VANCOUVER, BCFor both smokers and nonsmokers, adding clopidogrel to aspirin therapy is associated with a reduced risk of second stroke in the 90 days following a stroke or high-risk transient ischemic attack (TIA)—but that association is much stronger among smokers, according to findings presented at the 68th AAN Annual Meeting.

“In patients with minor stroke or TIA who received add-on clopidogrel versus placebo treatment to aspirin, compared to not smoking, cigarette smoking was associated with a lower risk of subsequent stroke, without a greater risk of hemorrhage,” said lead study author Bruce Ovbiagele, MD, MSc, Professor and Chair of the Medical University of South Carolina’s Department of Neurology, in Charleston, SC.

“This potential ‘smokers-clopidogrel paradox’ should not be seen as reason to continue smoking after stroke, since the risk of ischemic events is still higher in current smokers than in non-/ex-smokers,” he advised. “Indeed, if we do not implement effective smoking cessation programs, it is likely that smoking-related diseases and deaths will continue to rise.”

What it does suggest: “that clopidogrel might be the antiplatelet agent of choice in recent or current smokers for secondary stroke prevention,” he said.

Smoking is an established risk factor for stroke, and “has been linked to poor functional outcomes after acute ischemic stroke.”

Recently, “a smoking-thrombolysis paradox has been recognized among patients with an acute myocardial infarction and an acute ischemic stroke,” he noted. “In these studies, smokers were observed to have better outcomes after thrombolysis than nonsmokers.”

In addition, a smoking-clopidogrel paradox has been observed among symptomatic patients with coronary artery disease: “smokers treated with clopidogrel had a lower occurrence of myocardial infarction compared to nonsmokers,” he said. It is postulated that cigarette smoking may potentiate the antiplatelet effect of clopidogrel by influencing the activity of cytochrome P450 1A2.

To determine whether smoking status affects clopidogrel’s association with a reduced risk of second stroke, Dr. Ovbiagele and colleagues analyzed data from the multi-center, randomized, double-blind, placebo-controlled Clopidogrel in High-Risk Patients with Acute Non-disabling Cerebrovascular Events (CHANCE) clinical trial. Conducted in China, the CHANCE trial enrolled 5,170 patients with minor ischemic stroke or high-risk TIA who were randomly assigned within 24 hours of symptom onset to clopidogrel for 90 days plus aspirin for the first 21 days or placebo plus aspirin for 90 days.

Smoking status was self-reported at the time of enrollment. Among the participants, 2,949 (57.0%) were nonsmokers; 1,705 (33%) were current smokers; and 526 (10.0%) were ex-smokers, who were excluded from the analysis, Dr. Ovbiagele said.

“Current smokers were younger, more likely to be male and have hypercholesterolemia, but had lower ABCD2 scores and were less likely to have medical history of angina, congestive heart failure, atrial fibrillation, hypertension, and diabetes mellitus,” he added.

The study’s primary efficacy outcome was any stroke, ischemic or hemorrhagic, during the 90-day treatment.

A total of 1,468 (49.8%) nonsmokers and 870 (51.0%) current smokers were treated with clopidogrel plus aspirin and the others received aspirin alone.

Results showed that among current smokers, clopidogrel plus aspirin was superior to placebo plus aspirin, 6.8% second-strokes vs. 12% (hazard ratio [HR] 0.52; 95% CI: 0.38–0.73). Among nonsmokers, clopidogrel was more weakly associated with reduced second-stroke risk, 9.3% vs. 11.8% (HR 0.78; 95% CI: 0.62–0.98).

Among current smokers, patients on clopidogrel plus aspirin had a lower rate and risk of any stroke (P<0.01) and, among nonsmokers, aspirin was also better than aspirin but to a much lesser degree for the primary outcome (P=0.03).

“Smoking and clopidogrel treatment interaction for outcome of any stroke in the entire cohort showed a strong statistical trend (P=0.06),” he concluded.