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INSPIRES

Dual Antiplatelet Treatment up to 72 Hours after Ischemic Stroke

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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.

Link: https://www.nejm.org/doi/full/10.1056/NEJMoa2312949

PDF: https://www.nejm.org/doi/pdf/10.1056/NEJMoa2309137

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.

Content summarized and formatted by NeuroTrials.ai.

INSPIRES

(2023)

Objective

Dual anti-platelet therapy (clopidogrel and aspirin) initiated within 72 hours versus aspirin alone in patients with mild ischemic stroke or high risk TIA presumably caused by atherosclerosis

Study Summary

• Dual anti platelet therapy (clopidogrel-aspirin) initiated within 72 hours after stroke onset led to a lower risk of new stroke at 90 days in patients with mild ischemic stroke or high-risk TIA of presumed atherosclerotic etiology compared with aspirin alone, but was associated with a low but higher risk of moderate-to-severe bleeding.

Intervention

Patients were randomly assigned, in a 1:1 ratio, within 72 hours after symptom onset to receive clopidogrel (300 mg on day 1 and 75 mg daily on days 2 to 90) plus aspirin (100 to 300 mg on day 1 and 100 mg daily on days 2 to 21) or matching clopidogrel placebo plus aspirin (100 to 300 mg on day 1 and 100 mg daily on days 2 to 90).

Inclusion Criteria

Patients were eligible if they were 35 to 80 years of age and had had an ischemic stroke with an NIHSS score of 5 or less or a high-risk TIA with a score of 4 or higher on the ABCD scale (which estimates the risk of stroke on the basis of age, blood pressure, clinical features, duration of TIA, and the presence or absence of diabetes mellitus; range, 0 to 7, with higher scores indicating higher stroke risk) within 24 to 72 hours after symptom onset or had had an ischemic stroke (NIHSS score, 4 or 5) within 24 hours after symptom onset. Patients had to meet at least one of the following imaging criteria: at least 50% stenosis of a major intracranial or extracranial artery, as confirmed by carotid duplex ultrasonography or vascular imaging, that was likely to have accounted for the clinical presentation and cerebral infarction; or acute new multiple infarctions documented by computed tomography or magnetic resonance imaging of the head (excluding previous infarcts) of presumed large-artery atherosclerosis origin, including those with nonstenotic unstable plaque ipsilateral to the infarction.

Study Design

Arms: Clopidogrel plus aspirin vs. aspirin

Patients per Arm: Clopidogrel-aspirin: 3050, Aspirin: 3050

Outcome

• A new stroke occurred in 222 patients (7.3%) in the clopidogrel-aspirin group and in 279 (9.2%) in the aspirin group (hazard ratio, 0.79; 95% confidence interval [CI], 0.66 to 0.94; P=0.008). <br>• Moderate-to-severe bleeding occurred in 27 patients (0.9%) in the clopidogrel-aspirin group and in 13 (0.4%) in the aspirin group (hazard ratio, 2.08; 95% CI, 1.07 to 4.04; P=0.03)..

Bottom Line

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.

Study Design

Study Type: Multicenter, randomized, double-blind, placebo-controlled, two-by-two factorial trial
Randomization: Yes
Blinding: Double-blind with matching placebos for both drugs. Block size 8, stratified by center.
Sample Size: 6100
Follow-up: 90 days (randomized) + 9 months additional for adverse events
Centers: 222
Countries: China

Primary Outcome

Definition: Any new stroke (ischemic or hemorrhagic) within 90 days

Control	Intervention	HR/OR	P-value
279/3,050 (9.2%)	222/3,050 (7.3%)	0.79 (0.66-0.94)	0.008

Limitations & 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.

Citation

N Engl J Med 2023;389:2413-24.

View Original Publication →

INSPIRES

Dual Antiplatelet Treatment up to 72 Hours after Ischemic Stroke

Clinical Question

Bottom Line

Major Points

Design

Inclusion Criteria

Exclusion Criteria

Baseline Characteristics

Arms

Outcomes

Subgroup Analysis

Criticisms

Funding

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