Patients with acute ischemic stroke who had an inadequate early clinical response to intravenous tenecteplase achieved higher rates of excellent functional outcome at 90 days when treated with adjunctive intravenous tirofiban vs placebo, according to findings from the INSTANT randomized clinical trial published in JAMA.
The investigator-initiated, randomized, double-blind, placebo-controlled, double-dummy trial enrolled 359 patients at 37 hospitals in China. Eligible patients had acute ischemic stroke without large- or medium-vessel occlusion or a cardioembolic source, had a National Institutes of Health Stroke Scale (NIHSS) score of 4 or higher prior to randomization, and had received intravenous tenecteplase at 0.25 mg/kg, up to a maximum dose of 25 mg.
Patients were eligible if they demonstrated an inadequate clinical response within 4 to 24 hours following tenecteplase. Researchers defined this as no meaningful NIHSS score change (0- or 1-point increase or decrease), neurological deterioration of at least 2 points, or neurological fluctuation consisting of a 4-point increase followed by a 4-point decrease, or vice versa. Centralized adjudication was used to confirm eligibility criteria.
The trial excluded patients with intracranial hemorrhage following thrombolysis and prior to randomization, confirmed or suspected cardioembolic stroke, and large- or medium-vessel occlusion.
Participants were randomly assigned to intravenous tirofiban (n = 177) or placebo (n = 182). Tirofiban was administered as a 0.3-μg/kg/min bolus over 30 minutes followed by continuous infusion at 0.075 μg/kg/min for up to 47.5 hours. Under the double-dummy protocol, patients assigned to placebo began active oral antiplatelet therapy 24 hours following thrombolysis, whereas patients assigned to tirofiban initially received oral placebo before all patients transitioned to aspirin, clopidogrel, or both through 90-day follow-up.
At 90 days, 64% of patients assigned to tirofiban achieved an excellent outcome, defined as a modified Rankin Scale score of 0 or 1, compared with 52% assigned to placebo. The unadjusted primary analysis favored tirofiban, corresponding to a number needed to treat of 8.7 (95% confidence interval = 4.6–72.1). However, the prespecified adjusted analysis did not maintain statistical significance, an important limitation noted by the researchers.
The ordinal distribution of modified Rankin Scale scores and quality-of-life assessments favored tirofiban. However, secondary outcomes were considered exploratory because analyses were not adjusted for multiplicity.
Functional independence, defined as a modified Rankin Scale score of 0 to 2, occurred in 79% of patients assigned to tirofiban and 72% assigned to placebo, although the difference was not statistically significant. Independent ambulation and self-care, defined as a modified Rankin Scale score of 0 to 3, occurred in 93% and 90% of patients, respectively, which also did not reach statistical significance.
Early neurological improvement at 48 hours occurred in 54% of patients assigned to tirofiban and 50% assigned to placebo and likewise was not statistically significant.
The study population had predominantly mild-to-moderate neurological deficits, with a median NIHSS score of 6 in both groups and small infarct volumes reflected by high Alberta Stroke Program Early Computed Tomography Scores. Small artery occlusion accounted for 73% of strokes, large artery atherosclerosis for 11%, unknown cause for 15%, and cardioembolism for less than 1%.
Prespecified subgroup analyses did not demonstrate statistically significant treatment-effect heterogeneity, although point estimates appeared larger among younger patients and among those treated later following last known well time. The researchers cautioned that confidence intervals were not adjusted for multiple comparisons and should not be used to infer subgroup treatment effects.
Symptomatic intracranial hemorrhage within 48 hours occurred in 1 patient assigned to tirofiban and no patients assigned to placebo. Researchers noted that the single symptomatic hemorrhage event in the tirofiban group was fatal. Any radiologic intracranial hemorrhage within 48 hours occurred in 2 patients assigned to tirofiban and no patients assigned to placebo, although follow-up imaging was performed selectively rather than systematically in all enrolled patients. Ninety-day mortality occurred in 1 patient assigned to tirofiban and 3 patients assigned to placebo.
The researchers noted that tirofiban is widely used in myocardial infarction but remains off-label in acute ischemic stroke. They also emphasized that the findings may not apply to patients with minor stroke, cardioembolic stroke, large- or medium-vessel occlusion, or those treated outside the early thrombolysis window. Nearly 92% of enrolled patients received tenecteplase within 4.5 hours of last known well time.
The researchers additionally noted that all enrolled patients were Chinese, which may limit generalizability to other populations, particularly given known differences in intracranial atherosclerosis burden.
The trial protocol was amended in May 2025, prior to outcome analysis, to refine the definition of inadequate clinical response and add subgroup analyses related to treatment timing and antiplatelet strategy.
The researchers contextualized the findings within emerging evidence from the ASSET-IT and RESCUE BT2 trials. Unlike ASSET-IT, which administered tirofiban within 60 minutes following thrombolysis and included patients with large- or medium-vessel occlusion, INSTANT initiated tirofiban approximately 7 to 7.5 hours following thrombolysis and specifically targeted patients with inadequate clinical response despite the absence of large-vessel disease.
“These findings suggest that early intravenous tirofiban may represent a potential adjunctive treatment following intravenous tenecteplase in patients with evidence of limited clinical response,” wrote the researchers.
Disclosures: The study was funded by the National Natural Science Foundation of China, the Ganzhou People’s Hospital Talent Training Program, and the Special Fund for Clinical Discipline Construction of Guangxi Medical University. Lunan Pharmaceutical Group Co Ltd supplied study medications. Several researchers reported relationships with pharmaceutical, medical device, and biotechnology companies, including consulting fees, advisory roles, grants, and stock ownership. Full disclosures are available in the published study.
Source: JAMA
