title: Clopidogrel response variability is associated with endothelial dysfunction in coronary artery disease patients receiving dual antiplatelet therapy.
abstract: OBJECTIVE
  Dual antiplatelet therapy with aspirin and a platelet P2Y12 ADP receptor antagonist is the cornerstone of treatment following percutaneous coronary intervention (PCI). Several clinical and genetic factors can cause suboptimal clopidogrel response. We examined the impact of endothelial dysfunction on clopidogrel response variability in subjects with stable coronary artery disease (CAD) after PCI.
  
  
  METHODS
  We consecutively enrolled 198 patients with stable CAD one month after successful PCI. All patients were receiving dual antiplatelet therapy (clopidogrel 75 mg and aspirin 100 mg/day). Platelet reactivity was measured by VerifyNow P2Y12 assay (Accumetrics, San Diego, CA). VerifyNow reports its results in P2Y12 reaction units (PRU) and the diagnostic cut-off value is 230. Endothelial function was evaluated by flow mediated dilation (FMD).
  
  
  RESULTS
  Patients with high on treatment platelet reactivity (32% of the study population), compared to subjects with low on treatment platelet reactivity, presented decreased FMD values (4.35 ± 2.22% vs. 5.74 ± 3.29%, p = 0.01). Moreover, an inverse association between endothelial function measurement and platelet reactivity (r = -0.24, p = 0.001) was found. Importantly, multivariate analysis after adjustment for age, gender and confounders revealed by the univariate analysis (left ventricle ejection fraction, body mass index, diabetes, dyslipidemia, coronary lesion number) showed that for every decrease in FMD by 1% there is an anticipated increased in the odds of patients to have HPR by 1.66 (95% CI 1.03-2.57, p = 0.037).
  
  
  CONCLUSIONS
  Endothelial dysfunction is associated with clopidogrel response variability in patients after PCI receiving dual antiplatelet therapy. These findings shed some light on the mechanisms affecting individual platelet response to antiplatelet therapy and may explain the non-straight forward association between clopidogrel dose, platelet inhibition and cardiovascular outcome.
authors.affiliation: 1st Department of Cardiology, 'Hippokration' Hospital, University of Athens Medical School, Athens, Greece; Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Gerasimos
authors.initials: G
authors.lastname: Siasos
authors.affiliation: 1st Department of Cardiology, 'Hippokration' Hospital, University of Athens Medical School, Athens, Greece.
authors.forename: Evangelos
authors.initials: E
authors.lastname: Oikonomou
authors.affiliation: 1st Department of Cardiology, 'Hippokration' Hospital, University of Athens Medical School, Athens, Greece; Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Marina
authors.initials: M
authors.lastname: Zaromitidou
authors.affiliation: 1st Department of Cardiology, 'Hippokration' Hospital, University of Athens Medical School, Athens, Greece.
authors.forename: Stamatios
authors.initials: S
authors.lastname: Kioufis
authors.affiliation: 1st Department of Cardiology, 'Hippokration' Hospital, University of Athens Medical School, Athens, Greece.
authors.forename: Eleni
authors.initials: E
authors.lastname: Kokkou
authors.affiliation: 1st Department of Cardiology, 'Hippokration' Hospital, University of Athens Medical School, Athens, Greece.
authors.forename: Konstantinos
authors.initials: K
authors.lastname: Mourouzis
authors.affiliation: 1st Department of Cardiology, 'Hippokration' Hospital, University of Athens Medical School, Athens, Greece.
authors.forename: Konstantinos
authors.initials: K
authors.lastname: Vlasis
authors.affiliation: 1st Department of Cardiology, 'Hippokration' Hospital, University of Athens Medical School, Athens, Greece.
authors.forename: Manolis
authors.initials: M
authors.lastname: Vavuranakis
authors.affiliation: Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Peter H
authors.initials: PH
authors.lastname: Stone
authors.affiliation: Department of Biological Chemistry, University of Athens Medical School, Athens, Greece.
authors.forename: Athanasios G
authors.initials: AG
authors.lastname: Papavassiliou
authors.affiliation: 1st Department of Cardiology, 'Hippokration' Hospital, University of Athens Medical School, Athens, Greece. Electronic address: drtousoulis@hotmail.com.
authors.forename: Dimitris
authors.initials: D
authors.lastname: Tousoulis
mesh_terms: D065767:Activation, Metabolic / Q000235:genetics; D000368:Aged; D001241:Aspirin / Q000627:therapeutic use*; D001916:Brachial Artery / Q000503:physiopathology; D000077144:Clopidogrel; D003327:Coronary Disease / Q000097:blood / Q000188:drug therapy* / Q000503:physiopathology / Q000601:surgery; D065731:Cytochrome P-450 CYP2C19 / Q000235:genetics; D003920:Diabetes Mellitus / Q000453:epidemiology; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D004730:Endothelium, Vascular / Q000503:physiopathology*; D005260:Female; D005838:Genotype; D006801:Humans; D006949:Hyperlipidemias / Q000453:epidemiology; D008297:Male; D008875:Middle Aged; D009765:Obesity / Q000453:epidemiology; D062645:Percutaneous Coronary Intervention; D010975:Platelet Aggregation Inhibitors / Q000627:therapeutic use*; D010979:Platelet Function Tests; D011183:Postoperative Complications / Q000517:prevention & control; D011446:Prospective Studies; D058921:Purinergic P2Y Receptor Antagonists / Q000627:therapeutic use*; D012307:Risk Factors; D012907:Smoking / Q000453:epidemiology; D015607:Stents; D019851:Thrombophilia / Q000188:drug therapy* / Q000517:prevention & control; D013988:Ticlopidine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D014664:Vasodilation
chemical_list: D010975:Platelet Aggregation Inhibitors; D058921:Purinergic P2Y Receptor Antagonists; D000077144:Clopidogrel; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D013988:Ticlopidine; D001241:Aspirin
keywords: Atherosclerosis; Clopidogrel; Coronary artery disease; Endothelial function; Platelet function tests; Platelet reactivity