@article{c2d52912ef8548e8a4574b8c6c7b9249,
title = "The influence of smoking status on the pharmacokinetics and pharmacodynamics of clopidogrel and prasugrel: The paradox study",
abstract = "Objectives The goal of this study was to evaluate the effect of smoking on the pharmacokinetics and pharmacodynamics (PD) of clopidogrel and prasugrel therapy. Background Major randomized trial data demonstrated that nonsmokers experience less or no benefit from clopidogrel treatment compared with smokers (i.e., the {"}smokers' paradox{"}). Methods PARADOX was a prospective, randomized, double-blind, double-dummy, placebo-controlled, crossover study of objectively assessed nonsmokers (n = 56) and smokers (n = 54) with stable coronary artery disease receiving aspirin therapy. Patients were randomized to receive clopidogrel (75 mg daily) or prasugrel (10 mg daily) for 10 days and crossed over after a 14-day washout. PD was assessed by using VerifyNow P2Y 12 and vasodilator-stimulated phosphoprotein phosphorylation assays. Clopidogrel and prasugrel metabolite levels, cytochrome P450 1A2 activity, CYP2C19 genotype, and safety parameters were determined. Results During clopidogrel therapy, device-reported inhibition of platelet aggregation (IPA) trended lower in nonsmokers than smokers (least squares mean treatment difference ± SE: 7.7 ± 4.1%; p = 0.062). Device-reported IPA was significantly lower in clopidogrel-treated smokers than prasugrel-treated smokers (least squares mean treatment difference: 31.8 ± 3.4%; p < 0.0001). During clopidogrel therapy, calculated IPA was lower and P2Y 12 reaction units and vasodilator-stimulated phosphoprotein phosphorylation and platelet reactivity index were higher in nonsmokers than in smokers (p = 0.043, p = 0.005, and p = 0.042, respectively). Greater antiplatelet effects were present after prasugrel treatment regardless of smoking status (p < 0.001 for all comparisons). Conclusions PARADOX demonstrated lower clopidogrel active metabolite exposure and PD effects of clopidogrel in nonsmokers relative to smokers. Prasugrel was associated with greater active metabolite exposure and PD effects than clopidogrel regardless of smoking status. The poorer antiplatelet response in clopidogrel-treated nonsmokers may provide an explanation for the smokers' paradox. (The Influence of Smoking Status on Prasugrel and Clopidogrel Treated Subjects Taking Aspirin and Having Stable Coronary Artery Disease; NCT01260584).",
keywords = "CYP1A2, CYP2C19, clopidogrel, pharmacodynamics, pharmacokinetics, platelet, prasugrel, smoking",
author = "Gurbel, {Paul A.} and Bliden, {Kevin P.} and Logan, {Douglas K.} and Kereiakes, {Dean J.} and Lasseter, {Kenneth C.} and Alex White and Angiolillo, {Dominick J.} and Nolin, {Thomas D.} and Maa, {Jen Fue} and Bailey, {William L.} and Jakubowski, {Joseph A.} and Ojeh, {Clement K.} and Jeong, {Young Hoon} and Tantry, {Udaya S.} and Baker, {Brian A.}",
note = "Funding Information: This study was supported by research grants from Daiichi Sankyo, Inc. (Daiichi Sankyo) and Eli Lilly & Company (Lilly). The sponsors participated in the study design and development of the protocol, and provided logistical support during the trial. Monitoring of the study was performed by contract research organizations under contract with the sponsor. The sponsor maintained the trial database. Statistical analyses were performed by statisticians from the contract research organization with oversight from the statisticians at Daiichi Sankyo, Inc. Dr. Gurbel has served as a consultant for Daiichi Sankyo, Lilly, Pozen, Novartis, Bayer, AstraZeneca, Accumetrics, Nanosphere, sanofi-aventis, Boehringer Ingelheim, Merck, Medtronic, Iverson Genetics, CSL, and Haemonetics; has received grants or grants pending from the National Institutes of Health, Daiichi Sankyo, Lilly, Pozen, CSL, AstraZeneca, sanofi-aventis, Haemoscope, Medtronic, Harvard Clinical Research Institute, and Duke Clinical Research Institute; has received payment for lectures, including service on speaker's bureaus, from Lilly, Daiichi Sankyo, Nanosphere, sanofi-aventis, Merck, and Iverson Genetics; has received payment for the development of educational presentations from Schering-Plough, the Discovery Channel, and Pri-Med; holds stock or stock options in Merck, Medtronic, and Pfizer; and holds patents in the area of personalized antiplatelet therapy and interventional cardiology. Dr. Angiolillo has received honoraria for lectures from Bristol-Myers Squibb, sanofi-aventis, Lilly, Daiichi Sankyo, and AstraZeneca; consulting fees from Bristol-Myers Squibb, sanofi-aventis, Lilly, Daiichi Sankyo, The Medicines Company, Portola, Novartis, Medicure, Accumetrics, Arena Pharmaceuticals, AstraZeneca, Merck, Evolva, and Abbott Vascular; and research grants from Bristol-Myers Squibb, sanofi-aventis, GlaxoSmithKline, Otsuka, Lilly, Daiichi Sankyo, The Medicines Company, Portola, Accumetrics, Schering-Plough, AstraZeneca , and Eisai. Dr. Tantry has received payment for lectures and travel support from Accumetrics . Dr. Nolin has served as an uncompensated consultant for Daiichi Sankyo. Drs. Maa, Bailey, and Baker are employees of Daiichi Sankyo. Drs. Jakubowski and Ojeh are employees of Lilly. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. ",
year = "2013",
month = aug,
day = "6",
doi = "10.1016/j.jacc.2013.03.037",
language = "English (US)",
volume = "62",
pages = "505--512",
journal = "Journal of the American College of Cardiology",
issn = "0735-1097",
publisher = "Elsevier USA",
number = "6",
}