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ASSET-IT

Advancing Stroke Safety and Efficacy through Early Tirofiban Administration after Intravenous Thrombolysis

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Year of Publication: 2025

Authors: Chunrong Tao, Tianlong Liu, Tao Cui, ..., for the ASSET-IT Investigators

Journal: New England Journal of Medicine

Citation: N Engl J Med 2025;393:1191-201

Link: https://doi.org/10.1056/NEJMoa2503678

PDF: https://www.nejm.org/doi/pdf/10.1056/NEJMoa2503678

Clinical Question

Does early administration of tirofiban (a glycoprotein IIb-IIIa inhibitor) after intravenous thrombolysis improve functional outcomes in patients with acute ischemic noncardioembolic stroke who are not eligible for thrombectomy?

Bottom Line

In patients with mild-to-moderate noncardioembolic ischemic stroke treated with IVT within 4.5 hours, early tirofiban administration within 1 hour of thrombolysis completion significantly increased excellent functional outcomes at 90 days (65.9% vs 54.9%, NNT ~9), with a small increase in symptomatic ICH (1.7% vs 0%) but no difference in mortality.

        Major Points
        Phase 3 double-blind RCT of 832 patients at 38 centers in China
Tirofiban significantly increased mRS 0-1 at 90 days: 65.9% vs 54.9% (RR 1.20, 95% CI 1.07-1.34, p=0.001)
Functional independence (mRS 0-2) also improved: 80.4% vs 72.7%
Symptomatic ICH occurred in 1.7% with tirofiban vs 0% with placebo
Mortality similar between groups: 4.1% vs 3.8%
Benefit observed across subgroups including age, stroke severity, and thrombolytic agent type
Greater benefit seen in patients with NIHSS ≥8 (RR 1.54) and ASPECTS ≤8 (RR 1.41)
Predominantly large-artery atherosclerosis etiology (58%) - excluded cardioembolic strokes
Tirofiban administered within median 44 minutes after IVT completion

      

Design

Study Type: Phase 3, multicenter, double-blind, randomized, placebo-controlled trial

Randomization: 1

Blinding: Double-blind (all trial personnel and patients unaware of group assignments); outcome adjudication by independent blinded committee

Enrollment Period: March 14, 2024 to September 25, 2024

Follow-up Duration: 90 days

Centers: 38

Countries: China

Sample Size: 832

Analysis: Modified intention-to-treat; log-binomial regression for primary outcome; ordinal logistic regression for mRS shift analysis; per-protocol and sensitivity analyses performed; Stata version 17.0

Inclusion Criteria

Age ≥18 years
Acute ischemic noncardioembolic stroke
Received intravenous thrombolysis (alteplase or tenecteplase) within 4.5 hours of stroke onset
NIHSS score 4-25 at time of IVT
Randomization within 55 minutes after completing IVT
Tirofiban or placebo administered within 5 minutes after randomization
Pre-stroke mRS ≤1

Exclusion Criteria

Pre-stroke mRS >1
History or current ECG evidence of atrial fibrillation
Planned mechanical thrombectomy or other endovascular treatment
Evidence of intracranial hemorrhage on neuroimaging
NIHSS worsened by ≥2 points between start and completion of thrombolysis (required repeat imaging)

Baseline Characteristics

Characteristic	Control	Active
N	418	414
Age - Median (IQR)	69 years (59-76)	69 years (59-76)
Male	64.8%	62.8%
Female	35.2%	37.2%
Pre-stroke mRS 1	3.8%	6.8%
NIHSS - Median (IQR)	6 (5-9)	6 (5-9)
NCCT ASPECTS - Median (IQR)	10 (9-10)	10 (9-10)
CT parenchymal imaging	72.7%	76.6%
MRI parenchymal imaging	27.3%	23.4%
Previous stroke or TIA	29.9%	25.4%
Diabetes mellitus	23.9%	22.0%
Hypertension	80.4%	82.6%
Ischemic heart disease	9.8%	11.8%
Hyperlipidemia	13.9%	12.3%
Current smoker	23.4%	19.8%
Stroke cause - Large-artery atherosclerosis	56.7%	59.7%
Stroke cause - Small-artery occlusion	36.1%	33.6%
Stroke cause - Undetermined	6.2%	6.5%
Time onset to thrombolysis - Median (IQR)	170 min (129-220)	155 min (111-206)
Time IVT completion to randomization - Median (IQR)	30 min (13-47)	29 min (12-47)
Time IVT completion to drug administration - Median (IQR)	44 min (26-54)	44 min (27-55)
Alteplase	73.7%	75.8%
Tenecteplase	26.3%	24.2%
Antiplatelet monotherapy after 24h	29.0%	27.3%
Dual antiplatelet after 24h	65.8%	64.5%

