INSPIRES
Dual Antiplatelet Treatment up to 72 Hours after Ischemic Stroke
Year of Publication: 2023
Authors: Ying Gao, Weiqi Chen, Yuesong Pan, ..., for the INSPIRES Investigators
Journal: The New England Journal of Medicine
Citation: N Engl J Med 2023;389:2413-24.
PDF: Clinical Question
Does clopidogrel plus aspirin initiated within 72 hours of acute mild ischemic stroke or high-risk TIA of presumed atherosclerotic cause reduce the risk of new stroke compared with aspirin alone?
Bottom Line
DAPT with clopidogrel + aspirin within 72h reduced 90-day stroke by 21% compared with aspirin alone (7.3% vs 9.2%; HR 0.79; 95% CI 0.66-0.94; P=0.008) in atherosclerotic stroke/TIA. However, moderate-to-severe bleeding was doubled (0.9% vs 0.4%; HR 2.08; P=0.03). This extends the CHANCE/POINT benefit to a 72-hour window in an imaging-confirmed atherosclerotic population.
Major Points
- DAPT within 72h reduced stroke: 7.3% vs 9.2% (HR 0.79; 95% CI 0.66-0.94; P=0.008) — 21% relative risk reduction.
- Extends CHANCE/POINT time window: 87.2% of patients were randomized >24h; greatest benefit in 48-72h subgroup (HR 0.70; 95% CI 0.53-0.93).
- Atherosclerotic imaging criteria required: 82% had ≥50% symptomatic stenosis; 67.6% had multiple acute infarctions.
- Benefit concentrated in multiple infarction subgroup: HR 0.74 (0.61-0.90). TIA-only and single infarction subgroups showed no benefit (HR ~1.0).
- Bleeding cost is real: moderate-to-severe 0.9% vs 0.4% (HR 2.08; P=0.03); hemorrhagic stroke 0.5% vs 0.2% (HR 3.01; 95% CI 1.09-8.28).
- Functional outcome improved: poor outcome (mRS 2-6) 9.9% vs 11.4% (RR 0.87; 95% CI 0.76-0.99).
- Ischemic stroke specifically reduced: 6.8% vs 9.0% (HR 0.75; 95% CI 0.63-0.90).
- Two-by-two factorial design with statin component (not reported in this publication).
- Absolute benefit smaller than CHANCE (~2pp vs ~3.5pp) — likely from later treatment window.
- 6,100 patients, 222 Chinese hospitals, double-blind placebo-controlled.
Design
Study Type: Multicenter, randomized, double-blind, placebo-controlled, two-by-two factorial trial
Randomization: 1
Blinding: Double-blind with matching placebos for both drugs. Block size 8, stratified by center.
Enrollment Period: September 17, 2018 to October 15, 2022
Follow-up Duration: 90 days (randomized) + 9 months additional for adverse events
Centers: 222
Countries: China
Sample Size: 6100
Analysis: Intention-to-treat. Marginal Cox proportional hazards with center adjustment. 80% power to detect HR 0.80.
Inclusion Criteria
- Age 35-80 years.
- Mild ischemic stroke (NIHSS ≤5) or high-risk TIA (ABCD² ≥4) within 24-72 hours.
- At least one imaging criterion indicating atherosclerotic etiology: ≥50% stenosis of symptomatic artery OR acute multiple infarctions of presumed large-artery atherosclerosis origin.
- Protocol amendment: excluded NIHSS ≤3 stroke or TIA within 24h (after 2019 AHA/ASA guideline update).
Exclusion Criteria
- Received thrombolysis or endovascular therapy.
- Additional anticoagulant, defibrinogenation, or antiplatelet beyond aspirin/clopidogrel after index event.
- DAPT with aspirin+clopidogrel or intensive statin within 2 weeks before randomization.
- Presumed cardioembolic etiology.
- Other determined cause (dissection, vasculitis).
- Pre-existing disability (mRS ≥2).
- History of intracranial hemorrhage.
- Planned surgery/revascularization requiring drug discontinuation within 90 days.
