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CLINICAL RESEARCH: ANTIPLATELET THERAPY

The Association of Cigarette Smoking With Enhanced Platelet Inhibition by Clopidogrel

Kevin P. Bliden, BS^_*, Joseph DiChiara, BS^_*, Lookman Lawal, MD^_*, Anand Singla, MD^_*, Mark J. Antonino, BS^_*, Brian A. Baker, PharmD, William L. Bailey, PharmD, Udaya S. Tantry, PhD^_* and Paul A. Gurbel, MD, FACC^_*,_*

^_* Sinai Center for Thrombosis Research, Baltimore, Maryland
Medical Affairs Department, Daiichi Sankyo, Inc., Parsippany, New Jersey.

Manuscript received January 3, 2008; revised manuscript received April 18, 2008, accepted April 30, 2008.

^_* Reprint requests and correspondence: Dr. Paul A. Gurbel, Sinai Center for Thrombosis Research, Shapiro Building, Room 209, 2401 West Belvedere Avenue, Baltimore, Maryland 21215. (Email: pgurbel{at}lifebridgehealth.org).

Objectives: The purpose of this study was to examine the effect of cigarette smoking on the platelet response to clopidogrel.

Background: Response variability to clopidogrel therapy has been demonstrated. Clopidogrel is metabolically activated by several hepatic cytochrome P450 (CYP) isoenzymes, including CYP1A2. Cigarette smoking induces CYP1A2 and may, therefore, enhance the conversion of clopidogrel to its active metabolite.

Methods: Among 259 consecutive patients undergoing elective coronary stenting; 120 were on chronic clopidogrel therapy and were not loaded; and 139 were clopidogrel naïve and were loaded with 600 mg. There were 104 current smokers (CS) and 155 nonsmokers (NS). The adenosine diphosphate (ADP)-stimulated platelet aggregation (PA) was assessed by conventional aggregometry. The ADP-stimulated total and active glycoprotein (GP) IIb/IIIa expression were assessed with flow cytometry. Low PA was defined as the lowest quartile of 5 µmol/l ADP-induced post-treatment PA.

Results: Current smokers on chronic clopidogrel therapy displayed significantly lower PA and ADP-stimulated active GP IIb/IIIa expression compared with NS (p 0.0008 for both). Similarly, CS treated with 600 mg of clopidogrel displayed greater platelet inhibition and lower active GP IIb/IIIa expression compared with NS (p 0.05). In a multivariate Cox regression analysis, current smoking was an independent predictor of low PA (p = 0.0001).

Conclusion: Clopidogrel therapy in CS is associated with increased platelet inhibition and lower aggregation as compared with NS. The mechanism of the smoking effect deserves further study and may be an important cause of response variability to clopidogrel therapy.

Key Words: clopidogrel • platelets • smoking • stenting

Abbreviations and Acronyms   ADP = adenosine diphosphate   CS = current smokers   CYP = consecutive cytochrome P450   GP = glycoprotein   IPA = inhibition of platelet aggregation   MPA = maximum platelet aggregation   NS = nonsmokers   PCI = percutaneous coronary intervention

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