Clopidogrel plus aspirin may reduce stroke risk better than aspirin alone after TIA, minor stroke

Patients with transient ischemic attack (TIA) or minor stroke who received clopidogrel and aspirin within 24 hours of symptom onset had a lower stroke risk than those who received aspirin alone, with no apparent increase in hemorrhage risk, a new study indicated.

Researchers performed a randomized, double-blind, placebo-controlled trial at 114 centers in China involving patients who had had minor ischemic stroke or TIA. The study included patients who were at least 40 years or age or older, had been diagnosed with an acute minor ischemic stroke or TIA, and were able to start taking the study drug within 24 hours of symptom onset. Patients were randomly assigned to receive clopidogrel, 300 mg initially followed by 75 mg/d for 90 days, plus aspirin, 75 mg/d for the first 21 days, or placebo plus aspirin, 75 mg/d for 90 days. All patients received open-label aspirin, 75 to 300 mg as determined by their clinicians, on day 1. The study's primary outcome was ischemic or hemorrhagic stroke over 90 days in an intention-to-treat analysis. Results were published online June 26 by the New England Journal of Medicine.

A total of 42,561 patients were screened for the study between October 2009 and July 2012, and 5,170 were randomly assigned, 2,584 to the clopidogrel-aspirin group and 2,586 to the aspirin-alone group. Almost 34% of patients were women, and the median patient age was 62 years. Overall, 8.2% of patients in the clopidogrel-aspirin group and 11.7% of those in the aspirin-only group had a stroke during follow-up (hazard ratio, 0.68; P<0.001). Seven patients in the clopidogrel-aspirin group and eight patients in the aspirin-only group developed moderate or severe hemorrhage (0.3% per group; P=0.73). In addition, the hemorrhagic stroke rate was also 0.3% in each group.

The authors noted that their study was conducted in China, where access to stroke therapies, availability of secondary prevention practices, and distribution of stroke subtypes can differ from the U.S. and Europe, and that their results may not be generalizable to other patient populations with ischemic events. However, they concluded that 21 days of clopidogrel plus aspirin followed by 90 days of clopidogrel alone reduces subsequent stroke risk better than aspirin alone in patients with high-risk TIA or minor ischemic stroke who are first seen within 24 hours of symptom onset.

The author of an accompanying editorial called the results “impressive” but noted that they may not apply to many groups of patients, including those with major ischemic stroke, non-Chinese patients, patients with lower absolute risk for recurrent stroke, and patients who can take advantage of effective secondary stroke prevention. He also pointed out that the results apply only to the first 90 days after ischemic stroke and cannot be generalized beyond that.

“The implication of this trial is that Chinese patients with acute TIA or minor ischemic stroke (onset within the previous 24 hours) who are at high risk for recurrence should be regarded as a medical emergency,” the editorialist wrote. He said such patients should immediately receive clopidogrel plus aspirin for 21 days, then clopidogrel alone until 90 days, then long-term clopidogrel, aspirin, or aspirin plus extended-release dipyridamole. He recommended a bolus loading dose of 162 mg for aspirin and 300 mg for clopidogrel on day 1 in order to rapidly inhibit platelet aggression and stressed that dual antiplatelet therapy has the greatest effect soon after TIA and ischemic stroke.

The editorialist also called for continued enrollment of non-Chinese patients in large clinical trials examining the safety and efficacy of dual and triple antiplatelet therapy after acute TIA and minor ischemic stroke. “Moreover, I hope that researchers will evaluate new antiplatelet agents (e.g., ticagrelor and prasugrel) and new anticoagulant agents (e.g., rivaroxaban) that are effective in atherothrombotic acute coronary syndrome in patients with acute TIA and minor ischemic stroke due to arterial thromboembolism,” he concluded.