OBJECTIVE
  The aim of the present study was to investigate the impact of the combined presence of three risk factors for clopidogrel poor response, that is, the use of CCBs, PPIs and the carriage of CYP2C19*2, on on-treatment platelet reactivity and the occurrence of atherothrombotic events in 725 patients on dual antiplatelet therapy undergoing elective coronary stenting.
  
  
  METHODS
  In a prospective, follow-up study, on-treatment platelet reactivity was quantified using ADP-induced light transmittance aggregometry (LTA) and the VerifyNow P2Y12 assay. The clinical study endpoint was the composite of all-cause mortality, myocardial infarction, stent thrombosis and stroke at 1 year after stenting.
  
  
  RESULTS
  Patients with either one or more than one risk factor exhibited increased platelet reactivity (mean relative increase one risk factor: 11% and > 1 risk factor: 22%, respectively). Sixty-four events occurred during follow-up (8.8% of the study population). Patients with one risk factor for clopidogrel poor response did not have an increased risk of the composite endpoint. However, patients using both CCBs and PPIs and carriers of CYP2C19*2 who used CCBs had a statistically significant increased risk of the composite endpoint [hazard ratio(HR)(adj) 2.2 95% CI, 1.0-5.3, P = 0.044 and HR(adj) 3.3 95% CI, 1.1-9.8, P = 0.032, respectively].
  
  
  CONCLUSIONS
  The presence of more than one of the three investigated risk factors for clopidogrel poor response is associated with an increased risk of adverse cardiovascular events within 1 year after elective coronary stenting.
authors.affiliation: Department of Clinical Pharmacy, St. Antonius Hospital, Nieuwegein, the Netherlands.
authors.forename: A M
authors.initials: AM
authors.lastname: Harmsze
authors.forename: J W
authors.initials: JW
authors.lastname: van Werkum
authors.forename: P C
authors.initials: PC
authors.lastname: Souverein
authors.forename: N J
authors.initials: NJ
authors.lastname: Breet
authors.forename: H J
authors.initials: HJ
authors.lastname: Bouman
authors.forename: C M
authors.initials: CM
authors.lastname: Hackeng
authors.forename: H J T
authors.initials: HJ
authors.lastname: Ruven
authors.forename: J M
authors.initials: JM
authors.lastname: ten Berg
authors.forename: O H
authors.initials: OH
authors.lastname: Klungel
authors.forename: A
authors.initials: A
authors.lastname: de Boer
authors.forename: V H M
authors.initials: VH
authors.lastname: Deneer
mesh_terms: D000368:Aged; D017222:Angioplasty, Balloon, Laser-Assisted / Q000009:adverse effects*; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D002121:Calcium Channel Blockers / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D000077144:Clopidogrel; D065731:Cytochrome P-450 CYP2C19; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D015539:Platelet Activation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D054328:Proton Pump Inhibitors / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D012307:Risk Factors; D013927:Thrombosis / Q000201:enzymology / Q000517:prevention & control*; D013988:Ticlopidine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D002121:Calcium Channel Blockers; D010975:Platelet Aggregation Inhibitors; D054328:Proton Pump Inhibitors; D000077144:Clopidogrel; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D013988:Ticlopidine