November 30, 2012 — Results of a study investigating the effects of smoking on the antiplatelet medications clopidogrel and prasugrel were presented at the 24th annual Transcatheter Cardiovascular Therapeutics (TCT) scientific symposium.
Analyses from previous trials have demonstrated that nonsmokers receive less or no benefit from clopidogrel treatment as compared with smokers, who experience a clear treatment benefit. Clopidogrel and prasugrel are used in combination with aspirin to reduce blood clotting following an angioplasty or percutaneous coronary intervention (PCI). The PARADOX study is the first prospective, double-blind, placebo-controlled study comparing the pharmacokinetics and pharmacodynamics of clopidogrel versus prasugrel in smokers and nonsmokers.
Researchers randomized 54 nonsmokers and 54 smokers with stable coronary artery disease (CAD) on aspirin therapy to clopidogrel (75 mg daily for 10 days) or prasugrel (10 mg daily for 10 days) therapy and crossed-over after a 14-day washout. The co-primary objectives were the pharmacodynamics in clopidogrel-treated smokers versus clopidogrel-treated nonsmokers, and in prasugrel-treated smokers versus clopidogrel-treated smokers. Pharmacodynamics were assessed by the inhibition of platelet aggregation (IPA) as reported by the VerifyNow (VN)-P2Y12 assay.
Researchers found that clopidogrel-treated nonsmokers had lower device-reported IPA versus clopidogrel-treated smokers (mean treatment difference 7.7 percent; p=0.062), lower calculated IPA (mean treatment difference 9.1 percent; p=0.043), higher P2Y12 reaction units (mean treatment difference 36; p=0.005) and higher VASP-platelet reactivity index (mean treatment difference 7.6 percent; p=0.042). In addition, nonsmokers had lower clopidogrel active metabolite concentrations after adjustment for body weight than smokers. Prasugrel therapy was associated with a greater IPA and lower P2Y12 reaction units and VASP-platelet reactivity index compared to clopidogrel, regardless of smoking status (p<0.001 for all comparisons).
“Results from the PARADOX trial indicate that smoking influences the pharmacokinetics and pharmacodynamics of clopidogrel, but not of prasugrel. Nonsmokers had a reduced responsiveness to clopidogrel versus smokers, while prasugrel, compared to clopidogrel, had a greater antiplatelet effect regardless of smoking status,” said lead investigator Paul A. Gurbel, M.D. Gurbel is director of the Sinai Center for Thrombosis Research at the Sinai Hospital of Baltimore and an associate professor of medicine at Johns Hopkins University School of Medicine.
“The poorer antiplatelet response in clopidogrel-treated nonsmokers versus smokers may explain the inferior clinical benefit of clopidogrel in nonsmokers in major randomized trials, and deserves further investigation,” Gurbel said.
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November 03, 2026 
