Intravenous Thrombolysis Combined With Tirofiban in Acute Ischemic Stroke

Overview

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.

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.