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PARADOX: Smoking influences pharmacokinetics and pharmacodynamics of clopidogrel

Issue: December 2012

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MIAMI — Smoking appears to affect the pharmacokinetics and pharmacodynamics of clopidogrel, but not prasugrel, according to results from the PARADOX trial.

Paul A. Gurbel, MD, presented data on 54 nonsmokers and 54 smokers with stable CAD on aspirin therapy who were randomly assigned to clopidogrel (75 mg daily for 10 days) or prasugrel (10 mg daily for 10 days) and crossed over after a 14-day washout. The co-primary objectives were the pharmacodynamics in clopidogrel-treated smokers vs. clopidogrel-treated nonsmokers and in prasugrel-treated smokers vs. clopidogrel-treated smokers, according to a press release.

Compared with clopidogrel-treated smokers, clopidogrel-treated nonsmokers had:

• Lower device-related inhibition of platelet aggregation (mean treatment difference: 7.7%; P=.062);
• Lower calculated inhibition of platelet aggregation (mean treatment difference: 9.1%; P=.043).
• Higher P2Y12 reaction units (mean treatment difference: 36%; P=.005); and
• Higher VASP platelet reactivity index (mean treatment difference: 7.6%; P=.042).

In addition, nonsmokers had lower clopidogrel active metabolite concentrations after adjustment for body weight.

Prasugrel treatment was associated with greater inhibition of platelet aggregation and lower P2Y12 reaction units and VASP platelet reactivity index compared with clopidogrel, regardless of smoking status (P<.001 for all).

Paul A. Gurbel

“The poorer antiplatelet response in clopidogrel-treated nonsmokers vs. smokers may explain the inferior clinical benefit of clopidogrel in nonsmokers in major randomized trials, and deserves further investigation,” Gurbel, director of the Sinai Center for Thrombosis Research at the Sinai Hospital of Baltimore and associate professor of medicine at Johns Hopkins University School of Medicine, stated in the release.

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. The PARADOX study is the first prospective, double blind, placebo-controlled study comparing the pharmacokinetics and pharmacodynamics of clopidogrel vs. prasugrel in smokers and nonsmokers, according to the release.

Pharmacodynamics were assessed by the inhibition of platelet aggregation as reported by the VerifyNow-P2Y12 assay.

For more information:

Gurbel PA. Featured clinical research II. Presented at: TCT 2012; Oct. 22-26, 2012; Miami.

Disclosure: The trial was funded by research grants from Daiichi Sankyo and Eli Lilly. Gurbel reports research grant support from CSL Pharmaceuticals, Daiichi Sankyo/Lilly, Haemodynamics, HCRI, Nanosphere and the NIH. He also reports honoraria and consulting fees from Accumetrics, AstraZeneca, Beohringer, CSL, Daiichi Sankyo/Lilly, Medtronic, Merck, Pozen and t2 Biosystems.