Acute Ischemic Stroke
Conditions
Keywords
stroke, tirofiban, thrombolysis
Brief summary
This multicenter, prospective, double-blind, placebo-controlled, randomized trial (ANGEL-DRUG2) aims to evaluate the efficacy and safety of intravenous tirofiban following intravenous thrombolysis in patients with acute ischemic stroke who show insufficient neurological improvement after initial treatment. Eligible patients (≥18 years, baseline NIHSS ≥4, within 4.5 hours from last known well) will be randomized 1:1 to receive either tirofiban or placebo infusion for 24 hours, followed by standard oral antiplatelet therapy. The primary endpoint is the proportion of patients achieving functional independence (mRS 0-2) at 90 days. Secondary outcomes include changes in NIHSS score, vessel recanalization, infarct volume, distribution of mRS scores, recurrent stroke, and health-related quality of life. Safety outcomes focus on symptomatic intracranial hemorrhage and all-cause mortality. Approximately 976 patients will be enrolled across 30 sites in China.
Detailed description
Acute ischemic stroke (AIS) is a leading cause of death and disability worldwide. Intravenous thrombolysis (IVT) and endovascular therapy (EVT) are guideline-recommended treatments, but many patients continue to experience unsatisfactory neurological recovery after IVT alone. Early antiplatelet therapy is recommended as adjunctive management, and tirofiban, a selective and reversible intravenous glycoprotein IIb/IIIa receptor inhibitor, has shown promise in reducing platelet aggregation and thrombus formation without significantly increasing symptomatic intracranial hemorrhage. However, robust evidence regarding its efficacy and safety in AIS patients with poor neurological improvement after IVT is lacking. ANGEL-DRUG2 is designed to fill this knowledge gap. This trial will enroll 976 patients at 30 centers who present with acute ischemic stroke, have received IVT within 4.5 hours of onset, and demonstrate poor or worsening neurological improvement within 1 hour post-IVT (defined as NIHSS score decrease \<2 or increase ≥1). Patients will be randomized in a 1:1 ratio, stratified by center, to receive either tirofiban infusion (0.4 μg/kg/min for 30 minutes, then 0.1 μg/kg/min for 23.5 hours) or placebo (normal saline) infusion of the same regimen. Both groups will be transitioned at 20 hours to standard oral antiplatelet therapy (aspirin and/or clopidogrel). The primary efficacy endpoint is the proportion of patients achieving a modified Rankin Scale (mRS) score of 0-2 at 90±7 days. Secondary efficacy endpoints include NIHSS change at 36±12 hours, vessel recanalization on CTA/MRA, infarct volume, distribution of mRS scores at multiple timepoints, recurrent stroke within 90 days, and EQ-5D-5L quality-of-life scores. Safety endpoints include symptomatic intracranial hemorrhage within 48 hours (Heidelberg criteria), any intracranial hemorrhage, and all-cause mortality at 90 days. This rigorously designed study will provide high-quality evidence regarding whether tirofiban, when added to IVT in AIS patients with poor early response, can improve functional outcomes without unacceptable safety risks.
Interventions
DRUGTirofiban
After intravenous thrombolysis, if neurological improvement is insufficient (NIHSS score decrease \<2 within 1 hour or NIHSS increase ≥1), tirofiban infusion is initiated within 1 hour. The regimen consists of 0.4 μg/kg/min for 30 minutes, followed by 0.1 μg/kg/min for 23.5 hours (total 24 hours). At the 20th hour of infusion, oral antiplatelet therapy (aspirin 100 mg once daily and/or clopidogrel 75 mg once daily) is initiated, overlapping with tirofiban for 4 hours (bridge therapy). At 24 hours, tirofiban infusion is completed, and patients continue oral antiplatelet therapy per protocol.
Matched normal saline infusion using the same dosing schedule and pump rates as the tirofiban arm (0.4 μg/kg/min for 30 minutes, then 0.1 μg/kg/min for 23.5 hours; total 24 hours). At the 20th hour of infusion, oral antiplatelet therapy (aspirin 100 mg once daily and/or clopidogrel 75 mg once daily) is initiated, overlapping with placebo infusion for 4 hours (bridge therapy). At 24 hours, placebo infusion is completed, and patients continue oral antiplatelet therapy per protocol.
