PARADOX: Smoking Enhances Effect of Clopidogrel, Prasugrel Unaffected by Smoking Status

MIAMI BEACH, FLA.—The antiplatelet effect of clopidogrel is reduced in nonsmokers compared with smokers, but smoking status does not appear to have the same effect on prasugrel, according to a study presented on TCT 2012.

Prior analyses from clinical outcome studies including CAPRIE, CHARISMA, CLARITY-TIMI 28, CREDO and CURE have shown that smokers have much more robust treatment benefits than nonsmokers with clopidogrel. In addition, the efficacy of double-dose clopidogrel was confined to smokers in the PCI cohort of the CURRENT trial.

To determine the influence of smoking status on the pharmacokinetic and pharmacodynamic profiles of clopidogrel and prasugrel, Paul A. Gurbel, MD, from the Sinai Center for Thrombosis Research at Johns Hopkins University School of Medicine in Baltimore, and colleagues launched a prospective, double blind, placebo-controlled study of 56 nonsmokers and 54 smokers with stable CAD who were on aspirin therapy and randomized to clopidogrel (75 mg daily for 10 days) or prasugrel (10 mg daily for 10 days). Cross-over occurred after a 14-day washout period.

Pharmacodynamic profiles were assessed using VerifyNow P2Y12 assay (Accumetrics) and vasodilator-associated phosphoprotein platelet reactivity index (VASP PRI).

Prasugrel not affected by smoking

 In the primary analysis of the VerifyNow device-reported inhibition of platelet aggregation (IPA), nonsmokers on clopidogrel demonstrated greater platelet reactivity than any other group, while prasugrel showed significantly greater antiplatelet effects than clopidogrel regardless of smoking status (see Figure). Additionally, in the post-hoc analysis, the VerifyNow calculated-IPA showed a significantly lower level in nonsmokers compared to smokers on clopidogrel therapy.

“Irrespective of the smoking status, prasugrel was associated with a greater antiplatelet effect than clopidogrel, and smoking had no influence on the pharmacodynamic effect of prasugrel,” Gurbel said.

“In conclusion, PARADOX is the first prospective study to evaluate the influence of smoking status on pharmacokinetic and pharmacodynamic profile of clopidogrel and prasugrel,” Gurbel said. “Smoking influenced the pharmacokinetic and pharmacodynamic profile of clopidogrel, but not prasugrel. [In addition], nonsmokers exhibited reduced responsiveness to clopidogrel vs. smokers. The findings of this pharmacodynamic study may help to explain the results observed in the analyses of the large-scale clinical trials, suggesting an attenuated clinical effect of clopidogrel therapy in patients who do not smoke.”