Antithrombotic treatment for migraine in patients with patent foramen ovale: multicentre, randomised, active controlled, open label trial

Objectives To evaluate the efficacy and safety of antithrombotic treatment for migraine prevention in participants with patent foramen ovale (PFO). Design Investigator initiated, multicentre, prospective, randomised, active controlled, open label clinical trial with blinded outcome assessment and hierarchical hypothesis testing. Setting Secondary and tertiary care hospitals across 39 centres in China. Participants 1000 adults aged 18-64 years with a diagnosis of migraine for more than one year, experiencing at least four migraine days per month, and with PFO confirmed by echocardiography. All participants completed a 12 week screening period before randomisation during which eligibility was confirmed and baseline headache data were prospectively recorded. Participants with previous stroke, transient ischaemic attack, intracranial haemorrhage, non-PFO right-to-left shunt, or contraindications to study drugs were excluded. Of the randomised participants, 984 (75.1% female) were included in the full analysis set. Interventions After the screening phase, participants were randomised in a 1:1:1:1 ratio to receive aspirin (300 mg once daily), clopidogrel (75 mg once daily), rivaroxaban (20 mg once daily), or metoprolol (25 mg twice daily) for 12 weeks. No additional preventive migraine treatments were permitted during the intervention period. Main outcome measures The primary outcome was the proportion of participants achieving a ≥50% reduction in monthly migraine days or attacks from baseline to weeks 9-12. Safety outcomes included bleeding and other adverse events. Results For the primary endpoint, aspirin, clopidogrel, and rivaroxaban were all non-inferior to metoprolol. Responder rates were 61.7% (148/240) with aspirin, 66.8% (157/235) with clopidogrel, 78.4% (185/236) with rivaroxaban, and 61.8% (144/233) with metoprolol. Rivaroxaban further showed a statistically higher responder rate than metoprolol, with an absolute difference of 16.2% (98.33% confidence interval 6.0 to 26.4; P<0.001). Among secondary endpoints, rivaroxaban was associated with greater reductions in migraine days and attacks, higher rates of complete migraine cessation, and greater improvements in migraine specific quality-of-life scores than metoprolol. No major bleeding events occurred. Conclusions The antithrombotic agents evaluated in this trial (aspirin, clopidogrel, and rivaroxaban) were all non-inferior to metoprolol for responder rate in participants with PFO and migraine. Rivaroxaban also showed superior responder rates over metoprolol without an increase in major bleeding events. Trial registration ClinicalTrials.gov NCT05546320 .