Cigarette Smoking is Associated with a Dose-Response Effect in Clopidogrel Treated Patients with Diabetes Mellitus and Coronary Artery Disease: Results of a Pharmacodynamic Study

Objectives This study sought to assess the presence of a dose-response effect of cigarette smoking and its impact on high on-treatment platelet reactivity (HPR) in patients with diabetes mellitus treated with clopidogrel. Background Cigarette smoking is an inducer of cytochrome P450 1A2, a hepatic enzyme involved in clopidogrel metabolism. If cigarette smoking is associated with a dose-response effect on pharmacodynamic measures in clopidogrel-treated patients is unknown. Methods A total of 134 type 2 diabetes mellitus patients on maintenance aspirin and clopidogrel therapy were studied. Patients were divided into 3 groups according to cotinine levels: <3 ng/ml (nonsmokers), 3 to 199 ng/ml (light smokers), and >= 200 ng/ml (heavy smokers). Platelet function was assessed by light transmittance aggregometry, VerifyNow P2Y12 assay (Accumetrics, San Diego, California), and vasodilator-stimulated phosphoprotein. Rates of HPR were defined using established cutoff values. Results A dose-response effect was observed for all pharmacodynamic parameters tested. Serum cotinine levels were inversely associated with platelet reactivity as assessed by light transmittance aggregometry using 5 and 20 mu mol/l adenosine diphosphate (p < 0.0001 for all). Accordingly, platelet disaggregation increased with levels of serum cotinine (p < 0.0001). Similar results were found with P2Y12 reaction units (p < 0.0001) and inhibition of platelet aggregation (p = 0.005) as defined by VerifyNow P2Y12 testing, and platelet reactivity index (p = 0.002) as assessed by vasodilator-stimulated phosphoprotein. Higher serum cotinine levels were significantly associated with lower rates of HPR, as defined according to various pharmacodynamic cutoff measures. Conclusions Cigarette smoking is associated with a dose-response effect on clopidogrel-induced antiplatelet effects and lower rates of HPR in diabetes mellitus patients