Three antithrombotic medications (aspirin, clopidogrel, and rivaroxaban) demonstrate noninferiority to metoprolol for responder rate (RR) in patients with migraine and patent foramen ovale (PFO), a study has shown. Rivaroxaban also delivers the highest RR without increasing major bleeding events.
“Overall, antithrombotic treatment was associated with clinical comparability or meaningful improvements in migraine-related outcomes, without an apparent increase in adverse events, suggesting a favourable benefit-risk profile,” the researchers said.
This randomized controlled trial was conducted in secondary and tertiary care hospitals across 39 centres in China, including 1,000 adults aged 18‒64 years with a diagnosis of migraine for more than a year, experiencing at least 4 migraine days per month, and with PFO confirmed by echocardiography. Of the participants, 984 (75.1 percent) were included in the final analysis.
Eligible individuals were then randomized 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. Other preventive migraine treatments were not allowed during the intervention period.
The proportion of participants achieving at least a 50-percent decrease in monthly migraine days or attacks from baseline to weeks 9‒12 were comparable across interventions: aspirin (RR, 61.7 percent; 148/240), clopidogrel (RR, 66.8 percent; 157/235), rivaroxaban (RR, 78.4 percent; 185/236), and metoprolol (RR, 61.8 percent; 144/233). [BMJ 2026;394:e100103]
Notably, rivaroxaban demonstrated superior RR than metoprolol, with an absolute difference of 16.2 percent (98.33 percent confidence interval, 6.0‒26.4; p<0.001).
Rivaroxaban also resulted in higher reduction in migraine days and attack, higher rates of complete migraine cessation, and greater improvements in migraine-specific quality of life score relative to metoprolol. Furthermore, no major bleeding events were recorded.
“These findings suggest a possible microembolic mechanism contributes to migraine in patients with PFO,” the researchers said.
Mechanistic causality
This study was not designed to determine mechanistic causality, but the results point to a significant role played by thrombin generation and clot propagation in PFO-related migraine.
“This interpretation should not be taken to exclude a role for platelets. Thrombin is a key mediator of platelet activation through protease activated receptors, and reduced thrombin generation may attenuate downstream platelet activation,” the researchers said.
“The apparent benefit of rivaroxaban may therefore reflect interconnected effects on coagulation and platelet related pathways, rather than a mechanism independent of platelet function,” they added. [Arterioscler Thromb Vasc Biol 2020;40:2678-2685]
Rivaroxaban, unlike antiplatelet agents, directly inhibits factor Xa within the coagulation cascade. This may result in better suppression of microemboli originating from the peripheral venous system that may reach the cerebral circulation through a PFO, according to the researchers.
Such mechanistic possibility is supported by the established role of anticoagulants in preventing deep vein thrombosis. [Chest 2012;141:e419S-e496S; Chest 2021;160:2247-2259; Nat Rev Drug Discov 2011;10:61-75]
“Given the link between microembolic burden, aura frequency, and shunt size, rivaroxaban may serve as a more effective tool than antiplatelet agents for identifying patients with embolic migraine phenotypes,” the researchers said. “This link could help in selecting candidates most likely to benefit from PFO closure and enhance clinical decision-making.” [Medicine (Baltimore) 2021;100:e24175]