Gao Y, Chen W, Pan Y, et al. Dual Antiplatelet Treatment up to 72 Hours after Ischemic Stroke. N Engl J Med. 2023 Dec 28;389(26):2413-2424. doi: 10.1056/NEJMoa2309137. (Original study)

BACKGROUND: Dual antiplatelet treatment has been shown to lower the risk of recurrent stroke as compared with aspirin alone when treatment is initiated early (=24 hours) after an acute mild stroke. The effect of clopidogrel plus aspirin as compared with aspirin alone administered within 72 hours after the onset of acute cerebral ischemia from atherosclerosis has not been well studied.

METHODS: In 222 hospitals in China, we conducted a double-blind, randomized, placebo-controlled, two-by-two factorial trial involving patients with mild ischemic stroke or high-risk transient ischemic attack (TIA) of presumed atherosclerotic cause who had not undergone thrombolysis or thrombectomy. Patients were randomly assigned, in a 1:1 ratio, within 72 hours after symptom onset to receive 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) or matching clopidogrel placebo plus aspirin (100 to 300 mg on day 1 and 100 mg daily on days 2 to 90). There was no interaction between this component of the factorial trial design and a second part that compared immediate with delayed statin treatment (not reported here). The primary efficacy outcome was new stroke, and the primary safety outcome was moderate-to-severe bleeding - both assessed within 90 days.

RESULTS: A total of 6100 patients were enrolled, with 3050 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).

CONCLUSIONS: Among patients with mild ischemic stroke or high-risk TIA of presumed atherosclerotic cause, combined clopidogrel-aspirin therapy initiated within 72 hours after stroke onset led to a lower risk of new stroke at 90 days than aspirin therapy alone but was associated with a low but higher risk of moderate-to-severe bleeding. (Funded by the National Natural Science Foundation of China and others; INSPIRES ClinicalTrials.gov number, NCT03635749.).

Discipline Area Score
Hospital Doctor/Hospitalists 6 / 7
Internal Medicine 6 / 7
Neurology 6 / 7
Family Medicine (FM)/General Practice (GP) 6 / 7
General Internal Medicine-Primary Care(US) 6 / 7
Comments from MORE raters

General Internal Medicine-Primary Care(US) rater

This added information showing significant benefit by treating further out is highly relevant in primary care and would expand the treatment pool. I wonder whether there are genetic differences in the study population (mostly Han Chinese) that would not be found in other populations.

General Internal Medicine-Primary Care(US) rater

Although this trial provides important information, there are some issues with its generalizability. As mentioned by the authors, the population was Chinese and there are differences in clopidogrel metabolism in different populations. Also, the trial participants were primarily male. Most patients had multiple simultaneous infarcts, so the results may not apply to patients with a single infarct who may have a different mechanism of ischemia. Additionally, since few patients had a TIA rather than a stroke, the results may not apply to that population.

Hospital Doctor/Hospitalists rater

A fascinating trial that will add to the growing debate of early ischemic stroke management; but in isolation, it is probably not ultimately practice-changing for me. The treatment effect was NOT seen in all populations, including those that are relatively common in my practice (e.g., those on previous antiplatelet therapy, those on statin therapy, or those on immediate statin therapy). Given the narrow demographics of the study population and the lack of even distribution of the treatment effect, there are sufficient concerns for me to wait for national guideline updates.

Internal Medicine rater

This study demonstrates a possible clinical benefit of DAPT in an expanded time window for high-risk TIA and minor ischemic strokes. Although this has the potential to expand the population of patients who may benefit from DAPT, later treatment with DAPT was also associated with both an increased risk for bleeding as well as a smaller reduction of risk of subsequent strokes. Additionally, lacunar stroke syndromes were not included, and the population studied (98.5% Han Chinese) is not representative and may have different risk factors for stroke than a US population.

Neurology rater

Dual antiplatelet therapy compared with aspirin has already been studied in several RCTs. This extends the time window of 24 hours to 72 hours after onset, but does not make a huge difference since the highest risk of recurrence is known to be in the first week and rapidly diminishes thereafter. While significant, the study modifies current practice (if one restricted DAPT to 24 hours of onset) or confirms current practice (if already going beyond 24 hours).
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