Author + information
- Received July 27, 2011
- Revision received September 19, 2011
- Accepted September 28, 2011
- Published online March 1, 2012.
- Masafumi Ueno, MD⁎,†,
- José Luis Ferreiro, MD⁎,
- Bhaloo Desai, PhD⁎,
- Salvatore D. Tomasello, MD⁎,
- Antonio Tello-Montoliu, MD, PhD⁎,
- Davide Capodanno, MD⁎,
- Piera Capranzano, MD⁎,
- Murali Kodali, MD⁎,
- Kodlipet Dharmashankar, MD⁎,
- Ronald K. Charlton, PhD‡,
- Theodore A. Bass, MD⁎ and
- Dominick J. Angiolillo, MD, PhD⁎,⁎ ()
- ↵⁎Reprint requests and correspondence:
Dr. Dominick J. Angiolillo, Division of Cardiology, University of Florida College of Medicine–Jacksonville, 655 West 8th Street, Jacksonville, Florida, 32209
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 μmol/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.
Dr. Ferreiro has received honoraria for lectures from Daiichi Sankyo, Inc. and Eli Lilly Co. Dr. Bass has reported receiving honoraria for lectures from Eli Lilly Co. and Daiichi Sankyo, Inc., consulting fees from Eli Lilly Co. and Daiichi Sankyo, Inc., and research grants from Baxter. Dr. Angiolillo has received honoraria for lectures from Bristol-Myers Squibb, Sanofi-Aventis, Eli Lilly Co., and Daiichi Sankyo, Inc., consulting fees from AstraZeneca, Bristol-Myers Squibb, Sanofi-Aventis, Eli Lilly Co., Daiichi Sankyo, Inc., The Medicines Company, Portola Pharmaceuticals, Novartis, Medicure, Accumetrics, Arena Pharmaceuticals, AstraZeneca, and Abbott Vascular; and research grants and funding from Bristol-Myers Squibb, Sanofi-Aventis, GlaxoSmithKline, Otsuka, Eli Lilly Co., Daiichi Sankyo, The Medicines Company, Portola Pharmaceuticals, Accumetrics, Schering-Plough, AstraZeneca, Eisai, the James and Esther King Biomedical Research Program, and the University of Florida College of Medicine–Jacksonville. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. Drs. Ueno and Ferreiro contributed equally to this work.
- Received July 27, 2011.
- Revision received September 19, 2011.
- Accepted September 28, 2011.
- American College of Cardiology Foundation