Migraine attack is an episodic disorder that affects approximately 12% of the population. Previous studies have shown that 41-48% of migraineur have a combination of patent foramen ovale (PFO). Clinical observational studies have been linking medication therapies which include anticoagulation and anti-platelet therapy with the effectiveness in improving migraine symptoms and reducing the frequency of attacks in patients combined with a PFO. However, it has been unclear whether the effectiveness of anticoagulation or anti-platelet therapy outweigh the conventional migraine medication therapy, as a result, we designed a multi-center randomized clinical trial aiming to examine the effectiveness of anticoagulation versus anti-platelet versus migraine medication therapy in migraine patients with PFO and provide a clinical guidance for migraineur.

Inclusion Criteria

Participants must meet all of the following criteria:

1. Aged 18 to 64 years at Visit 1.
2. Diagnosis of migraine with or without aura confirmed by a neurologist, according to the International Classification of Headache Disorders, 3rd edition (ICHD-3) criteria.
3. History of migraine for more than 1 year, with an average of at least 4 migraine days per month during the 12-week screening period, as recorded in a headache diary and confirmed by the investigator at Visit 2.
4. Patent foramen ovale (PFO) diagnosed by transcranial Doppler (TCD), transthoracic echocardiography (TTE), or transesophageal echocardiography (TEE), with a right-to-left shunt at the atrial level.
5. Provision of written informed consent and willingness to comply with follow-up procedures.

Exclusion Criteria

Participants will be excluded if any of the following apply:

1. Secondary headache attributable to other causes.
2. History of transient ischemic attack, stroke, or intracranial hemorrhage.
3. History of pacemaker implantation, atrial septal defect closure, or left atrial appendage closure.
4. Right-to-left intracardiac shunt due to causes other than PFO.
5. Contraindications to antiplatelet or anticoagulant therapy, including thrombocytopenia, major trauma, active bleeding, decompensated cirrhosis, or drug allergy.
6. Contraindications to beta-blocker therapy, including hypotension, severe bradycardia, atrioventricular block, asthma, or drug allergy.
7. Poorly controlled atrial fibrillation at Visit 1.
8. Poorly controlled hypertension at Visit 1, defined as blood pressure >160/90 mmHg despite regular medication.
9. Inability to maintain a headache diary or to reliably report headache symptoms.
10. Use of anticoagulants (e.g., warfarin, rivaroxaban) or antiplatelet agents (e.g., aspirin, clopidogrel, ticagrelor) within 12 weeks prior to Visit 2.
11. Use of metoprolol within 12 weeks prior to Visit 2.
12. Pregnancy, intention to become pregnant during the study period, or planned elective surgery during the study period.
13. Any condition that, in the investigator's opinion, may pose significant risk, confound study results, or interfere with participation.
14. Any other reasons (e.g., likely non-adherence, inability to attend follow-up visits, or planned relocation) that render the participant unsuitable for the study in the investigator's judgment.

Deidentified individual participant data underlying the results reported in this study will be made available upon the publication of the study.

Open-label treatment allocation with blinded outcome assessment based on prospectively completed headache diaries reviewed by independent neurologists blinded to treatment assignment.