This is a multicenter, randomized, open-label, blinded-endpoint clinical trial designed to evaluate the efficacy and safety of early administration of eptifibatide following intravenous thrombolysis in patients with acute ischemic stroke who present 4.5 to 24 hours after symptom onset.

Several clinical trials (e.g., TRACE-3, EXPECTS, HOPE) have successfully extended the time window for intravenous thrombolysis (IVT) from the conventional 4.5 hours up to 24 hours after symptom onset by utilizing advanced imaging selection techniques. Consequently, the 2024 Chinese guidelines for reperfusion therapy recommend IVT for patients presenting 4.5 to 24 hours after onset, based on imaging selection criteria. However, clinical practice indicates that a considerable proportion of patients exhibit suboptimal recanalization outcomes or even experience early neurological deterioration (END) despite receiving standard IVT. Previous research, such as the ASSET-IT trial, has primarily focused on patients treated within 4.5 hours of onset. For the growing population of "extended-window" (4.5-24 hours) patients receiving IVT facilitated by advances in imaging, the optimal antiplatelet strategy following thrombolysis remains an area with no high-level evidence. Therefore, this study aims to evaluate the efficacy and safety of early administration of eptifibatide following standard IVT (with tenecteplase or alteplase) in patients with acute ischemic stroke who present 4.5 to 24 hours after symptom onset. Patients who have received standard IVT but exhibit early neurological deterioration, fluctuation, or lack of significant improvement within 1 hour post-thrombolysis will be randomized 1:1 to receive either eptifibatide (a single intravenous bolus followed by a 2-hour infusion) plus standard medical therapy or standard medical therapy alone. The primary efficacy outcome is the proportion of patients achieving an excellent functional outcome (modified Rankin Scale score of 0-1) at 90 days. The primary safety outcome is the incidence of symptomatic intracranial hemorrhage within 48 hours after randomization. A total of 786 participants are planned to be enrolled to detect a 10% absolute difference in the primary outcome with 80% power.

Inclusion Criteria:

1. Age ≥ 18 years.

2. Acute ischemic stroke, with the time interval from last known well to hospital presentation being 4.5 to 24 hours.

3. NIHSS score ≥ 4 before randomization; if large or medium vessel occlusion is present, an NIHSS score ≤ 10 is also required.

4. Presence of any of the following conditions after completion of standard intravenous thrombolysis:

   1. No significant neurological improvement within 1 hour (defined as a change in NIHSS score ≤ 1 point from baseline).
   2. Early neurological deterioration within 1 hour of onset (defined as an increase in NIHSS score ≥ 2 points from baseline).
   3. Neurological fluctuation within 24 hours after symptom onset (defined as an increase in NIHSS score ≥ 2 points from the lowest value post-thrombolysis).

5. Ability to receive the assigned study drug within 60 minutes after intravenous thrombolysis.

6. Signed written informed consent obtained from the patient or their legal representative.

Exclusion Criteria:

1. Intracranial hemorrhage confirmed by CT or MRI.
2. Planned endovascular therapy.
3. Presence of any definite cardioembolic source, including: chronic or paroxysmal atrial fibrillation, sick sinus syndrome, mitral stenosis, mechanical heart valve, endocarditis, intracardiac thrombus or vegetation, myocardial infarction within 3 months, dilated cardiomyopathy, spontaneous echo contrast in the left atrium, or ejection fraction < 30%.
4. Pre-stroke modified Rankin Scale (mRS) score ≥ 2.
5. Renal insufficiency (glomerular filtration rate < 30 ml/min or serum creatinine > 220 μmol/L [2.5 mg/dL]).
6. Known hypercoagulable state.
7. Platelet count < 100 × 10⁹/L.
8. Pregnancy or lactation.
9. Allergy to eptifibatide, other glycoprotein IIb/IIIa inhibitors, aspirin, or clopidogrel.
10. History of non-atherosclerotic arteriopathy, including moyamoya disease, arterial dissection, or fibromuscular dysplasia.
11. Pre-existing neurological or psychiatric disease that would preclude accurate neurological assessment.
12. History of bleeding diathesis, severe cardiac disease, liver disease, or sepsis.
13. Brain tumor with mass effect on imaging (except for small meningiomas).
14. Evidence of intracranial arteriovenous malformation or aneurysm with diameter > 5 mm on CT or MR angiography.
15. Current participation in another clinical trial.
16. Any terminal illness with life expectancy < 6 months.
17. Anticipated inability to complete follow-up.