Neurology · Medical Literature
Antithrombotic treatment for migraine in patients with patent foramen ovale: multicentre, randomised, active controlled, open label trial.
Abstract
To evaluate the efficacy and safety of antithrombotic treatment for migraine prevention in participants with patent foramen ovale (PFO). Investigator initiated, multicentre, prospective, randomised, active controlled, open label clinical trial with blinded outcome assessment and hierarchical hypothesis testing. Secondary and tertiary care hospitals across 39 centres in China. 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. 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. 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. 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. 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. ClinicalTrials.gov NCT05546320.
Clinical relevance
Migraine affects a substantial proportion of adults with patent foramen ovale (PFO), yet optimal pharmacological prevention in this subgroup remains undefined, with most trials focusing on device closure rather than antithrombotic strategies. This trial addresses a critical evidence gap by directly comparing antithrombotic agents (aspirin, clopidogrel, rivaroxaban) against a standard beta-blocker (metoprolol) in PFO-confirmed migraineurs experiencing ≥4 migraine days/month. The findings are immediately clinically relevant as they offer neurologists and cardiologists a evidence-based antithrombotic framework for migraine prevention in PFO patients who are not candidates for or decline septal closure.
Key findings
1. Rivaroxaban 20 mg once daily achieved a ≥50% responder rate of 78.4% (185/236), significantly superior to metoprolol, with an absolute risk difference of +16.2% (98.33% CI: 6.0–26.4%; P<0.001). 2. Aspirin 300 mg once daily achieved a responder rate of 61.7% (148/240), demonstrating non-inferiority to metoprolol (61.8%; 144/233). 3. Clopidogrel 75 mg once daily achieved a responder rate of 66.8% (157/235), also meeting non-inferiority criteria versus metoprolol. 4. Rivaroxaban was associated with superior reductions in monthly migraine days and attacks, higher rates of complete migraine cessation, and greater improvements in migraine-specific quality-of-life scores compared to metoprolol across pre-specified secondary endpoints. 5. No major bleeding events were recorded in any of the four treatment arms over the 12-week intervention period, supporting an acceptable short-term safety profile for all antithrombotic agents studied. 6. The full analysis set comprised 984 participants (75.1% female), aged 18–64, with PFO confirmed by echocardiography and prospectively recorded baseline headache data across 39 centres, lending the findings robust generalisability within this phenotype.
Practice implications
For adult migraineurs (18–64 years) with echocardiographically confirmed PFO experiencing ≥4 migraine days/month who are not candidates for septal closure, rivaroxaban 20 mg once daily should be considered as a first-line preventive agent given its superior responder rate and secondary endpoint benefits over metoprolol, provided there are no contraindications to anticoagulation. Aspirin 300 mg and clopidogrel 75 mg once daily are reasonable alternatives when anticoagulation is contraindicated, as both demonstrated non-inferiority to metoprolol without major bleeding. Clinicians should note that this trial excluded patients with prior stroke, TIA, or intracranial haemorrhage, so these data apply specifically to migraine prevention in neurologically intact PFO patients, and longer-term bleeding surveillance beyond the 12-week window remains warranted before routine adoption.