国家神经系统疾病临床医学研究中心数据管理与共享系统
Data Management And Sharing System of China National Clinical Research Center for Neurological Diseases
Effect of Clopidogrel by Smoking Status on Secondary Stroke Prevention
基本信息
- 负责人：Bruce Ovbiagele,Jing Wang
- 数据来源： CHANCE
- 论文编号：CHANCE20190036
- 发表时间：2017-01-17
2017-01-17
已发表文章
主要研究背景及目的
Smoking is an established risk factor for stroke and has been linked to poor functional outcomes after acute ischemic stroke. But recently, a smoking-clopidogrel paradox among patients with symptomatic coronary artery disease was observed: smokers treated with clopidogrel had a lower occurrence of MI compared to non-smokers1. It has been postulated that cigarette smoking could influence the antiplatelet effect of clopidogrel by influencing the activity of cytochrome P450 1A2 (CYP1A2)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.
方法
We analyzed the data from the Clopidogrel in High-Risk Patients with Acute Non-disabling Cerebrovascular Events (CHANCE) trial3. In this trial, smoking status was self-reported at the time of enrollment. Subjects were asked if they smoked or had ever smoked > 5 cigarettes per day for at least 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 more than 1 month; non-smokers were defined as those who never smoked or patients who smoked ≤ 5 cigarettes per day currently or previously4. Also, 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 HRs 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.
结论
Our analysis of the CHANCE trial dataset showed that, there was a statistical interaction between smoking and clopidogrel treatment, indicating that smoking status modified the effect of clopidogrel treatment on outcome. This is to say, compared to patients who never smoked, current smokers with a recent minor stroke or TIA had a greater benefit in stroke prevention at 90 days from clopidogrel. Current smokers are predisposed to cardiovascular events through the mechanisms of increasing inflammation, oxidative stress, etc, which are largely thrombotic5, but clopidogrel likely has an enhanced effect in smokers vs. non-smokers because smoking is an inducer of clopidogrel metabolism, resulting in greater degrees of platelet inhibition and lesser platelet aggregation with clopidogrel2. However large prospective trials are needed to confirm this effect among stroke patients.
主要结果
Among the 5,170 patients enrolled in this trial, 2949 (57.0%) were non-smokers, 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%); HR 0.52, 95% CI: 0.38-0.73, p<0.01], and for non-smokers the combination treatment was also better but to a much lesser degree [137 (9.3%) vs. 174 (11.8%); HR 0.78, 95% CI: 0.62-0.98, p=0.03]. The smoking and clopidogrel treatment interaction for entire cohort was p=0.06.