In the Intensive Statin and Antiplatelet Therapy for Acute High-Risk Intracranial or Extracranial Atherosclerosis (INSPIRES) trial, Chinese patients with mild ischemic stroke or high-risk transient ischemic attack (TIA) of presumed atherosclerotic cause who were treated with combined clopidogrel–aspirin therapy within 72 hours after stroke onset had a lower risk of new stroke at 90 days than with aspirin therapy alone, researchers report. The findings extend the known benefits of treatment begun within 24 hours after acute mild strokes. However, dual antiplatelet treatment in this study was associated with a low but higher risk of moderate-to-severe bleeding.
Conducted at 222 hospitals in China, the double-blind, randomized, placebo-controlled, 2 X 2 factorial trial included patients with mild ischemic stroke or high-risk TIA of presumed atherosclerotic cause who had not undergone thrombolysis or thrombectomy. Clopidogrel 300 mg on day 1 and 75 mg daily on days 2 to 90 plus aspirin 100 to 300 mg on day 1 and 100 mg daily on days 2 to 21 were compared with clopidogrel placebo and aspirin in the same doses.
Based on a primary efficacy outcome of a new stroke and a primary safety outcome of moderate-to-severe bleeding within 90 days, the investigators found: “A total of 6,100 patients were enrolled, with 3,050 assigned to each trial group. TIA was the qualifying event for enrollment in 13.1% of the patients. A total of 12.8% of the patients were assigned to a treatment group no more than 24 hours after stroke onset, and 87.2% were assigned after 24 hours and no more than 72 hours after stroke onset. A new stroke occurred in 222 patients (7.3%) in the clopidogrel–aspirin group and in 279 (9.2%) in the aspirin group (hazard ratio, 0.79; 95% confidence interval [CI], 0.66 to 0.94; P = 0.008). Moderate-to-severe bleeding occurred in 27 patients (0.9%) in the clopidogrel–aspirin group and in 13 (0.4%) in the aspirin group (hazard ratio, 2.08; 95% CI, 1.07 to 4.04; P = 0.03).”
Editorial: “The INSPIRES trial … provides justification for the inclusion of patients with slightly more severe stroke symptoms than have been evaluated in previous trials (up to an NIHSS score of ≤5, as had been applied in the THALES trial, as compared with the threshold of ≤3 that had been used in the CHANCE and POINT trials); however, this expanded inclusion criterion comes at the cost of a small but accruing bleeding risk that is roughly proportional to the duration of treatment,” writes an editorialist. “This bleeding signal is a reminder that the appropriate duration of dual antiplatelet therapy to balance early benefit and bleeding risk seems to be approximately 21 days and that long-term use of clopidogrel–aspirin is not recommended, given that this approach has not proved beneficial and almost certainly increases bleeding risk. The results of the INSPIRES trial also cannot be generalized to patients with heightened bleeding risks (such as those with a history of cerebral or systemic hemorrhage), to those with severe stroke or cardioembolic stroke (not considered to be atherosclerotic in origin), or to patients undergoing or anticipated to undergo thrombolysis or thrombectomy. In addition, there is uncertain generalization to non–Han Chinese patients, given that Han Chinese patients made up almost the entire trial population.”