title: The association of cigarette smoking with enhanced platelet inhibition by clopidogrel.
abstract: OBJECTIVE
  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 micromol/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 < or = 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 < or = 0.05). In a multivariate Cox regression analysis, current smoking was an independent predictor of low PA (p = 0.0001).
  
  
  CONCLUSIONS
  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.
authors.affiliation: Sinai Center for Thrombosis Research, Baltimore, Maryland 21215, USA.
authors.forename: Kevin P
authors.initials: KP
authors.lastname: Bliden
authors.forename: Joseph
authors.initials: J
authors.lastname: Dichiara
authors.forename: Lookman
authors.initials: L
authors.lastname: Lawal
authors.forename: Anand
authors.initials: A
authors.lastname: Singla
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Antonino
authors.forename: Brian A
authors.initials: BA
authors.lastname: Baker
authors.forename: William L
authors.initials: WL
authors.lastname: Bailey
authors.forename: Udaya S
authors.initials: US
authors.lastname: Tantry
authors.forename: Paul A
authors.initials: PA
authors.lastname: Gurbel
mesh_terms: D000244:Adenosine Diphosphate; D000328:Adult; D000368:Aged; D000077144:Clopidogrel; D019388:Cytochrome P-450 CYP1A2 / Q000187:drug effects; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D010974:Platelet Aggregation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000187:drug effects; D016016:Proportional Hazards Models; D012907:Smoking / Q000009:adverse effects*; D015607:Stents; D013988:Ticlopidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D010975:Platelet Aggregation Inhibitors; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D000244:Adenosine Diphosphate; D000077144:Clopidogrel; D019388:Cytochrome P-450 CYP1A2; D013988:Ticlopidine