INSPIRES Factorial
(2026)Objective
Test whether combining clopidogrel-aspirin dual antiplatelet therapy with immediate intensive statin further reduces 90-day new stroke risk in acute mild ischemic stroke or high-risk TIA of presumed atherosclerotic cause, using a 2x2 factorial design.
Study Summary
• Clopidogrel-aspirin + delayed statin was the best-performing arm: 7.0% vs 9.9% (HR 0.69, 95% CI 0.54-0.89) — benefit was mainly driven by DAPT, not by immediate statin
• No synergistic efficacy of DAPT + immediate statin (P for interaction = 0.16); poor functional outcome improved (9.4% vs 12.5%, OR 0.72)
• Moderate-to-severe bleeding was higher with DAPT + immediate statin: 1.1% vs 0.5% (HR 2.44, 95% CI 1.01-5.90, p=0.047); low absolute risk but a possible synergistic bleeding signal
Intervention
Clopidogrel-aspirin dual antiplatelet therapy (300-mg clopidogrel load then 75 mg daily x90d + aspirin 100 mg; placebo aspirin days 22-90) combined with immediate intensive statin (atorvastatin 80 mg daily days 1-21, then 40 mg days 22-90) versus aspirin + delayed intensive statin (placebo atorvastatin days 1-3, then 40 mg atorvastatin) in a 2x2 factorial with two other DAPT/statin combinations.
Inclusion Criteria
Age 35-80 with mild ischemic stroke (NIHSS ≤5) or high-risk TIA (ABCD2 ≥4) within 24-72h of onset, or acute ischemic stroke (NIHSS 4-5) within 24h; ≥50% stenosis of a major intracranial/extracranial artery or acute multiple infarctions; presumed atherosclerotic cause.
Study Design
Arms: 4 arms (1,525 each): (1) Clopidogrel-aspirin + immediate intensive statin, (2) Clopidogrel-aspirin + delayed intensive statin, (3) Aspirin + immediate intensive statin, (4) Aspirin + delayed intensive statin (reference).
Patients per Arm: 1,525 per arm (total N=6,100)
Outcome
• Ischemic stroke: 7.1% vs 9.7% (HR 0.72, 0.56-0.92)
• Composite vascular events: 7.9% vs 9.9% (HR 0.78, 0.61-0.99)
• Poor functional outcome (mRS 2-6) at 90d: 9.4% vs 12.5% (OR 0.72, 0.57-0.90)
• Primary safety (moderate-to-severe bleeding): 1.1% vs 0.5% (HR 2.44, 1.01-5.90, p=0.047)
• No significant differences in hepatotoxicity, myotoxicity, all-cause mortality, or any bleeding
• No treatment interaction (P-interaction=0.16 efficacy, 0.33 bleeding)
Clinical Question
In patients with acute mild ischemic stroke or high-risk TIA of presumed atherosclerotic cause within 72 hours, does the combination of clopidogrel-aspirin dual antiplatelet therapy and immediate intensive statin reduce the risk of new stroke at 90 days compared with aspirin alone plus delayed intensive statin, and is there a synergistic effect between the two treatments?
Bottom Line
Clopidogrel-aspirin plus immediate intensive statin reduced 90-day new stroke vs aspirin plus delayed intensive statin (7.6% vs 9.9%, HR 0.76), but the effect was driven by DAPT with no synergistic efficacy of adding immediate statin; combination therapy roughly doubled moderate-to-severe bleeding (1.1% vs 0.5%).
Major Points
- Prespecified 2×2 factorial analysis of the INSPIRES trial (6,100 patients, 222 Chinese hospitals, Sept 2018-Oct 2022) testing DAPT (clopidogrel-aspirin vs aspirin) crossed with statin timing (immediate 80 mg atorvastatin vs 3-day delayed intensive statin).
- Primary efficacy outcome (new stroke within 90 days): 7.6% combo vs 9.9% aspirin+delayed statin, HR 0.76 (95% CI 0.60-0.97), p=0.03, ARR 2.2%, NNT 45.
- Clopidogrel-aspirin + delayed statin was numerically the best arm (7.0%, HR 0.69, 95% CI 0.54-0.89); no synergistic efficacy for adding immediate statin (P for interaction = 0.16).
- Ischemic stroke reduced (7.1% vs 9.7%, HR 0.72, 95% CI 0.56-0.92); poor functional outcome (mRS 2-6) improved with combo (9.4% vs 12.5%, OR 0.72, 95% CI 0.57-0.90).
- Primary safety: moderate-to-severe bleeding 1.1% (combo) vs 0.5% (control), HR 2.44 (95% CI 1.01-5.90), p=0.047 — possible synergistic bleeding signal, though absolute risk remained low.
- No significant differences in hepatotoxicity, myotoxicity, all-cause mortality, or intracranial hemorrhage between the combination and control arms.
- Chinese population only; findings may not generalize to White or Black patients given differences in intracranial atherosclerosis prevalence and hepatic drug metabolism.
- Class I evidence that clopidogrel-aspirin + delayed intensive statin is superior to aspirin + delayed intensive statin for 90-day stroke prevention in mild stroke/TIA of atherosclerotic cause.
Study Design
- Study Type
- Randomized Controlled Trial (2×2 Factorial, Prespecified Analysis)
- Randomization
- Yes
- Blinding
- Double-blind, placebo-controlled
- Sample Size
- 6100
- Follow-up
- 90 days (primary); total 12 months
- Centers
- 222
- Countries
- China
Primary Outcome
Definition: New stroke (ischemic or hemorrhagic) within 90 days — comparison of clopidogrel-aspirin + immediate intensive statin vs aspirin + delayed intensive statin
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| 150/1,525 (9.9%) | 116/1,525 (7.6%) | 0.76 (0.60-0.97) | 0.03 |
Limitations & Criticisms
- Exclusively Chinese population — generalizability to White and Black populations is limited given differences in intracranial atherosclerosis prevalence (30-50% Asian vs 8% non-Asian) and hepatic drug metabolism.
- Excluded patients with cardioembolic sources, moderate/severe stroke, and thrombolysis/thrombectomy candidates — findings do not apply to these groups.
- CYP2C19 genotype (affecting clopidogrel activation) was not part of trial entry or stratification.
- Statin comparison confounds both timing (immediate vs 3-day delayed) and intensity (80 mg vs 40 mg atorvastatin days 4-21).
- No adjustment for multiple comparisons; secondary outcomes should be considered exploratory/hypothesis-generating.
- The 'best-performing' arm was clopidogrel-aspirin + delayed statin (HR 0.69), suggesting the incremental benefit of adding immediate statin to DAPT is uncertain while bleeding risk rises.
- Absolute bleeding risk is low, so the 2.44-fold hazard ratio is based on a small number of events (17 vs 7) and could partly reflect chance.
Citation
Neurology 2026;107(2):e218128