Smoking, clopidogrel, and mortality in patients with established cardiovascular disease.
BACKGROUND
Smoking increases platelet aggregability and the degree of platelet inhibition by clopidogrel on ex vivo platelet function tests. Whether smoking status affects the relationship between clopidogrel and clinical outcomes is unknown.


RESULTS
We evaluated the relationship between smoking status (current smoker, former smoker, or never-smoker) and treatment with clopidogrel on the risk of all-cause, cardiovascular, and cancer mortality among the 12 152 participants from the CHARISMA (Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance) trial who had established cardiovascular disease. Current smoking was associated with an increase in all-cause (adjusted hazard ratio [HR] 2.58, 95% confidence interval [CI] 1.85 to 3.60), cardiovascular (HR 2.26, 95% CI 1.48 to 3.45), and cancer (HR 3.56, 95% CI 1.96 to 6.46) mortality compared with never smoking. The impact of clopidogrel on mortality differed by smoking status (P for interaction=0.018 for current smokers). Among current smokers, clopidogrel was associated with a reduction in all-cause mortality (HR 0.68, 95% CI 0.49 to 0.94); clopidogrel did not reduce all-cause mortality among former smokers (HR 0.95, 95% CI 0.75 to 1.19) or never-smokers (HR 1.14, 95% CI 0.83 to 1.58). A similar pattern was noted for cardiovascular mortality. As expected, no relationship was observed between clopidogrel and cancer mortality by smoking status. The risk of bleeding appeared to differ according to smoking status; randomized clopidogrel was associated with a significantly increased risk of severe or moderate bleeding (HR 1.62, P=0.04) among current smokers but a smaller and nonsignificant increase among never-smokers (HR 1.31, P=0.15).


CONCLUSIONS
Clopidogrel therapy may be more effective in current smokers, but it may also confer a greater bleeding risk than in nonsmokers. Further studies are needed to investigate this possibility.
Berger
Jeffrey S
JS
New York University School of Medicine, New York, NY, USA.
Bhatt
Deepak L
DL
Steinhubl
Steven R
SR
Shao
Mingyuan
M
Steg
P Gabriel
PG
Montalescot
Gilles
G
Hacke
Werner
W
Fox
Keith A
KA
Lincoff
A Michael
AM
Topol
Eric J
EJ
Berger
Peter B
PB
D000368:Aged; D002318:Cardiovascular Diseases / Q000188:drug therapy* / Q000401:mortality*; D000077144:Clopidogrel; D004311:Double-Blind Method; D005260:Female; D005500:Follow-Up Studies; D006470:Hemorrhage / Q000139:chemically induced / Q000209:etiology; D006801:Humans; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D012907:Smoking / Q000009:adverse effects / Q000188:drug therapy* / Q000401:mortality*; D013988:Ticlopidine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use
D000077144:Clopidogrel; D013988:Ticlopidine