Antiplatelet Effect of Clopidogrel Attenuated in Nonsmokers

The pharmacokinetics and pharmacodynamics (PK/PD) of clopidogrel are attenuated in nonsmoking patients with stable coronary artery disease also treated with aspirin, according to a study published April 16 in the Journal of the American College of Cardiology.

In the study, clopidogrel-treated nonsmokers had lower active metabolite levels and lower levels of platelet inhibition than clopidogrel-treated smokers. However, smoking status did not affect platelet inhibition with prasugrel.

The trial, known as PARADOX and led by Paul A. Gurbel, MD, FACC, Sinai Center for Thrombosis Research, Baltimore, randomized 56 smokers and 54 nonsmokers with stable coronary artery disease treated with aspirin to clopidogrel or prasugrel. Platelet function was determined by VerifyNow® P2Y12 and vasodilator-stimulated phosphoprotein phosphorylation (VASP-P), and pharmacokinetics with high-performance liquid chromatography of stable plasma samples.

Based on device-reported inhibition of platelet aggregation, platelet inhibition was 7.7 percent lower among clopidogrel-treated nonsmokers than smokers (p=0.062). Platelet inhibition was a significant 31.8 percent lower in clopidogrel-treated smokers than prasugrel-treated smokers (p<0.0001). Clopidogrel-treated smokers, as compared to nonsmokers, also had lower P2Y12 reaction units and a higher VASP-P index. Overall antiplatelet effects were higher with prasugrel regardless of smoking status (p<0.001).

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"PARADOX is the first prospective study to evaluate the influence of smoking status on the PK and PD profile of clopidogrel and prasugrel. Nonsmokers had reduced responsiveness to clopidogrel compared with smokers," wrote the investigators. "Smoking was associated with [an] approximately twofold decreased odds ratio estimate for high on-treatment platelet reactivity during clopidogrel therapy. However, smoking did not significantly influence the antiplatelet response to prasugrel."

"The poorer antiplatelet response in clopidogrel-treated nonsmokers may provide an explanation for less clinical benefit of clopidogrel treatment in nonsmokers observed in major randomized trials and deserves further investigation," they concluded.

Keywords: Odds Ratio, Coronary Artery Disease, Platelet Aggregation Inhibitors, Thiophenes, Baltimore, Ticlopidine, Piperazines, Blood Platelets, Smoking, Chromatography, Liquid, Thrombosis, Platelet Aggregation, Platelet Activation, Phosphorylation, United States

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