“To the best of our knowledge the present investigation is the first pharmacodynamic study to examine and demonstrate the presence of a dose-response effect of smoking on clopidogrel effects in diabetic patients by using an objective measure to quantify cigarette smoking, more precisely by assessing serum cotinine levels,” senior author Dr. Dominick J. Angiolillo, from the University of Florida College of Medicine in Jacksonville, told Reuters Health by email.
“Whereas the optimal healthcare saving goal to reduce atherothrombotic risk is smoking cessation, this objective is not always achieved and many patients with established atherosclerotic disease continue smoking,” he and his colleagues wrote in their paper.
“Defining the optimal antiplatelet treatment strategy in these patients becomes of key importance,” they added.
Cigarette smoking induces CYP1A2, the main isoenzyme responsible for converting clopidogrel into its active metabolite. CYP1A2 metabolism is generally reduced in patients with diabetes.
The current study involved 134 type 2 diabetics on maintenance clopidogrel therapy. Serum cotinine levels were below 3 ng/mL in the 85 nonsmokers, between 3 and 199 ng/mL in the 27 light smokers, and at least 200 ng/mL in the 22 heavy smokers.
The research team found that serum cotinine levels were inversely associated with on-treatment platelet reactivity, and enhanced clopidogrel-induced antiplatelet effects were associated with increased cotinine levels using several measures of platelet reactivity.
Higher serum cotinine levels were significantly associated with lower rates of HPR as defined by all pharmacodynamic cutoff measures.
In multivariable logistic regression analysis, light smokers were 76% less likely than nonsmokers — and heavy smokers were 90% less likely — to have HPR as assessed by light transmittance aggregometry. Results were similar for other methods of assessing HPR.
The authors warn, however, “Despite the fact that clopidogrel effects are enhanced in smokers versus nonsmokers, cardiovascular event rates, including mortality, still remain markedly higher among smokers irrespective of type of antiplatelet treatment regimen used.”
“Given the high risk for recurrent events for smokers, in particular patients with diabetes, it is even more important to emphasize with these patients the importance of complying with their clopidogrel therapy,” Dr. Angiolillo said.
J Am Coll Cardiol Intv 2012;5:293-300.