Arms

Field	Tirofiban	Control
Intervention	Tirofiban IV: 0.4 µg/kg bolus over 30 minutes, followed by 0.1 µg/kg/min maintenance infusion for 23.5 hours (total 24 hours). Started within 5 minutes of randomization (median 44 min after IVT completion). After 24 hours, standard stroke management per guidelines.	Visually identical saline placebo administered IV in identical volume and infusion rate to tirofiban regimen for 24 hours. After 24 hours, standard stroke management per guidelines.
Duration	24 hours infusion, 90-day follow-up	24 hours infusion, 90-day follow-up

Outcomes

Outcome	Type	Control	Intervention	HR / OR / RR	P-value
Excellent functional outcome defined as mRS score 0-1 at 90 days, adjudicated by trained central evaluators blinded to treatment allocation	Primary	229/417 (54.9%)	273/414 (65.9%)	RR 1.20 (95% CI 1.07-1.34)	0.001
mRS 0-2 (functional independence) at 90 days	Secondary	303/417 (72.7%)	333/414 (80.4%)	RR 1.11 (1.03-1.19)
mRS 0-3 at 90 days	Secondary	354/417 (84.9%)	365/414 (88.2%)	RR 1.04 (0.98-1.10)
NIHSS at 24-72 hours - Median (IQR)	Secondary	4 (2-6)	3 (1-6)	Beta 0.00 (-0.71 to 0.71)
NIHSS at 5-7 days or discharge - Median (IQR)	Secondary	2 (1-5)	2 (1-4)	Beta -0.21 (-0.92 to 0.49)
Barthel Index 95-100 at 90 days	Secondary	294/417 (70.5%)	319/414 (77.1%)	RR 1.09 (1.01-1.19)
EQ-5D-5L at 90 days - Median (IQR)	Secondary	0.96 (0.84-1)	1 (0.88-1)	Beta 0.03 (-0.01 to 0.07)
Radiologic intracranial hemorrhage	Secondary	14/418 (3.3%)	22/414 (5.3%)	RR 1.58 (0.82-3.06)
Symptomatic intracranial hemorrhage within 36 hours	Adverse	0/418 (0%)	7/414 (1.7%)	Risk difference 1.71 (0.45-2.97)
Asymptomatic intracranial hemorrhage	Adverse	14/418 (3.3%)	15/414 (3.6%)	RR 1.07 (0.52-2.19)
Death at 90 days	Adverse	16/417 (3.8%)	17/414 (4.1%)	RR 1.07 (0.55-2.09)
Systemic bleeding	Adverse	6 (1.4%)	11 (2.7%)

Subgroup Analysis

No significant heterogeneity across prespecified subgroups. Numerically greater benefit with tirofiban seen in: patients aged ≥70 years (RR 1.33 vs 1.08 for <70), NIHSS ≥8 (RR 1.54 vs 1.07 for <8), ASPECTS ≤8 (RR 1.41 vs 1.17 for >8), and time ≥4 hours from onset (RR 1.23 vs 1.10 for <4 hours). Similar benefit with alteplase (RR 1.18) and tenecteplase (RR 1.18).

Criticisms

Conducted exclusively in China with predominantly large-artery atherosclerosis etiology (58%), limiting generalizability to Western populations where cardioembolic stroke is more common
Excluded patients with atrial fibrillation/cardioembolic stroke - limits applicability to a significant stroke population
Relatively mild stroke severity (median NIHSS 6) - may not generalize to more severe strokes
Symptomatic ICH occurred only in tirofiban group (1.7% vs 0%) - safety signal despite low absolute rate
SITS-MOST criteria for sICH assessed only within 36 hours - may have missed late hemorrhages
Lack of systematic vascular imaging before and after treatment limits assessment of recanalization/reocclusion
Reasons for not performing thrombectomy in patients with LVO not systematically recorded
High proportion with prior stroke (27.6%) may affect generalizability
Substantial proportion of eligible patients declined participation - potential selection bias
Secondary outcomes not adjusted for multiplicity - no conclusions can be drawn from these
Brant test indicated violation of proportional odds assumption for mRS shift analysis

Funding

Fundamental Research Funds for Central Universities (Grant YD9110002014). Tirofiban and placebo provided by Lunan Pharmaceutical Group (no role in design, conduct, analysis, or reporting).

Based on: ASSET-IT (New England Journal of Medicine, 2025)