The influence of smoking status on the pharmacokinetics and pharmacodynamics of clopidogrel and prasugrel: the PARADOX study

J Am Coll Cardiol. 2013 Aug 6;62(6):505-12. doi: 10.1016/j.jacc.2013.03.037. Epub 2013 Apr 16.


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 P2Y12 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 P2Y12 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: AM; AUC; C-IPA; CAD; CI; CYP; CYP1A2; CYP2C19; DR-IPA; EM; HPR; LS; ORE; P2Y(12) reaction units; PD; PK; PRI; PRU; RM; VASP; active metabolite; area under the curve; calculated inhibition of platelet aggregation; clopidogrel; confidence interval; coronary artery disease; cytochrome; device-reported inhibition of platelet aggregation; extensive metabolizers; high on-treatment platelet reactivity; least squares; odds ratio estimates; pharmacodynamics; pharmacokinetics; platelet; platelet reactivity index; prasugrel; reduced metabolizer; smoking; vasodilator-stimulated phosphoprotein phosphorylation.

Publication types

  • Multicenter Study
  • Randomized Controlled Trial

MeSH terms

  • Aged
  • Aryl Hydrocarbon Hydroxylases / genetics
  • Aspirin / therapeutic use
  • Clopidogrel
  • Coronary Artery Disease / drug therapy
  • Coronary Artery Disease / metabolism*
  • Cross-Over Studies
  • Cytochrome P-450 CYP1A2 / metabolism
  • Cytochrome P-450 CYP2C19
  • Double-Blind Method
  • Drug Therapy, Combination
  • Female
  • Humans
  • Male
  • Middle Aged
  • Piperazines / pharmacokinetics*
  • Piperazines / therapeutic use
  • Platelet Aggregation Inhibitors / pharmacokinetics*
  • Platelet Aggregation Inhibitors / therapeutic use
  • Platelet Function Tests
  • Prasugrel Hydrochloride
  • Prospective Studies
  • Purinergic P2Y Receptor Antagonists / pharmacokinetics*
  • Purinergic P2Y Receptor Antagonists / therapeutic use
  • Smoking / metabolism*
  • Thiophenes / pharmacokinetics*
  • Thiophenes / therapeutic use
  • Ticlopidine / analogs & derivatives*
  • Ticlopidine / pharmacokinetics
  • Ticlopidine / therapeutic use


  • Piperazines
  • Platelet Aggregation Inhibitors
  • Purinergic P2Y Receptor Antagonists
  • Thiophenes
  • Clopidogrel
  • Aryl Hydrocarbon Hydroxylases
  • CYP1A2 protein, human
  • CYP2C19 protein, human
  • Cytochrome P-450 CYP1A2
  • Cytochrome P-450 CYP2C19
  • Prasugrel Hydrochloride
  • Ticlopidine
  • Aspirin

Associated data