The association of cigarette smoking with enhanced platelet inhibition by clopidogrel.
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.
Bliden
Kevin P
KP
Sinai Center for Thrombosis Research, Baltimore, Maryland 21215, USA.
Dichiara
Joseph
J
Lawal
Lookman
L
Singla
Anand
A
Antonino
Mark J
MJ
Baker
Brian A
BA
Bailey
William L
WL
Tantry
Udaya S
US
Gurbel
Paul A
PA
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
D010975:Platelet Aggregation Inhibitors; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D000244:Adenosine Diphosphate; D000077144:Clopidogrel; D019388:Cytochrome P-450 CYP1A2; D013988:Ticlopidine