Baltimore, MD - Current smokers have increased platelet inhibition and lower platelet aggregation on clopidogrel than nonsmokers, a new study has shown [1]. The authors say that the mechanism of this smoking effect deserves further study and may be an important cause of response variability to clopidogrel therapy.

The study, published in the August 12, 2008 issue of the Journal of the American College of Cardiology (online August 4), was conducted by a group led by Dr Kevin Bliden (Sinai Center for Thrombosis Research, Baltimore, MD)

Senior author Dr Paul Gurbel (Sinai Center for Thrombosis Research) commented to heartwire: "We had a hint of this reaction before, as a previous study we conducted in 96 patients treated with 300 mg of clopidogrel for elective coronary artery stenting showed that 28% of the responders to clopidogrel were smokers, compared with 13% of the nonresponders. And another study by Matetzky et al has reported that smokers were less often clopidogrel resistant."

"We didn't really make much of our earlier observation, as it was such a small study, but then there was an abstract presented at the ACC in 2006 suggesting that smoking appeared to influence the clinical effect of clopidogrel in the CREDO study, with a larger reduction in clinical events seen with the drug in smokers than in nonsmokers. And there has subsequently been an analysis of the CLARITY trial showing a similar observation. This gave us the interest to look further at our data set," Gurbel said. He added that smoking has also been shown to induce the CYP1A2 enzyme, which converts clopidogrel to its active metabolite.

His team therefore analyzed platelet-function data in 259 patients (104 smokers and 155 nonsmokers) undergoing elective PCI treated with clopidogrel consecutively enrolled in clinical trials at their hospital. Previous smokers were excluded. Of the patients included, 120 were on chronic clopidogrel therapy and were not loaded and 139 were clopidogrel naive and were loaded with 600 mg. ADP-stimulated platelet aggregation was assessed by conventional aggregometry and the ADP-stimulated total and active GP IIb/IIIa expression were assessed with flow cytometry.

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

Gurbel commented to heartwire: "Although there have already been some data suggesting that smoking may affect the response to clopidogrel, our findings show that this can be translated into an antiplatelet effect." Noting that clopidogrel has to be activated by cytochrome P450 enzymes, which produce the active metabolite, and that smoking induces one of these enzymes, Gurbel added: "We think that smoking upregulates this pathway." He noted that many other agents that can modulate P450 activity may have an effect on the amount of clopidogrel active metabolite produced. These include Saint John's wort, which also upregulates the pathway, and omeprazole, which competes for the site on the P450 enzymes and therefore slows production of the clopidogrel active metabolite.

Gurbel said that it is not possible to make any clinical recommendations on altering the dose of clopidogrel in smokers or nonsmokers on the basis of these data. "Our trial is not a prospective study, and while we believe our observations are real, they are not enough to base clinical decisions on," he told heartwire. "In addition, the effect of smoking will probably not be a simple formula, as its influence will differ from one individual to another. I certainly do not suggest people start smoking to get an increased effect from clopidogrel. Rather, this study highlights the limitations of using a prodrug that needs to be metabolized to exert an antiplatelet effect and suggests that a direct-acting antiplatelet agent would make more sense," he added.