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The benefit of dual antiplatelet therapy (DAPT) for a minor ischemic stroke seems to apply outside the 24-hour time window and minimal stroke symptoms for which the treatment is currently recommended, based on results from the INSPIRES trial.

Administered within 72 hours after onset of mild ischemic stroke or high-risk transient ischemic attack (TIA), the combination of clopidogrel (Plavix) plus aspirin resulted in a decrease in any new stroke within 90 days compared with aspirin alone (7.3% vs 9.2%; HR 0.79, 95% CI 0.66-0.94).

The downside was a doubling in moderate-to-severe bleeding at 90 days (0.9% vs 0.4%; HR 2.08, 95% CI 1.07-4.04), reported Yilong Wang, MD, PhD, of Beijing Tiantan Hospital in China, and colleagues in the .

"The results of our trial potentially broaden the time window for the initiation of treatment, although there was more bleeding with the dual regimen than with the monotherapy," the INSPIRES authors concluded.

For their trial, Wang and colleagues enrolled people with minor ischemic stroke (National Institutes of Health Stroke Scale [NIHSS] score ≤5) and high-risk TIA (score of 4 or higher on the ABCD² [age, blood pressure, clinical features, duration of symptoms, and presence of diabetes] scale), which marks a step up from the NIHSS threshold of ≤3 that had been used in the and trials that established DAPT's benefit for secondary stroke prevention.

INSPIRES also expanded the pool of patients receiving DAPT by testing it within 72 hours. POINT and CHANCE had tested this therapy within 12 and 24 hours, respectively, as this early period is thought to carry the highest risk of recurrent stroke.

Based on these two older trials, the American Heart Association in 2019 updated its guidelines with a class Ia starting within 24 hours for patients with noncardioembolic ischemic stroke and NIHSS scores of 3 or less who didn't get IV thrombolytics.

With the addition of INSPIRES, there is evidence to support expanding the time window for DAPT to 72 hours, commented Anthony Kim, MD, of University of California, San Francisco.

"This timing should nevertheless be interpreted as 'as soon as possible, but within 72 hours' and still necessitates a loading dose of clopidogrel, since its omission would be akin to delaying treatment," Kim urged in .

"Overall, for every 1,000 patients with TIA or mild stroke who were treated with clopidogrel–aspirin, approximately 19 fewer strokes and 5 additional moderate-to-severe bleeding events would be expected as compared with aspirin alone, by my rough calculation," he wrote.

For now, DAPT appears to be underutilized in practice: a recent study found that from 2018 to 2021, just over 40% of stroke patients with an NIHSS score of 3 or less were prescribed DAPT after minor stroke or transient ischemic attack in a population-based registry from the University of Maryland Medical System.

INSPIRES was a double-blind 2x2 factorial trial conducted at 222 hospitals in China.

Participants were 6,100 people with mild ischemic stroke or high-risk TIA -- largely the former -- presumably caused by atherosclerotic stenosis of extracranial or intracranial artery ipsilateral to the ischemic field, or multiple infarctions with nonstenotic atherosclerotic plaque ipsilateral to the ischemic field.

Study protocol had people randomly assigned within 72 hours after symptom onset to DAPT with clopidogrel (300 mg on day 1 and 75 mg daily on days 2 to 90) plus aspirin (100-300 mg on day 1 and 100 mg daily on days 2 to 21) or aspirin plus placebo.

The cohort had a median age of 65 years, with just over 35% women. Three in four individuals had a NIHSS ≤3, and the remaining quarter had severity scores reach 4 or 5. Approximately 13% of patients were treated within 24 hours of stroke onset.

Subgroup analysis suggested that DAPT prevented recurrent strokes mainly in people randomized between 48 hours and 72 hours -- no earlier.

Additionally, the risk of any bleeding was higher in the clopidogrel-aspirin group (3.1% vs 2.1%, HR 1.50, 95% CI 1.09-2.06).

"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," Kim noted.

Chief among the limitations of INSPIRES was a selected cohort that excluded people with presumed cardioembolic TIA or ischemic stroke, people with moderate or severe stroke, patients already on DAPT or intensive statin therapy before the trial, and those who had undergone thrombolysis or thrombectomy. Results may have limited generalizability given a study population that was predominantly Han Chinese.

Furthermore, other antiplatelet regimens were not studied in this trial.

"The incremental expansion of indications for [DAPT] that was shown in this trial is welcome. Perhaps new, more targeted antithrombotic agents on the horizon may hold promise for delivering an even more favorable balance of benefits and risks among patients with stroke," Kim wrote.

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