Baseline Characteristics
| Characteristic | Clopidogrel-Aspirin (N=3,050) | Aspirin (N=3,050) |
|---|---|---|
| Age median (IQR) | 65 (57-71) | 65 (57-71) |
| Female | 1,063 (34.9%) | 1,122 (36.8%) |
| Hypertension | 2,047 (67.1%) | 2,036 (66.8%) |
| Diabetes | 830 (27.2%) | 828 (27.1%) |
| Previous ischemic stroke | 901 (29.5%) | 908 (29.8%) |
| Current smoker | 892 (29.2%) | 891 (29.2%) |
| Qualifying — TIA | 399 (13.1%) | 402 (13.2%) |
| Qualifying — Single infarction | 588 (19.3%) | 586 (19.2%) |
| Qualifying — Multiple infarctions | 2,063 (67.6%) | 2,062 (67.6%) |
| ≥50% symptomatic stenosis | 2,448/2,985 (82.0%) | 2,467/2,983 (82.7%) |
| Time to randomization ≤24h | 401 (13.1%) | 382 (12.5%) |
| Time >24-48h | 1,255 (41.1%) | 1,297 (42.5%) |
| Time >48-72h | 1,394 (45.7%) | 1,371 (45.0%) |
Arms
| Field | Clopidogrel + Aspirin | Control |
|---|---|---|
| Intervention | Clopidogrel 300 mg loading Day 1, then 75 mg/day Days 2-90. Aspirin 100-300 mg Day 1, then 100 mg/day Days 2-21, then aspirin placebo Days 22-90. | Clopidogrel placebo for 90 days. Aspirin 100-300 mg Day 1, then 100 mg/day Days 2-90. |
| Duration | 90 days | 90 days |
Outcomes
| Outcome | Type | Control | Intervention | HR / OR / RR | P-value |
|---|---|---|---|---|---|
| Any new stroke (ischemic or hemorrhagic) within 90 days | Primary | 279/3,050 (9.2%) | 222/3,050 (7.3%) | 0.79 | 0.008 |
| Composite CV event (stroke/MI/CV death) | 95% CI: 0.67-0.96 | Secondary | 282 (9.3%) | 229 (7.5%) | HR 0.80 | |
| Ischemic stroke | 95% CI: 0.63-0.90 | Secondary | 274 (9.0%) | 208 (6.8%) | HR 0.75 | |
| Hemorrhagic stroke | 95% CI: 1.09-8.28 | Secondary | 5 (0.2%) | 15 (0.5%) | HR 3.01 | |
| TIA | 95% CI: 0.32-0.91 | Secondary | 39 (1.3%) | 21 (0.7%) | HR 0.54 | |
| Poor functional outcome (mRS 2-6) at 90d | 95% CI: 0.76-0.99 | Secondary | 346/3,046 (11.4%) | 301/3,047 (9.9%) | RR 0.87 | |
| Six-level ordinal shift (stroke/TIA + mRS) | 95% CI: 0.64-0.91 | Secondary | — | — | Common OR 0.76 | |
| Moderate-to-severe bleeding (GUSTO) | Adverse | 13 (0.4%) | 27 (0.9%) | HR 2.08 | 0.03 |
| Any bleeding | Adverse | 63 (2.1%) | 94 (3.1%) | HR 1.50 | |
| Intracranial hemorrhage | Adverse | 8 (0.3%) | 17 (0.6%) | HR 2.13 | |
| Death from any cause | Adverse | 30 (1.0%) | 37 (1.2%) | HR 1.24 |
Subgroup Analysis
Benefit concentrated in multiple infarctions (HR 0.74; 0.61-0.90); no benefit in TIA-only (HR 1.09) or single infarction (HR 1.03). By time window: ≤24h HR 0.84; >24-48h HR 0.84; >48-72h HR 0.70 (0.53-0.93). No significant interaction with statin factorial component (P=0.16). No benefit in prior antiplatelet users (HR 1.13) or prior statin users (HR 1.26).
Criticisms
- 98.5% Han Chinese — generalizability uncertain for other ethnicities.
- Excluded cardioembolic, moderate-severe stroke, thrombolysis/thrombectomy patients.
- Smaller absolute benefit than CHANCE (~2pp vs ~3.5pp) due to later window.
- More bleeding than prior DAPT trials: moderate-severe 0.9% vs 0.4%.
- CYP2C19 genotype not assessed despite known effects on clopidogrel efficacy.
- Protocol amendment mid-trial excluding NIHSS ≤3/TIA within 24h.
- Secondary outcomes not adjusted for multiplicity.
Funding
National Natural Science Foundation of China; National Key R&D Program; Sanofi; Beijing Jialin Pharmaceutical.
Based on: INSPIRES (The New England Journal of Medicine, 2023)
Authors: Ying Gao, Weiqi Chen, Yuesong Pan, ..., for the INSPIRES Investigators
Citation: N Engl J Med 2023;389:2413-24.
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