Stroke is the second leading cause of death worldwide, and ischemic stroke is the most frequent type. Intravenous thrombolysis with recombinant tissue plasminogen activator within 4.5 hours of symptom onset is the most effective therapy for patients with acute ischemic stroke. However, ischemic stroke progression and early reocclusion are not an uncommon phenomenon in patients after intravenous thrombolysis, resulting in neurological deterioration, which is associated with unfavorable functional outcomes. The underlying mechanism mainly involves the augmented platelet activation, triggered by the activated coagulation cascade during thrombolysis, which peaks within 2 hours of initiating rt-PA administration. Therefore, early antiplatelet therapy following intravenous thrombolysis represents a promising therapeutic approach to prevent neurological deterioration and improve the functional outcome of patients treated with intravenous thrombolysis.

Currently, guidelines recommend initiating antiplatelet therapy 24 hours after intravenous thrombolysis due to the potential risk of increased bleeding. The safety and efficacy of early antiplatelet treatment following intravenous thrombolysis in patients with acute ischemic stroke remain clear.

The study aims to test the hypothesis that in patients with acute ischemic stroke treated with intravenous thrombolysis, early administration of oral aspirin will improve functional outcomes without increasing the risk of intracranial hemorrhage.

Inclusion Criteria:

1. Age ≥18 years old;
2. Acute ischemic stroke treated with intravenous thrombolysis with alteplase or tenecteplase within 4.5 hours of onset or time last known well, and can receive the study drug treatment within 3 hours of initiating intravenous thrombolysis.
3. Residual NIHSS score > 5 points assessed 1 hour after initiation of intravenous thrombolysis and prior to randomization.
4. Informed consent obtained from patients or an authorized representative.

Exclusion Criteria:

1. Stroke caused by definite large vessel occlusion (including A1/A2 segments of the anterior cerebral artery, M1/M2 segments of the middle cerebral artery, P1/P2 segments of the posterior cerebral artery, intracranial/extracranial segments of the internal carotid artery, basilar artery, and bilateral vertebral artery occlusion) confirmed by vessel imaging (including computed tomography angiography [CTA] or magnetic resonance angiography [MRA]), or scheduled for endovascular treatment (including mechanical thrombectomy, intra-arterial thrombolysis, and angioplasty).
2. Intracranial hemorrhage confirmed by imaging post-thrombolysis.
3. Definite or suspected cardioembolic stroke.
4. Stroke caused by other determined causes, including nonatherosclerotic vasculopathies (moyamoya disease, artery dissection, arteritis), hypercoagulable states, or hematological disorders.
5. Use of antiplatelet therapy within one week prior to stroke onset, novel anticoagulant drugs within 48 hours prior to stroke onset, or treatment with warfarin with an international normalized ratio (INR)>1.7.
6. Prior history of moderate or severe ischemic stroke events with residual neurological disability.
7. Pre-stroke mRS score > 1.
8. Severe consciousness disturbance with NIHSS item 1a (level of consciousness) ≥ 2 points.
9. Post-thrombolysis imaging indicates an infarct area larger than 1/2 responsible artery supply area.
10. Known contraindications for antiplatelet therapy, such as coagulation disorders, or systemic bleeding
11. History of aspirin allergy.
12. Anticipated indications for anticoagulant therapy during the study period (e.g., atrial fibrillation, mechanical heart valve, deep vein thrombosis, pulmonary embolism, antiphospholipid syndrome, hypercoagulable state)
13. Presence of malignant tumors, chronic hemodialysis, severe renal insufficiency (GFR < 30 mL/min or serum creatinine > 220 μmol/L [2.5 mg/dL]), severe hepatic insufficiency (serum alanine aminotransferase [ALT] >2 times the upper limit of normal, or serum aspartate aminotransferase [AST] >2 times the upper limit of normal), severe heart failure (New York Heart Association [NYHA] Functional Classification Class III or IV)
14. Severe non-cardiovascular complications with an expected survival of less than 6 months.
15. Unavailability for follow-up.
16. Presence of dementia, psychiatric disorders, or other known neurological conditions that complicate follow-up.
17. Current participation in another therapeutic study with ongoing treatment and follow-up.
18. Other conditions that make the patient unsuitable for participation in the study as determined by the investigator.