Publications of the Week: Dual antiplatelet therapy following ischemic stroke

A McMaster Perspective interview discussing these findings will follow soon.

Background: Dual antiplatelet therapy (DAPT), typically involving acetylsalicylic acid (ASA) and a P2Y₁₂ inhibitor, can decrease the risk of recurrent stroke as compared with ASA alone when treatment is started within 24 hours after a mild acute ischemic stroke. The effect of DAPT when started within 72 hours after the onset of acute cerebrovascular ischemia is uncertain.

Methods: This was a randomized, double-blind, placebo-controlled trial involving patients in China with mild ischemic stroke or high-risk transient ischemic attack (TIA) due to presumed atherosclerosis, who did not receive thrombolytic therapy or thrombectomy. Patients were randomly allocated within 72 hours after symptom onset to receive clopidogrel (300 mg on day 1 and 75 mg/d on days 2-90) plus ASA (100-300 mg on day 1 and 100 mg/d on days 2-21) or matching clopidogrel placebo plus ASA (100-300 mg on day 1 and 100 mg/d on days 2-90). The primary efficacy outcome was new stroke, and the primary safety outcome was moderate-to-severe bleeding occurring within 90 days.

Results: There were 6100 patients enrolled, 3050 in each treatment group. TIA was the qualifying event in 13.1% of patients; 12.8% of patients were assigned to the treatment groups within 24 hours after stroke onset and 87.2%, within 24 to 72 hours after stroke onset. A new stroke occurred in 7.3% (222 patients) in the clopidogrel-ASA group and in 9.2% (279 patients) in the ASA group (hazard ratio [HR], 0.79; 95% CI, 0.66-0.94; P = .008). Moderate-to-severe bleeding occurred in 0.9% (n = 27) of patients in the clopidogrel-ASA group and in 0.4% (n = 13) of patients in the ASA group (HR, 2.08; 95% CI, 1.07-4.04; P = .03).

Conclusions: In patients with mild ischemic stroke or high-risk TIA of presumed atherosclerotic cause, combined clopidogrel-ASA therapy initiated within 72 hours after stroke onset led to a lower risk of a new stroke at 90 days than ASA therapy alone but was associated with a higher risk of moderate-to-severe bleeding.

McMaster editors’ commentary: The generalizability of results is a concern, as this trial was done mainly in Han Chinese men (only 35% of those enrolled were women), while there are genetic factors that affect the bioavailability and action of clopidogrel. As expected, the bleeding risk was higher in the DAPT group, but the overall risk was low. These concerns aside, this study provides evidence that DAPT can be extended >24 hours after symptom onset if clinicians are uncertain about its use and validates an extended time window for DAPT initiation for those clinicians who are already doing it. Patients with high-risk TIA (ABCD² score >4) or mild ischemic stroke (National Institutes of Health Stroke Scale [NIHSS] score <5) of a presumed atherosclerotic, noncardioembolic origin should be considered for rapid initiation of DAPT and risk factor modification.