INSPIRES Trial: DAPT for Atherosclerotic Minor Stroke or TIA Within 72 Hours
In patients with minor ischemic stroke or high-risk TIA of presumed atherosclerotic cause, does 21-day clopidogrel + aspirin started within 24–72 hours reduce 90-day stroke recurrence compared with aspirin monotherapy?
Gao Y, et al. (NEJM 2023) · doi:10.1056/NEJMoa2309137 · 6,100 patients
Population
Included
- Age 35–80
- Acute mild ischemic stroke (NIHSS ≤5) OR high-risk TIA (ABCD² ≥4)
- Within 24–72 hours of symptom onset
- Presumed atherosclerotic mechanism: ≥50% stenosis of intracranial/extracranial artery OR multiple acute infarctions of presumed large-artery origin
Core qualifying event
- 35 to 80 years of age
- Ischemic stroke with an NIHSS score of 5 or less or a high-risk TIA with an ABCD2 score of 4 or higher within 24 to 72 hours after symptom onset
- Or an ischemic stroke (NIHSS score 4 or 5) within 24 hours after symptom onset
- Presumed atherosclerotic cause (stenosis of an extracranial or intracranial artery ipsilateral to the ischemic field, or multiple infarctions with nonstenotic atherosclerotic plaque ipsilateral to the ischemic field)
Imaging (at least one)
- At least 50% stenosis of a major intracranial or extracranial artery likely accounting for the presentation and infarction
- Or acute new multiple infarctions on CT or MRI of presumed large-artery atherosclerosis origin, including nonstenotic unstable plaque ipsilateral to the infarction
Excluded
- Received thrombolysis or endovascular therapy
- Presumed cardioembolic cause (AF, prosthetic valve)
- Other determined cause (dissection, vasculitis)
- Pre-existing disability (mRS ≥2)
- ICH history; planned surgery within 90 days
- Dual antiplatelet or intensive statin within prior 2 weeks
Prior / index therapy
- Received thrombolysis or endovascular therapy
- Additional anticoagulant, defibrinogenation, or antiplatelet therapy other than clopidogrel and aspirin after the index event
- Dual antiplatelet therapy or intensive statin within 2 weeks before randomization
Cause / mechanism
- A presumed cardioembolic TIA or ischemic stroke
- Other determined cause of stroke or TIA (e.g., aortic dissection, vasculitis)
Disability / bleeding / surgery
- A preexisting modified Rankin scale score of 2 or higher
- A history of intracranial hemorrhage
- Planned surgery or revascularization requiring discontinuation of trial medications within 90 days
Source: Gao et al., N Engl J Med 2023· Retrieved 2026-06-09
Primary Outcome
Negligible absolute difference
Stroke-free at 90 Days
Study Arms
- Agent
- Clopidogrel plus aspirin
- Dose
- Clopidogrel 300 mg loading on day 1, then 75 mg daily on days 2 to 90; aspirin 100 to 300 mg on day 1, then 100 mg daily on days 2 to 21, then aspirin placebo on days 22 to 90
- Route
- Oral
- Frequency
- Once daily
- Duration
- Clopidogrel through day 90; aspirin through day 21 (DAPT to day 21, then clopidogrel monotherapy to day 90)
- Co-interventions
- Standard care per current AHA-ASA and Chinese guidelines; day-1 aspirin dose at physician discretion; first doses within 1 hour after assignment
Antiplatelet component of a 2-by-2 factorial trial (the other factor compared immediate vs delayed intensive statin)
- Agent
- Aspirin plus matching clopidogrel placebo
- Dose
- Matching clopidogrel placebo for 90 days; aspirin 100 to 300 mg on day 1, then 100 mg daily on days 2 to 90
- Route
- Oral
- Frequency
- Once daily
- Duration
- 90 days
- Co-interventions
- Standard care per current AHA-ASA and Chinese guidelines; day-1 aspirin dose at physician discretion
Aspirin monotherapy with matching clopidogrel placebo (double-blind control)
Safety
Moderate-to-severe bleeding (GUSTO) at 90d
0.9%
0.4%
HR 2.08 (95% CI 1.07–4.04, P=0.03). Bleeding risk approximately doubles with DAPT. NNH ~200. Favorable net clinical benefit vs efficacy NNT 53, but bleeding risk is real.
Hemorrhagic stroke (secondary)
0.5%
0.2%
HR 3.01 (95% CI 1.09–8.28). Uncommon but elevated. Exclude ICH history, uncontrolled hypertension, MRI microbleeds when feasible.
Trial Design
Type
- Multicenter randomized double-blind 2×2 factorial trial
- 222 centers in China
- 1:1 allocation (DAPT vs aspirin) in antiplatelet arm
- Second factor: intensive vs standard statin (independent)
- Treatment window: within 72 hours of symptom onset
Timeline
Enrolled 2019–2023; published NEJM 2024
N
6,100
Enrollment
6,100 patients at 222 hospitals in China; 2×2 factorial. Enrolled 2019–2023. Published NEJM 2023.
ClinicalTrials.gov
NCT03635749Bedside Pearl
For atherosclerotic minor stroke or high-risk TIA presenting 24–72 hours after onset, clopidogrel + aspirin × 21 days then clopidogrel alone through day 90 reduces recurrent stroke (NNT ≈ 53). Requires ≥50% stenosis on vascular imaging. Within 24h, CHANCE/POINT remain the primary evidence base.