Effect of Clopidogrel by Smoking Status on Secondary Stroke Prevention
Authors: Bruce Ovbiagele, Jing Wang, S. Claiborne Johnston, Anxin Wang, David Wang, Yongjun Wang, Xingquan Zhao, Yilong Wang
Journal: Circulation (2017)

moking is an established risk factor for stroke and has been linked to poor functional outcomes after acute ischemic stroke.Recently, a smoking-clopidogrel paradox among patients with symptomatic coronary artery disease was observed: smokers treated with clopidogrel had a lower occurrence of myocardial infarction compared with nonsmokers. 1 It has been postulated that cigarette smoking could influence the antiplatelet effect of clopidogrel by influencing the activity of cytochrome P450 1A2. 2 However, whether clopidogrel has a differential effect by smoking status among stroke patients is unknown.The objective of this study was to assess whether clopidogrel has a differential effect on secondary stroke prevention by smoking status.We analyzed the data from the CHANCE trial (Clopidogrel in High-Risk Patients with Acute Non-Disabling Cerebrovascular Events). 3 The CHANCE protocol was approved by the ethics committee at each study center.All participants or their legal proxies provided written informed consent.In this trial, smoking status was self-reported at the time of enrollment.Subjects were asked whether they smoked or had ever smoked >5 cigarettes per day for ≥1 month in their lives.Current smokers were defined as those who smoked >5 cigarettes per day during the last month; ex-smokers were defined as those who had smoked >5 cigarettes previously and had stopped for ˃1 month; nonsmokers were defined as those who never smoked or patients who smoked ≤5 cigarettes per day currently or previously. 4Also, since the time of quitting in ex-smokers can be highly variable; ex-smokers were excluded from this analysis.The primary efficacy outcome was any stroke (ischemic or hemorrhagic) during 90 days.Cox proportional hazards regression model was used to calculate hazard ratios of primary outcomes according to smoking status as well as treatment, and log-rank tests were used to calculated P values.P for smoking status x treatment was also calculated in the Cox proportional hazards regression model.The Kaplan-Meier curves for primary outcomes by smoking status and treatment were plotted and compared using the log-rank test.All statistical tests were 2-sided, and significant level was set at 0.05.Among the 5170 patients enrolled in this trial, 2949 (57.0%) were nonsmokers, 1705 (33.0%) were current smokers, and 516 (10.0%) were ex-smokers (excluded).For secondary stroke prevention, clopidogrel + aspirin was superior to aspirin alone in smokers (59 [6.8%] vs 100 [12.0%]; hazard ratio 0.52, 95% confidence interval, 0.38-0.73;P<0.01); and for nonsmokers, the combination treatment was also better but to a much lesser degree (137 [9.3%] vs 174 [11.8%]; hazard ratio 0.78, 95% confidence interval, 0.62-0.98;P=0.03).The smoking and clopidogrel treatment interaction for the entire cohort was P=0.06.The benefit of clopidogrel-aspirin in the group of current smokers compared with the other 3 groups (clopidogrelaspirin-treated nonsmokers, aspirin-treated current smokers, and aspirin-treated nonsmokers) for the primary outcome is illustrated in the Figure .Our analysis of the CHANCE trial dataset showed a statistical interaction between smoking and clopidogrel treatment, indicating that smoking status modified the effect of clopidogrel treatment on outcome.