Apixaban with or without Clopidogrel in stroke patients with NVAF and intracranial/extracranial atherosclerosis

Inclusion Criteria:

1. Adults aged 19 years or older at the time of enrollment.
2. Patients with non-valvular atrial fibrillation (NVAF) documented by electrocardiography or medical records.
3. Acute ischemic stroke confirmed by brain MRI (diffusion-weighted and FLAIR sequences), with neurological symptoms occurring within 5 days prior to randomization.
4. Presence of clinically significant atherosclerosis in the cerebral or aortic arteries, meeting at least one of the following criteria:

   ① ≥30% stenosis in the relevant artery (the artery supplying the infarcted territory) demonstrated by CTA, MRA, or DSA - using the WASID criteria for intracranial arteries and NASCET criteria for extracranial arteries.

   ② High-risk atherosclerotic plaque features in the relevant artery demonstrated by CTA, MRA, or ultrasound, such as ulceration, intraplaque hemorrhage, mobile plaque, or a large lipid core (involving ≥25% of plaque cross-sectional area) on CTA/MRA, or ulceration, mobile plaque, or hypoechoic/echolucent plaque on ultrasound; or presence of branch artery occlusive disease (BAOD).

   ③ Complex aortic plaque (≥4 mm in thickness, mobile, or ulcerative) identified in the ascending aorta or aortic arch by transthoracic/transesophageal echocardiography or coronary CT angiography.
5. Ability and willingness to provide written informed consent for participation in the study.

Exclusion Criteria:

1. Presence of mechanical heart valves or rheumatic mitral stenosis.
2. Requirement for antiplatelet agents other than clopidogrel.
3. Planned percutaneous coronary intervention, coronary artery bypass graft surgery, carotid endarterectomy, or intracranial stenting within 3 months after enrollment.
4. Presence of mural thrombus in the heart confirmed by imaging.
5. Renal impairment with creatinine clearance ≤30 mL/min/1.73 m².
6. Severe hepatic impairment, including acute hepatitis, chronic active hepatitis, hepatic lesions or coagulopathy, hepatic failure, or laboratory evidence of AST/ALT \>2× the upper limit of normal (ULN) or total bilirubin \>1.5× ULN.
7. Small-vessel occlusion (lacunar infarction) according to the TOAST classification.
8. History within the past 30 days of gastrointestinal bleeding, vascular malformation of the brain or spinal cord, recent brain, spinal, or ophthalmologic surgery or trauma, esophageal varices, or intracranial hemorrhage at any time; or chronic regular use of NSAIDs (≥3 days per week for ≥2 consecutive weeks).
9. Ischemic stroke occurring despite concurrent use of both NOAC and antiplatelet therapy.
10. Planned surgery or high-bleeding-risk procedure within 3 months, or presence of active bleeding at enrollment.
11. Anemia (hemoglobin \< 8.0 g/dL) or thrombocytopenia (platelet count \< 100,000/µL).
12. Pre-stroke modified Rankin Scale (mRS) ≥ 2.
13. Severe comorbid illness or malignancy not in complete remission with an expected life expectancy \<1 year.
14. Known hypersensitivity or allergy to apixaban or clopidogrel.
15. Pregnant or breastfeeding women.
16. Uncontrolled diabetes mellitus (HbA1c \> 10.0%) or severe hypertension (systolic ≥ 220 mmHg or diastolic ≥ 120 mmHg).
17. Concomitant use of strong CYP3A4 and P-glycoprotein inhibitors that can significantly increase apixaban exposure (e.g., ketoconazole, itraconazole, ritonavir, clarithromycin).
18. Concomitant use of strong CYP2C19 inducers that can reduce clopidogrel antiplatelet effect (e.g., rifampin, carbamazepine, phenytoin, phenobarbital, St. John's wort).
19. Clinically significant mass effect due to space-occupying cerebral infarction, or patients expected to require decompressive craniectomy, including those with midline shift \> 5 mm, loss of basal cisterns, herniation, fourth-ventricle compression, or obstructive hydrocephalus in posterior fossa infarcts.
20. Intracranial hemorrhage or hemorrhagic transformation (PH1 or PH2) according to ECASS criteria.
21. Participation in another interventional clinical trial within the past 30 days or concurrent participation in another interventional study (non-interventional observational or registry studies may be allowed at the investigator's discretion).
22. Any other condition that, in the investigator's judgment, would make participation or continued involvement in the study inappropriate or infeasible.