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ARAMIS

Dual Antiplatelet Therapy vs Alteplase for Patients With Minor Nondisabling Acute Ischemic Stroke: The ARAMIS Randomized Clinical Trial

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Year of Publication: 2023

Authors: Hui-Sheng Chen, Yu Cui, Zhong-He Zhou, ..., Thanh N. Nguyen

Journal: JAMA

Citation: JAMA. 2023;329(24):2135–2144. doi:10.1001/jama.2023.7827

Link: https://jamanetwork.com/journals/jama/fullarticle/2806532

PDF: https://jamanetwork.com/journals/jama/fullarticle/2806532

Clinical Question

Is dual antiplatelet therapy noninferior to intravenous thrombolysis in patients with minor nondisabling acute ischemic stroke?

Study Overview

Objective

To determine whether dual antiplatelet therapy (aspirin plus clopidogrel) is noninferior to intravenous alteplase for patients with minor nondisabling acute ischemic stroke.

Study Summary

Dual antiplatelet therapy (DAPT) was noninferior to alteplase in achieving excellent functional outcome at 90 days with excellent outcome (mRS 0–1) achieved in 93.8% with DAPT vs. 91.4% with alteplase.
Symptomatic intracerebral hemorrhage occurred in 0.3% with DAPT vs. 0.9% with alteplase.

Intervention

Dual antiplatelet therapy (clopidogrel 300 mg day 1, then 75 mg daily for 12±2 days; aspirin 100 mg daily for 12±2 days) vs. intravenous alteplase (0.9 mg/kg, max 90 mg). All patients received guideline-based secondary prevention thereafter.

Bottom Line

DAPT (clopidogrel 300mg load + aspirin 100mg for 12 days) was noninferior to IV alteplase for mRS 0-1 at 90 days in minor nondisabling stroke within 4.5h (93.8% vs 91.4%; RD +2.3%; lower CI bound -1.5% > -4.5% margin; P<0.001 for noninferiority). DAPT had fewer bleeding events (1.6% vs 5.4%; P=0.006) and less early neurological deterioration (4.6% vs 9.1%; P=0.02). 719 patients (FAS), 38 Chinese hospitals.

        Major Points
        Noninferiority confirmed: DAPT mRS 0-1 93.8% vs alteplase 91.4% (RD +2.3%; lower bound -1.5% > -4.5% margin; P<0.001).
Fewer bleeding events with DAPT: 1.6% vs 5.4% (RD -3.8%; P=0.006). sICH 0.3% vs 0.9% (NS).
Less early neurological deterioration with DAPT: 4.6% vs 9.1% (RD -4.5%; P=0.02).
NIHSS 4-5 subgroup numerically favored alteplase (85.9% vs 88.6%) — not significant but warrants study.
High crossover rate: 20.4% (87 DAPT→alteplase, 60 alteplase→DAPT). Noninferiority robust across all analyses.
33.7% missing vessel imaging data — limits large artery occlusion subgroup analysis.
Predominantly undetermined etiology (61-63%). Small vessel 23%, large artery 13-15%.
Short DAPT: 12±2 days (based on CHANCE data showing benefit plateau ~day 10).
Chinese population only. Excellent outcome rates (91-94%) much higher than PRISMS (78-82%).
With PRISMS, strongest evidence that IV alteplase not needed in minor nondisabling stroke when DAPT available.

