PURPOSE:Clopidogrel requires conversion with cytochrome P450 to an active metabolite. High interindividual variability in the drug efficacy is well known. The aim of this analysis was to identify factors that influence the efficacy of 600mg clopidogrel pretreatment in patients with stable coronary artery disease undergoing elective PCI.
METHODS:In the laboratory substudy of the PRAGUE-8 trial (ClinicalTrials.gov identifier NCT00432120), the time course of platelet inhibition was investigated in 105 patients pretreated with clopidogrel ≥6h before coronary angiography±PCI. Flow cytometric analysis of the vasodilator stimulated phosphoprotein (VASP) phosphorylation state was performed, and a Platelet Reactivity Index (PRI) was calculated before, and 12, 28, 36, 60, 84 and 108h after, 600mg of clopidogrel. The influences of age, sex, BMI>30, hypertension, hyperlipidemia, diabetes mellitus, tobacco smoking, renal insufficiency, statin, heparin and aspirin therapy on the course of clopidogrel efficacy were investigated using logistic regression analysis.
RESULTS:Diabetes was associated with the highest baseline platelet reactivity to adenosine diphosphate (ADP). The time-curve of the 600mg clopidogrel-mediated inhibition of platelet reactivity had a downward trend until 28h after the drug administration. At 12 hours, 47% of patients had PRI ≥50% (mean (SD) value 45 (21) %). After adjustments for all investigated factors, tobacco smoking was independent predictor for the most robust drop in ADP-induced platelet reactivity at this time point (p=0.027). In contrast, the lowest decrease in PRI was seen in obese patients and those with diabetes (p=0.1). The maximal inhibition of ADP-induced platelet reactivity was achieved by 28h after drug; PRI mean for all patients 36± 23%, for smokers 28±13%. Logistic regression showed that the magnitude of total PRI decrease at 28 hours was not significantly influenced by cigarette smoking (p=0.12).
CONCLUSION:Cigarette smoke is independently associated with a prompt antiplatelet response to clopidogrel.
CLINICAL IMPLICATIONS:This could imply an association between tobacco smoke and CYP3AY and 3A5 induction. Is there a relationship between this observation and the published better outcomes of smokers after primary PCI?
DISCLOSURE:Zuzana Motovska, No Financial Disclosure Information; No Product/Research Disclosure Information