IMPORTANCE: Although recent trials have shown benefit with early tirofiban after thrombolysis, its efficacy remains uncertain in patients with acute ischemic stroke who do not have a large or medium vessel occlusion or a cardioembolic source and who show an inadequate clinical response to intravenous tenecteplase.
OBJECTIVE: To assess the efficacy and safety of intravenous tirofiban administered after an inadequate response to intravenous tenecteplase in this specific patient population.
DESIGN, SETTING, AND PARTICIPANTS: Investigator-initiated, randomized, double-blind, placebo-controlled trial conducted at 37 hospitals in China, enrolling 359 patients with acute ischemic stroke, without large or medium vessel occlusion or cardioembolic etiology, and with an insufficient clinical response to intravenous tenecteplase (defined as no significant change from baseline, neurological deterioration, or neurological fluctuation based on serial assessment of the National Institutes of Health Stroke Scale score within 4-24 hours after infusion). Recruitment took place between April 24, 2024, and July 16, 2025, with final follow-up on October 11, 2025.
INTERVENTIONS: Intravenous tirofiban (n = 177), administered as a 0.3-µg/kg/min bolus over 30 minutes, followed by a continuous infusion of 0.075 µg/kg/min for up to 47.5 hours, or matching placebo (n = 182), initiated within 4 to 24 hours after intravenous tenecteplase. Oral antiplatelet therapy (aspirin and/or clopidogrel) was started 24 hours after thrombolysis in the placebo group and 44 hours after thrombolysis in the tirofiban group and continued in all patients through 90-day follow-up.
MAIN OUTCOMES AND MEASURES: The primary outcome was an excellent outcome (defined as a score of 0 or 1 on the modified Rankin Scale; range, 0-6, with higher scores indicating more severe disability) at 90 days. Safety outcomes included incidence of symptomatic intracranial hemorrhage within 48 hours and 90-day mortality.
RESULTS: Among 359 patients randomized (mean age, 66 years; 141 females [39.3%]), 358 (99.7%) completed the trial. An excellent outcome at 90 days was observed in 113 patients (63.8%) in the tirofiban group and in 95 patients (52.2%) in the placebo group (risk ratio, 1.22; 95% CI, 1.02-1.46; P = .03). Symptomatic intracranial hemorrhage within 48 hours occurred in 1 patient (0.9%) in the tirofiban group and no patients in the placebo group; 90-day mortality was 0.6% and 1.6%, respectively.
CONCLUSIONS AND RELEVANCE: Among patients with acute ischemic stroke without large or medium vessel occlusion or a cardioembolic source who had an inadequate clinical response to intravenous tenecteplase, adjunctive intravenous tirofiban increased the likelihood of an excellent outcome at 90 days.
TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05604638.
| Discipline Area | Score |
|---|---|
| Emergency Medicine |  |
| Hospital Doctor/Hospitalists | |
| Internal Medicine | |
| Neurology |  |
If verified in subsequent trials, INSTANT RCT provides additional pharmacological alternatives for post-tNK acute ischemic stroke patients. Rather surprising that addition of tirofiban after thrombolysis would not increase observed symptomatic intracranial hemorrhage rates.
In this RCT, tirofiban improved functional outcomes in those who received TNK but did not have an LVO or MVO or cardioembolic source. This furthers the evidence about its role for acute stroke therapy. Several things to note, however: 1) the indication was based on "insufficient clinical response," which could be no earlier than 4 hours post TNK. Since evidence suggest that improvement in outcomes are based over a longer period of time, it's not clear whether using a 4-hour cutoff is ideal versus giving the drug upfront; and 2) the complexity of treating acute stroke has gone up significantly with various treatment pathways for various types of ischemic stroke. This now requires either systems to prevent potential errors in treating various types of patients with stroke or using centralized expertise such as telestroke. The world is finally moving beyond just TNK or thrombectomy.
In the this RCT, tirofiban administered 4-24 hours after tenecteplase caused patients to have higher rates of excellent outcomes. However, this outcome is not the gold standard outcome for stroke patients (90-day mRS 0-2). If the authors used the gold standard outcome, it is suspected there would be statistical significance. Also, tirofiban is not available in many hospitals, so this study's results may not be widely applicable.
Needs further investigation.
A positive trial against the previous literature opens interest for more research.