      

Design

Study Type: Randomized, open-label, blinded endpoint, noninferiority trial

Randomization: 1

Blinding: Blinded outcome assessment only

Enrollment Period: October 2018 to April 2022

Follow-up Duration: 90 days

Centers: 38

Countries: China

Sample Size: 760

Analysis: Generalized linear models (risk difference, RR); full analysis set; adjusted and sensitivity analyses

Inclusion Criteria

Age ≥18 years
Acute ischemic stroke with NIHSS ≤5
Minor nondisabling deficits (≤1 point on single items like language, limb weakness)
mRS score 0–1 before stroke
Onset to treatment within 4.5 hours

Exclusion Criteria

Prestroke disability (mRS >1)
History of intracerebral hemorrhage
Indication for anticoagulation
NIHSS >5 or disabling deficit
Presentation >4.5h after symptom onset

Baseline Characteristics

Characteristic	Control	Active
Median Age	64 (56–71)	65 (57–71)
Sex - Female	31.4%	30.6%
Current Smoker	33.7%	33.1%
Current Drinker	16.0%	16.0%
Hypertension	48.3%	57.2%
Diabetes	24.6%	27.4%
Prior Ischemic Stroke	22.0%	22.2%
SBP	151 (139–162)	150 (137–166)
DBP	88 (80–95)	88 (81–95)
Blood Glucose >7.0 mmol/L	38.5%	35.4%
NIHSS score	2 (1–3)	2 (1–3)

Arms

Field	Dual Antiplatelet Therapy	Control
Intervention	Clopidogrel 300 mg loading then 75 mg daily for 12±2 days; Aspirin 100 mg daily for 12±2 days; followed by guideline-based treatment to 90 days	Intravenous alteplase 0.9 mg/kg (max 90 mg) per guidelines, followed by antiplatelet therapy after 24h
Duration	90 days	90 days

Outcomes

Outcome	Type	Control	Intervention	HR / OR / RR	P-value
Excellent functional outcome (mRS 0–1 at 90 days)	Primary	91.4% (320/350)	93.8% (346/369)		<0.001 for noninferiority
Favorable outcome (mRS 0–2 at 90 days)	Secondary	95.4% (334/350)	95.9% (354/369)	RR 1.12 (0.56 to 2.24)	0.74
mRS ordinal shift at 90 days	Secondary	—	—	OR 1.16 (0.83 to 1.61)	0.39
Early neurological improvement at 24h (≥2-point NIHSS decrease)	Secondary	21.1% (74/350)	16.8% (62/369)	RR 0.95 (0.89 to 1.02)	0.16
Early neurological deterioration at 24h (≥2-point NIHSS increase)	Secondary	9.1% (32/350)	4.6% (17/369)	RR 0.50 (0.29 to 0.89)	0.02
Change in NIHSS score at 24h from baseline (log-transformed)	Secondary	0 (−0.69 to 0)	0 (−0.41 to 0)	Geometric mean ratio 0.03 (−0.05 to 0.11)	0.51
Stroke or other vascular events within 90 days	Secondary	0.6% (2/350)	0.3% (1/369)	HR 0.47 (0.04 to 5.20)	0.54
Death at 90 days	Secondary	0.9% (3/350)	0.5% (2/369)	RR 0.63 (0.11 to 3.76)	0.61
Symptomatic Intracerebral Hemorrhage	Adverse	0.9% (3/352)	0.3% (1/371)	RR 0.32 (0.03 to 3.02)	0.30
Any Bleeding Events	Adverse	5.4% (19/352)	1.6% (6/371)	RR 0.30 (0.12 to 0.74)	0.006

Subgroup Analysis

No treatment heterogeneity observed across subgroups (e.g., age, sex, diabetes, NIHSS, vessel stenosis)

Criticisms

Open-label design may introduce bias despite blinded outcome assessment
High crossover rate (~20%) may affect internal validity
Limited generalizability outside Chinese population
Exclusion of cardioembolic strokes and lower female enrollment
Ceiling effect due to very high primary outcome rates

Funding

National Key R&D Program of China (2017YFC1308203) and Science and Technology Project Plan of Liao Ning Province (2014225008, 2018225023, 2019JH2/10300027); sponsored by the Cerebrovascular Disease Collaboration Innovation Alliance Office. Aspirin and clopidogrel donated by Shenzhen Salubris Pharmaceutical Co, Ltd. Alteplase was paid for by patients, who later received reimbursement from the national insurance system.

Based on: ARAMIS (JAMA, 2023)