This trial aims to compare the safety and efficacy of apixaban alone versus apixaban combined with clopidogrel in patients with acute ischemic stroke associated with non-valvular atrial fibrillation and concomitant symptomatic intracranial or extracranial atherosclerosis. Participants will be randomly assigned in a 1:1 ratio to receive apixaban monotherapy or dual therapy with clopidogrel for 30 days. The primary outcome is the incidence of symptomatic or asymptomatic recurrent ischemic lesions detected on brain MRI (DWI/FLAIR) at 30 ± 5 days after initiation of study medication.

"Although oral anticoagulants are effective in preventing cardioembolic stroke in patients with non-valvular atrial fibrillation (NVAF), a considerable proportion of ischemic strokes in these patients are caused by concomitant large artery atherosclerosis. Carotid or intracranial artery stenosis is present in a substantial number of patients with NVAF and is associated with a higher risk of recurrent cerebral infarction despite standard anticoagulation. In such patients, adding an antiplatelet agent to oral anticoagulation may theoretically reduce atherothrombotic events, but it also raises concern for increased bleeding risk. Recent clinical evidence on this issue remains limited, and the optimal antithrombotic strategy for patients with NVAF and coexisting symptomatic atherosclerotic stenosis has not been clearly established.

The BEACON-AA trial is a multicenter, randomized, open-label, blinded-endpoint (PROBE) study designed to compare the safety and efficacy of apixaban monotherapy versus apixaban combined with clopidogrel in patients with acute ischemic stroke associated with non-valvular atrial fibrillation (NVAF) and concomitant symptomatic intracranial or extracranial atherosclerosis. Participants will be randomized in a 1:1 ratio to receive apixaban alone or apixaban plus clopidogrel for 30 days, followed by apixaban monotherapy thereafter.

Brain MRI including diffusion-weighted and FLAIR sequences will be performed at baseline and at 30 ± 5 days to assess new or recurrent ischemic lesions. The primary efficacy outcome is the incidence of symptomatic or asymptomatic recurrent ischemic lesions detected on brain MRI (DWI/FLAIR) at 30 ± 5 days after initiation of study medication. Secondary efficacy outcomes include: 1) incidence of symptomatic ischemic stroke or transient ischemic attack within 90 days, 2) incidence of acute coronary syndrome within 90 days,3) cardiovascular mortality within 90 days, 4) composite major cardiovascular events within 90 days, 5) all-cause mortality within 90 days, 6) proportion of patients with modified Rankin Scale (mRS) 0-2 at 90 days, and 7) proportion of patients with mRS 0-3 at 90 days. The primary safety outcomes are: 1) incidence of major bleeding within 90 days, defined according to the International Society on Thrombosis and Haemostasis (ISTH) criteria and 2) incidence of new asymptomatic cerebral hemorrhages detected on brain MRI (DWI/FLAIR) at 30 ± 5 days after initiation of study medication. All imaging and clinical events will be independently adjudicated by blinded central adjudication committees."

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.