Neurology Clinical Trial Database
INSPIRES Factorial
Dual Antiplatelet Therapy and Immediate Intensive Statin in Mild Ischemic Stroke: A Randomized Trial (INSPIRES 2×2 Factorial Analysis)
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.
Design
Study Type: Randomized Controlled Trial (2×2 Factorial, Prespecified Analysis)
Randomization: 1
Blinding: Double-blind, placebo-controlled
Enrollment Period: September 17, 2018 - October 15, 2022
Follow-up Duration: 90 days (primary); total 12 months
Centers: 222
Countries: China
Sample Size: 6100
Analysis: Intention-to-treat (full analysis set); per-protocol sensitivity analysis
Inclusion Criteria
- Age 35-80 years
- Mild ischemic stroke (NIHSS ≤5) or high-risk TIA (ABCD2 ≥4) within 24-72 hours of symptom onset
- OR ischemic stroke with NIHSS 4-5 within 24 hours of symptom onset
- ≥50% stenosis of a major intracranial or extracranial artery, or acute multiple infarctions on imaging
- Presumed atherosclerotic cause
- Written informed consent
Exclusion Criteria
- Received intravenous thrombolysis or endovascular therapy for the index event
- Planned surgery or revascularization within 90 days
- Planned nonstudy treatment with additional anticoagulant, defibrinogenation, or antiplatelet therapy after the index event
- Received DAPT with clopidogrel-aspirin or intensive statin therapy within 2 weeks before randomization
- History of intracranial hemorrhage
- Presumed cardioembolic TIA or ischemic stroke
- Ischemic stroke or TIA of other determined etiologies (e.g., aortic dissection, vasculitis)
Arms
| Field | Clopidogrel-aspirin + Immediate Intensive Statin | Clopidogrel-aspirin + Delayed Intensive Statin | Aspirin + Immediate Intensive Statin | Control |
|---|---|---|---|---|
| Intervention | Clopidogrel 300 mg loading dose day 1, then 75 mg daily days 2-90 + aspirin 100-300 mg day 1 then 100 mg daily days 2-21 (placebo aspirin days 22-90) + atorvastatin 80 mg daily days 1-21, then 40 mg daily days 22-90 | Clopidogrel + aspirin regimen as above + placebo atorvastatin days 1-3, then 40 mg atorvastatin daily days 4-90 | Placebo clopidogrel 90 days + aspirin 100-300 mg day 1 then 100 mg daily days 2-90 + atorvastatin 80 mg daily days 1-21, then 40 mg daily days 22-90 | Placebo clopidogrel 90 days + aspirin as above + placebo atorvastatin days 1-3, then 40 mg atorvastatin daily days 4-90 |
| Duration | 90 days | 90 days | 90 days | 90 days |
Outcomes
| Outcome | Type | Control | Intervention | HR / OR / RR | P-value |
|---|---|---|---|---|---|
| New stroke (ischemic or hemorrhagic) within 90 days — comparison of clopidogrel-aspirin + immediate intensive statin vs aspirin + delayed intensive statin | Primary | 150/1,525 (9.9%) | 116/1,525 (7.6%) | 0.76 | 0.03 |
| New stroke — Clopidogrel-aspirin + delayed statin vs aspirin + delayed statin | Secondary | 9.9% | 7.0% (106/1,525) | 0.69 | 0.003 |
| New stroke — Aspirin + immediate statin vs aspirin + delayed statin | Secondary | 9.9% | 8.5% (129/1,525) | 0.85 | 0.17 |
| Ischemic stroke within 90 days (combo vs control) | Secondary | 9.7% | 7.1% | 0.72 | |
| Composite vascular events (stroke, MI, vascular death) within 90 days | Secondary | 151/1,525 (9.9%) | 120/1,525 (7.9%) | 0.78 | |
| Poor functional outcome (mRS 2-6) at 90 days — combo vs control | Secondary | 190/1,522 (12.5%) | 143/1,523 (9.4%) | 0.72 | |
| Poor functional outcome — clopidogrel-aspirin + delayed statin vs control | Secondary | 12.5% | 10.4% | 0.81 | |
| Poor functional outcome — aspirin + immediate statin vs control | Secondary | 12.5% | 10.2% | 0.79 | |
| Ordinal shift (6-level stroke/TIA severity + mRS) at 90 days — combo vs control | Secondary | reference | shift toward less severe events | 0.73 | |
| Post hoc: composite of ischemic stroke, moderate-to-severe bleeding, and death — combo vs control | Secondary | 158 (10.4%) | 124 (8.1%) | 0.77 | |
| Primary safety — Moderate-to-severe bleeding (GUSTO) — combo vs control | Adverse | 17 (1.1%) vs 7 (0.5%); HR 2.44 (95% CI 1.01-5.90), p=0.047 | |||
| Moderate-to-severe bleeding — clopidogrel-aspirin + delayed statin vs control | Adverse | 10 (0.7%) vs 7 (0.5%); HR 1.44 (0.55-3.79), p=0.46 | |||
| Moderate-to-severe bleeding — aspirin + immediate statin vs control | Adverse | 6 (0.4%) vs 7 (0.5%); HR 0.87 (0.29-2.58), p=0.80 | |||
| Interaction for bleeding (antiplatelet × statin) | Adverse | P for interaction = 0.33 (possible but non-significant synergistic bleeding effect) | |||
| Any adverse event (combo vs control) | Adverse | 348/1,525 (22.8%) vs 303/1,525 (19.9%) | |||
| Serious adverse events (combo vs control) | Adverse | 54/1,525 (3.5%) vs 47/1,525 (3.1%) | |||
| Hepatotoxicity | Adverse | No significant difference between combo and control (ALP or AST >3x ULN) | |||
| Muscle toxicity | Adverse | No significant difference (CK >10x ULN, myopathy, or rhabdomyolysis) | |||
| All-cause mortality | Adverse | No significant difference between combo and control | |||
| Intracranial hemorrhage | Adverse | No significant difference between combo and control | |||
| Any bleeding | Adverse | No significant difference between combo and control | |||
Subgroup Analysis
Effect of clopidogrel-aspirin + immediate intensive statin on the primary outcome was consistent across prespecified subgroups (age, sex, systolic blood pressure, index event type [ischemic stroke vs TIA], NIHSS, ABCD2, symptomatic ≥50% stenosis, diabetes). Per-protocol analyses were consistent with intention-to-treat.
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.
Funding
Chinese Academy of Medical Sciences (National Center for Neurological Disorders); Beijing Tiantan Hospital / China National Clinical Research Center for Neurological Diseases; Research Unit of Artificial Intelligence in Cerebrovascular Disease (Chinese Academy of Medical Sciences).
Based on: INSPIRES Factorial (Neurology, 2026)
Authors: Pan Y, Gao Y, Chen W, ..., Bath PM
Citation: Neurology 2026;107(2):e218128
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