Clopidogrel and Aspirin in Acute Ischemic Stroke and High-Risk TIA

Abstract

Background: Combination antiplatelet therapy with clopidogrel and aspirin may reduce the rate of recurrent stroke during the first 3 months after a minor ischemic stroke or transient ischemic attack (TIA). A trial of combination antiplatelet therapy in a Chinese population has shown a reduction in the risk of recurrent stroke. We tested this combination in an international population.

Methods: In a randomized trial, we assigned patients with minor ischemic stroke or high-risk TIA to receive either clopidogrel at a loading dose of 600 mg on day 1, followed by 75 mg per day, plus aspirin (at a dose of 50 to 325 mg per day) or the same range of doses of aspirin alone. The dose of aspirin in each group was selected by the site investigator. The primary efficacy outcome in a time-to-event analysis was the risk of a composite of major ischemic events, which was defined as ischemic stroke, myocardial infarction, or death from an ischemic vascular event, at 90 days.

Results: A total of 4881 patients were enrolled at 269 international sites. The trial was halted after 84% of the anticipated number of patients had been enrolled because the data and safety monitoring board had determined that the combination of clopidogrel and aspirin was associated with both a lower risk of major ischemic events and a higher risk of major hemorrhage than aspirin alone at 90 days. Major ischemic events occurred in 121 of 2432 patients (5.0%) receiving clopidogrel plus aspirin and in 160 of 2449 patients (6.5%) receiving aspirin plus placebo (hazard ratio, 0.75; 95% confidence interval [CI], 0.59 to 0.95; P=0.02), with most events occurring during the first week after the initial event. Major hemorrhage occurred in 23 patients (0.9%) receiving clopidogrel plus aspirin and in 10 patients (0.4%) receiving aspirin plus placebo (hazard ratio, 2.32; 95% CI, 1.10 to 4.87; P=0.02).

Conclusions: In patients with minor ischemic stroke or high-risk TIA, those who received a combination of clopidogrel and aspirin had a lower risk of major ischemic events but a higher risk of major hemorrhage at 90 days than those who received aspirin alone. (Funded by the National Institute of Neurological Disorders and Stroke; POINT ClinicalTrials.gov number, NCT00991029 .).

Figure 1.. Enrollment and Outcomes (Intention-to-Treat Analysis).

Patients who discontinued a trial drug were included in the intention-to-treat analysis, as were patients who withdrew consent or were lost to follow-up. In the as-treated analysis, data for patients who received a trial drug were censored at the time of discontinuation.

Figure 2.. Primary Efficacy and Safety Outcomes.

Shown are the percentages of patients with the primary efficacy outcome (a composite of ischemic stroke, myocardial infarction, or death from ischemic vascular causes) (Panel A) and the primary safety outcome of major hemorrhage (Panel B). Inset graphs show the same data on an expanded y axis.

Figure 3.. Primary Efficacy Outcome, According to Predefined Subgroup.

Race was determined by the investigator. Among patients with ischemic stroke, the qualifying score for participation in the trial was 3 or less on the National Institutes of Health Stroke Scale (NIHSS), which ranges from 0 to 42, with higher scores indicating greater stroke severity. The NIHSS score was missing at baseline for 23 patients, and 6 patients had an NIHSS score above 3 and were excluded from the subgroup analysis of NIHSS score (score of 0 or 1 vs. score of 2 or 3). Among patients with transient ischemic attack (TIA), the qualifying score was 4 or more on the ABCD² scale, which is used to estimate the risk of recurrent stroke on the basis of age, blood pressure, clinical features, duration of symptoms, and presence of diabetes, with scores ranging from 0 to 7, with higher scores indicating a greater risk of stroke. CT denotes computed tomography, and MRI magnetic resonance imaging.