Sponsors
Beijing Anzhen Hospital
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Age ≥18 years. 2. Pre-stroke modified Rankin Scale (mRS) score of 0-1. 3. Acute ischemic stroke symptoms within 4.5 hours of last known well time. 4. Baseline National Institutes of Health Stroke Scale (NIHSS) score ≥4. 5. Poor neurological improvement 1 hour after intravenous thrombolysis, defined as NIHSS decrease \<2 points, or neurological worsening within 1 hour, defined as NIHSS increase ≥1 point. 6. Not planned for or not eligible for endovascular treatment. 7. Subject or legally authorized representative can provide written informed consent.
Exclusion criteria
1. Evidence of intracranial hemorrhage on imaging before randomization. 2. Non-ischemic intracranial pathologies, such as vascular malformation, aneurysm, tumor, abscess, or demyelinating disease. 3. Large or medium vessel stenosis requiring thrombectomy or intra-arterial thrombolysis. 4. Contraindications to tirofiban, including but not limited to:Known hypersensitivity to tirofiban; Severe hepatic dysfunction (ALT \>2× ULN or AST \>2× ULN); Severe renal dysfunction (serum creatinine \>1.5× ULN); Advanced heart failure (NYHA class III-IV); Coagulation disorders or history of systemic bleeding; History of thrombocytopenia or neutropenia; Prior drug-induced hematologic disease or liver dysfunction; Leukopenia (\<2×10\^9/L) or platelet count \<100×10\^9/L. 5. Use of tirofiban or other GP IIb/IIIa inhibitors before randomization, or planned use of such agents after randomization. 6. Definite cardioembolic source, including but not limited to: chronic or paroxysmal atrial fibrillation, sick sinus syndrome, mitral stenosis, mechanical prosthetic heart valves, infective endocarditis, history of intracardiac thrombus, myocardial infarction within 3 months, dilated cardiomyopathy, spontaneous left atrial echo contrast, or left ventricular ejection fraction \<30%. 7. Pregnancy or lactation. 8. Expected survival \<6 months. 9. Pre-existing neurological or psychiatric disorders that may interfere with outcome assessment. 10. Unlikely to complete 90-day follow-up.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of patients with mRS 0-2 at 90 days | 90±7 days post-randomization | Proportion of patients with Modified Rankin Scale (mRS) 0-2, Modified Rankin Scale（0-6）, A lower MRS score indicates better functional status for the patient. |
| Symptomatic Intracranial Hemorrhage (sICH) within 48 hours | Randomization to 48 hours | Heidelberg Bleeding Classification with clinical worsening criteria. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in NIHSS from baseline to 36±12 hours | 36±12 hours post-randomization | Change in National Institute of Health stroke scale score from baseline.The NIH Stroke Scale (NIHSS) score ranges from 0 to 42 points, with lower scores indicating better neurological function |
| Vascular recanalization rate assessed by CT/MR angiography | 36±12 hours post-randomization | Vascular recanalization rate assessed by CT/MR angiography |
| Change in infarct volume at 7±3 days/discharge | 7±3 days post-randomization or discharge | Change in infarct volume |
| mRS distribution | 7±3 days/discharge；90±7 days post-randomization | Modified Rankin Scale（0-6）, A lower MRS score indicates better functional status for the patient. |
| Proportion with mRS 0-3 at 90 days | 90±7 days | Proportion of patients with Modified Rankin Scale (mRS) 0-3, Modified Rankin Scale（0-6）, A lower MRS score indicates better functional status for the patient |
| EQ-5D-5L score at 90±7 days | 90±7 days | The EuroQol 5-Dimension 5-Level Utility Score (EQ-5D-5L utility score) ranges from -0.594 to 1.000 (Chinese value set), assessing health-related quality of life, with higher scores indicating better health status. |
| Any Intracranial Hemorrhage within 48 hours | Randomization to 48 hours | Heidelberg Bleeding Classification with clinical worsening criteria. |
| All-cause mortality at 90 days | 90±7 days post-randomization | All-cause mortality |
| Proportion with mRS 0-1 at 90 days | 90±7 days | Proportion of patients with Modified Rankin Scale (mRS) 0-1, Modified Rankin Scale（0-6）, A lower MRS score indicates better functional status for the patient. |
| Stroke recurrence at 90 ± 7 days. | 90±7 days post-randomization | Stroke recurrence |
Countries
China
Contacts
Primary ContactXiaochuan Huo
Backup ContactXin Tong
Outcome results
None listed