Table 1 Inclusion and exclusion criteria

Inclusion criteria

 1. Subject is aged between 16 and 60 years old.

 2. Subject is diagnosed of PFO with right-to-left shunt, confirmed by Transthoracic echocardiography (TTE) or transesophageal echocardiography (TEE) with agitated saline contrast.

 3. Subject is diagnosed of right-to-left shunt, confirmed by transcranial doppler with agitated saline contrast.

 4. Subject is diagnosed of migraine without identifiable cause of headache.

 5. Subject signs an informed Consent Form and is willing to participate in follow-up visits; 6. Primary and secondary endpoints.

Exclusion criteria:

 1. Subject is diagnosed of headache with clear etiology.

 2. Subject had cerebral hemorrhage, bleeding events in other organs within 3 months or was in high risk of bleeding.

 3. Subject presents with ischemic lesions as indicated by brain CT/MR imaging.

 4. Subject is diagnosed of hepatic insufficiency: ALT or AST > 3 × ULN at the screening visit.

 5. Subject is diagnosed of moderate to severe renal insufficiency: eGFR < 30 ml/min/1.73m2 at the screening visit.

 6. Subject has uncontrolled arrhythmia with clinical significance within 90 days.

 7. Subject is diagnosed of unstable angina, severe coronary atherosclerosis or myocardial infarction within 90 days.

 8. Subject is diagnosed of pulmonary artery embolism, peripheral artery embolism or deep Vein Thrombosis.

 9. Subject cannot follow the study procedure due to other acute or chronic diseases.

 10. Subject is pregnant or lactating.

 11. Subject is under other RCT.

 12. Subject has a life expectancy < 1 year.

 13. Subject cannot follow the study procedure due to other reasons in the opinion of the investigators.