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

Study Questions:

What is the dose-response effect of cigarette smoking and its impact on high on-treatment platelet reactivity (HPR) in patients with diabetes mellitus treated with clopidogrel?


A total of 134 type 2 diabetes mellitus patients on maintenance aspirin and clopidogrel therapy were studied. Patients were divided into three groups according to cotinine levels: <3 ng/ml (nonsmokers), 3-199 ng/ml (light smokers), and ≥200 ng/ml (heavy smokers). Platelet function was assessed by light transmittance aggregometry, VerifyNow P2Y12 assay (Accumetrics, San Diego, CA), and vasodilator-stimulated phosphoprotein. Rates of HPR were defined using established cutoff values. Control for potential confounders and analysis of independent correlates of HPR were performed with a logistic regression model.


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 ┬Ámol/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.


The authors concluded that cigarette smoking is associated with a dose-response effect on clopidogrel-induced antiplatelet effects and lower rates of HPR in diabetes mellitus patients.


This study examines and demonstrates the presence of a dose-response enhancement effect of smoking on clopidogrel response. Despite the fact that clopidogrel effects are enhanced in smokers versus nonsmokers, cardiovascular event rates, including mortality, still remain markedly higher among smokers irrespective of type of antiplatelet treatment regimen used. Smoking is a major risk factor for atherothrombotic cardiovascular processes, and smoking cessation is a Class I recommendation for secondary prevention of ischemic events in patients with vascular disease, and should be actively pursued in each and every patient.

Clinical Topics: Prevention, Smoking

Keywords: Microfilament Proteins, Platelet Aggregation Inhibitors, Diabetes Mellitus, Type 2, Coronary Disease, Ticlopidine, Blood Platelets, Smoking, Cotinine, Platelet Aggregation, Phosphoproteins, Cell Adhesion Molecules, Logistic Models

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