INSTANT
(2026)Objective
To assess the efficacy and safety of intravenous tirofiban administered after an inadequate clinical response to intravenous tenecteplase in patients with acute ischemic stroke without large or medium vessel occlusion or a cardioembolic source.
Study Summary
• Symptomatic intracranial hemorrhage within 48h: 0.9% tirofiban vs 0% placebo
• 90-day mortality: 0.6% tirofiban vs 1.6% placebo
• Adjunctive IV tirofiban increased likelihood of excellent functional outcome at 90 days
Intervention
Intravenous tirofiban (0.3 μg/kg/min bolus over 30 min, then continuous infusion of 0.075 μg/kg/min for up to 47.5 hours) vs matching placebo, initiated 4-24 hours after IV tenecteplase. Oral antiplatelet therapy (aspirin and/or clopidogrel) started at 24h in placebo group and 44h in tirofiban group, continued through 90 days.
Inclusion Criteria
Age ≥18 years; acute ischemic stroke; NIHSS ≥4 before randomization; insufficient clinical response to IV tenecteplase (no significant change [±0-1 NIHSS point], neurological deterioration [≥2-point NIHSS worsening], or neurological fluctuation) assessed 4-24 hours after infusion; no large or medium vessel occlusion; no cardioembolic etiology.
Study Design
Arms: IV tirofiban (n=177) vs matching placebo (n=182)
Patients per Arm: Tirofiban n=177; Placebo n=182
Outcome
• Safety: Symptomatic ICH within 48h — 0.9% (1 patient) tirofiban vs 0% placebo
• 90-day mortality — 0.6% tirofiban vs 1.6% placebo
• 358/359 (99.7%) completed trial
Bottom Line
In acute ischemic stroke patients without large/medium vessel occlusion or cardioembolic source who show an inadequate response to IV tenecteplase, adjunctive IV tirofiban (started 4-24h after thrombolysis) significantly increased the likelihood of an excellent functional outcome (mRS 0-1) at 90 days (63.8% vs 52.2%; RR 1.22; P=.03) with a very low rate of symptomatic intracranial hemorrhage.
Major Points
- Adjunctive IV tirofiban increased excellent outcome (mRS 0-1) at 90 days from 52.2% to 63.8% (RR 1.22; 95% CI 1.02-1.46; P=.03).
- Absolute risk difference ~11.6%, yielding an NNT of approximately 9 for an excellent functional outcome.
- Symptomatic intracranial hemorrhage was rare in both groups (0.9% tirofiban vs 0% placebo).
- 90-day mortality was low in both arms (0.6% tirofiban vs 1.6% placebo).
- Tirofiban was initiated 4-24 hours after tenecteplase with delayed oral antiplatelet (44h vs 24h in placebo group).
- Findings support a benefit of GP IIb/IIIa inhibition as rescue therapy in non-LVO, non-cardioembolic AIS with inadequate response to tenecteplase.
Study Design
- Study Type
- Investigator-initiated, multicenter, randomized, double-blind, double-dummy, placebo-controlled trial
- Randomization
- Yes
- Blinding
- Double-blind, double-dummy (patients, trial personnel, and outcome assessors blinded; identically appearing study drug and oral antiplatelet placebos)
- Sample Size
- 359
- Follow-up
- 90 days (final follow-up October 11, 2025)
- Centers
- 37
- Countries
- China
Primary Outcome
Definition: Excellent outcome defined as modified Rankin Scale (mRS) score of 0 or 1 (centrally adjudicated by 2 certified neurologists using standardized video/voice recordings)
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| 95/182 (52.2%) | 113/177 (63.8%) | - (1.02-1.46) | 0.03 |
Limitations & Criticisms
- Single-country enrollment (all 37 sites in China) may limit generalizability to other populations and healthcare systems.
- Open-label aspect of timing of oral antiplatelet introduction (24h vs 44h) introduces a potential confounder, although double-dummy design preserved blinding.
- Definition of 'inadequate response' to tenecteplase relies on serial NIHSS assessment and may be subject to inter-rater variability despite centralized adjudication.
- Modest sample size (n=359); CI for the primary RR (1.02-1.46) is wide and lower bound is close to 1.0.
- Secondary outcomes were exploratory without multiplicity correction.
- No head-to-head comparison with earlier initiation of antiplatelet therapy alone.
Citation
JAMA. doi:10.1001/jama.2026.5245. Published online May 8, 2026.