title: Impact of the proton pump inhibitors and CYP2C19*2 polymorphism on platelet response to clopidogrel as assessed by four platelet function assays.
abstract: BACKGROUND
  Previous studies suggested a possible negative interference of proton pump inhibitors (PPIs) on clopidogrel's antiplatelet effect because of the competitive inhibition of the CYP 2C19 isoenzyme. Moreover, carriers of the loss-of-function allele of CYP2C19 polymorphism (CYP2C19*2) display significantly lower responses to clopidogrel. In this study, we investigated the association between CYP2C19*2 genotype, PPI intake and clopidogrel resistance in patients with coronary artery disease (CAD) and their effect on clinical outcome.
  
  
  METHODS
  We recruited 95 patients with CAD receiving chronic clopidogrel therapy in combination with aspirin. Platelet reactivity was simultaneously assessed by INNOVANCE PFA-100 P2Y, ADP-induced light transmission aggregometry (LTA), flow-cytometric vasodilator-stimulated phosphoprotein (VASP)-phosphorylation assay and multiple electrode aggregometry (Multiplate). Cardiovascular outcomes were recorded during 1-year follow-up period.
  
  
  RESULTS
  Only platelet reactivity assessed by measuring platelet phosphorylated-VASP demonstrated a significant higher platelet reactivity in carriers of CYP2C19*2 (p=0.023). The other methods displayed higher - but not statistically significant - platelet reactivity in patients carrying the CYP2C19*2 variant as compared with non-carriers. Patients on PPIs demonstrated almost similar suppression of platelet reactivity in comparison with those not treated with PPIs by all platelet function assays. In logistic regression analysis none of the platelet function assays measurements were related with clinical outcomes. Similarly neither CYP2C19*2 genetic variant nor PPI treatment were associated with adverse clinical events.
  
  
  CONCLUSIONS
  PPI co-administration did not influence clopidogrel's antiplatelet effect on laboratory testing by all platelet function assays used. On the contrary, patients carrying CYP2C19*2 genotype had significantly higher residual platelet reactivity as estimated by VASP-phosphorylation assay.
authors.affiliation: Laboratory of Haematology and Blood Bank Unit, "Attiko" University Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens - Greece. Electronic address: atsantes@yahoo.com.
authors.forename: Argirios E
authors.initials: AE
authors.lastname: Tsantes
authors.forename: Ignatios
authors.initials: I
authors.lastname: Ikonomidis
authors.forename: Ioannis
authors.initials: I
authors.lastname: Papadakis
authors.forename: Stefanos
authors.initials: S
authors.lastname: Bonovas
authors.forename: Argiri
authors.initials: A
authors.lastname: Gialeraki
authors.forename: Christine
authors.initials: C
authors.lastname: Kottaridi
authors.forename: Elias
authors.initials: E
authors.lastname: Kyriakou
authors.forename: Styliani
authors.initials: S
authors.lastname: Kokori
authors.forename: Panagiota
authors.initials: P
authors.lastname: Douramani
authors.forename: Petros
authors.initials: P
authors.lastname: Kopterides
authors.forename: Petros
authors.initials: P
authors.lastname: Karakitsos
authors.forename: John
authors.initials: J
authors.lastname: Lekakis
authors.forename: Violetta
authors.initials: V
authors.lastname: Kapsimali
mesh_terms: D000368:Aged; D000483:Alleles; D001189:Aryl Hydrocarbon Hydroxylases / Q000097:blood / Q000235:genetics*; D001241:Aspirin / Q000008:administration & dosage; D001792:Blood Platelets / Q000187:drug effects* / Q000201:enzymology*; D000077144:Clopidogrel; D003324:Coronary Artery Disease / Q000097:blood / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics; D065731:Cytochrome P-450 CYP2C19; D004351:Drug Resistance; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010979:Platelet Function Tests; D011110:Polymorphism, Genetic; D054328:Proton Pump Inhibitors / Q000008:administration & dosage*; D013988:Ticlopidine / Q000008:administration & dosage / Q000031:analogs & derivatives*
chemical_list: D054328:Proton Pump Inhibitors; D000077144:Clopidogrel; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D013988:Ticlopidine; D001241:Aspirin
keywords: ACS; AUC; CAD; CT; CYP; CYP2C19*2 polymorphism; Clopidogrel resistance; LTA; MEA; PCI; PFA; PPI; PPP; PRI; PRP; Platelet function assay; Proton pump inhibitor; RT-PCR; Real-time polymerase chain reaction; SNP; ST-elevation myocardial infarction; STEMI; VASP; acute coronary syndrome; area under the curve; closure time; coronary artery disease; cytochrome P450; flow-cytometric vasodilator-stimulated phosphoprotein; light transmittance aggregometry; multiple electrode aggregometry; percutaneous coronary intervention; platelet function analyzer; platelet reactivity index; platelet-poor plasma; platelet-rich plasma; proton pump inhibitors; single-nucleotide polymorphism