INSTANT
(2026)Objective
To assess the efficacy and safety of intravenous tirofiban administered after an inadequate clinical response to intravenous tenecteplase in acute ischemic stroke patients without large or medium vessel occlusion or cardioembolic etiology.
Study Summary
• Symptomatic intracranial hemorrhage within 48 hours occurred in 0.9% of the tirofiban group vs 0% in placebo
• 90-day mortality was 0.6% in the tirofiban group vs 1.6% in the placebo group
Intervention
Intravenous tirofiban (0.3 μg/kg/min bolus over 30 minutes, followed by 0.075 μg/kg/min continuous infusion for up to 47.5 hours) initiated 4-24 hours after intravenous tenecteplase
Inclusion Criteria
Adults ≥18 years with acute ischemic stroke; NIHSS ≥4 before randomization; no large or medium vessel occlusion; no cardioembolic etiology; insufficient clinical response to IV tenecteplase (no significant NIHSS change, neurological deterioration, or fluctuation) within 4-24 hours after infusion
Study Design
Arms: Tirofiban 0.3 μg/kg/min bolus then 0.075 μg/kg/min infusion (n=177) vs Matching placebo (n=182)
Patients per Arm: 177 tirofiban; 182 placebo
Outcome
• Symptomatic ICH within 48 hours: 0.9% tirofiban vs 0% placebo
• 90-day mortality: 0.6% tirofiban vs 1.6% placebo
Bottom Line
In acute ischemic stroke patients without large vessel occlusion or cardioembolic source who show an inadequate response to tenecteplase, adjunctive IV tirofiban significantly increases the likelihood of an excellent 90-day outcome (mRS 0-1: 63.8% vs 52.2%, NNT≈9) with a low rate of symptomatic intracranial hemorrhage, supporting its use as rescue antiplatelet therapy in this specific population.
Major Points
- Tirofiban significantly increased excellent 90-day outcomes (mRS 0-1) compared with placebo: 63.8% vs 52.2% (RR 1.22, 95% CI 1.02-1.46, P=.03); NNT≈9
- The safety profile was acceptable: symptomatic ICH within 48 hours occurred in only 0.9% of the tirofiban group vs 0% in placebo
- 90-day mortality was numerically lower with tirofiban (0.6%) vs placebo (1.6%), though secondary outcome analyses are exploratory
- The trial was specifically designed for a pathophysiologically coherent subgroup — stroke without large/medium vessel occlusion or cardioembolic source — where microcirculatory mechanisms are most relevant
- Tirofiban was initiated 4-24 hours after tenecteplase, with oral antiplatelet therapy delayed to 44 hours post-thrombolysis in the tirofiban group to avoid stacking
- Trial completion rate was 99.7% (358/359), lending high internal validity to the primary result
Study Design
- Study Type
- Multicenter, randomized, double-blind, double-dummy, placebo-controlled trial
- Randomization
- Yes
- Blinding
- Double-blind, double-dummy; trial personnel, participants, and outcome assessors blinded to treatment allocation
- 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 score of 0 or 1 at 90 days, centrally adjudicated by 2 certified neurologists blinded to treatment allocation
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| 52.2% (95/182) | 63.8% (113/177) | - (1.02-1.46) | .03 |
Limitations & Criticisms
- Trial conducted exclusively in China at 37 centers — generalizability to other ethnic populations and healthcare settings is uncertain
- Secondary outcomes are exploratory due to absence of multiplicity correction
- Protocol amendment in May 2025 refined eligibility criteria during active enrollment, which may introduce bias
- Follow-up imaging was performed only for suspected neurological deterioration or at clinical discretion, not systematically, potentially underdetecting asymptomatic hemorrhage
- Definition of 'insufficient clinical response' is complex and required centralized adjudication, which may be difficult to replicate in routine practice
- Results are not available for the full text of secondary efficacy outcomes in this source
Citation
INSTANT Trial Authors for the INSTANT Investigators. Intravenous Tirofiban After Tenecteplase in Acute Ischemic Stroke: The INSTANT Randomized Clinical Trial. JAMA. Published online May 8, 2026. doi:10.1001/jama.2026.5245