Impact of Cigarette Smoking on Levels on Platelet P2Y12 Mediated Platelet Inhibition in Prasugrel Treated Patients: Results of a Pharmacodynamic Study

Introduction: In patients with established vascular disease, smoking is a strong independent risk factor for adverse outcomes, including mortality. Several investigations have shown that cigarette smoking induces cytochrome P450 enzymatic activity which in turn increases clopidogrel metabolism leading to enhanced pharmacodynamic (PD) effects compared with non-smokers. These findings may explain the heightened clinical benefits of clopidogrel in smokers compared with nonsmokers. Prasugrel has superior PD and clinical effects compared with clopidogrel. The aim of this study was to evaluate the impact of cigarette smoking on platelet P2Y 12 mediated effects among patients on maintenance prasugrel therapy. Methods: A total of 156 patients on maintenance prasugrel therapy (10mg/qd) for at least 7-days, in addition to aspirin (81mg/qd), who previously underwent a percutaneous coronary intervention in the setting of an acute coronary syndrome were studied. An objective assessment of smoking status was performed by measuring serum levels of cotinine (the major stable degradation product of nicotine metabolite). Cotinine levels >3 ng/ml identified patients as smokers. PD assessments to determine platelet P2Y 12 activity was performed by flow cytometric assessment of vasodilator-stimulated phosphoprotein (VASP). Results were reported as platelet reactivity index (PRI). A PRI>50% identified patients with high on-treatment platelet reactivity (HPR). Results: According to cotinine serum levels, patients were divided into smokers (n=55) and nonsmokers (n=101). PRI values in the overall population were not normally distributed (median [interquartile range (IQR)] 30 [19.1-38.9]) and 14.6% of patients had HPR. PRI levels were not significantly different between smokers and nonsmokers (33.7 [13.6-46.9] vs 28.8 [21.7-37.3], p= 0.56). There was no correlation between PRI values and cotinine levels (r=0.03; p=0.74). Accordingly, HPR rates were similar between smokers and nonsmokers (18.2% vs 12.9%; p=0.25). Conclusions: In patients on maintenance prasugrel therapy, cigarette smoking status, as objectively assessed by serum levels of cotinine, does not affect the degree of platelet P2Y 12 mediated inhibition.