Clopidogrel response variability is associated with endothelial dysfunction in coronary artery disease patients receiving dual antiplatelet therapy

Atherosclerosis. 2015 Sep;242(1):102-8. doi: 10.1016/j.atherosclerosis.2015.07.009. Epub 2015 Jul 11.

Abstract

Objectives: 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.

Keywords: Atherosclerosis; Clopidogrel; Coronary artery disease; Endothelial function; Platelet function tests; Platelet reactivity.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Activation, Metabolic / genetics
  • Aged
  • Aspirin / therapeutic use*
  • Brachial Artery / physiopathology
  • Clopidogrel
  • Coronary Disease / blood
  • Coronary Disease / drug therapy*
  • Coronary Disease / physiopathology
  • Coronary Disease / surgery
  • Cytochrome P-450 CYP2C19 / genetics
  • Diabetes Mellitus / epidemiology
  • Drug Synergism
  • Drug Therapy, Combination
  • Endothelium, Vascular / physiopathology*
  • Female
  • Genotype
  • Humans
  • Hyperlipidemias / epidemiology
  • Male
  • Middle Aged
  • Obesity / epidemiology
  • Percutaneous Coronary Intervention
  • Platelet Aggregation Inhibitors / therapeutic use*
  • Platelet Function Tests
  • Postoperative Complications / prevention & control
  • Prospective Studies
  • Purinergic P2Y Receptor Antagonists / therapeutic use*
  • Risk Factors
  • Smoking / epidemiology
  • Stents
  • Thrombophilia / drug therapy*
  • Thrombophilia / prevention & control
  • Ticlopidine / analogs & derivatives*
  • Ticlopidine / therapeutic use
  • Vasodilation

Substances

  • Platelet Aggregation Inhibitors
  • Purinergic P2Y Receptor Antagonists
  • Clopidogrel
  • CYP2C19 protein, human
  • Cytochrome P-450 CYP2C19
  • Ticlopidine
  • Aspirin