COMPETE
(2026)Objective
To evaluate the efficacy and safety of antithrombotic treatment (aspirin, clopidogrel, or rivaroxaban) versus metoprolol for migraine prevention in adults with patent foramen ovale (PFO).
Study Summary
• All three antithrombotics were non-inferior to metoprolol; rivaroxaban was also superior to metoprolol (absolute difference 16.2%, 98.33% CI 6.0 to 26.4; P<0.001)
• Rivaroxaban superiority most pronounced in participants with migraine aura (difference 27.3%, 98.33% CI 5.3-49.4) and grade 3 right-to-left shunt (18.8%, 5.8-31.8)
• Rivaroxaban also significantly higher complete migraine cessation (12.5%, 4.1-20.8) and larger MSQ quality-of-life gains vs metoprolol
• No major bleeding events in any group; 2 SAEs total (1 rivaroxaban corpus luteum haemorrhage, 1 metoprolol acute cholecystitis)
Intervention
Aspirin 300 mg once daily, clopidogrel 75 mg once daily, rivaroxaban 20 mg once daily, or metoprolol 25 mg twice daily, for 12 weeks.
Inclusion Criteria
Adults 18-64 years with migraine (with or without aura) for >1 year, ≥4 migraine days/month, PFO with right-to-left shunt confirmed by echocardiography; no prior stroke/TIA/ICH.
Study Design
Arms: Aspirin vs Clopidogrel vs Rivaroxaban vs Metoprolol (1:1:1:1)
Patients per Arm: ≈246 per arm (984 total in full analysis set; 1000 randomized)
Outcome
• Aspirin (61.7%) and clopidogrel (66.8%) non-inferior but not superior to metoprolol
• Rivaroxaban reduced migraine days (difference 1.0, 95% CI 0-2.0) and attacks (1.0, 0-2.0) vs metoprolol
• Complete migraine cessation at 12 weeks: rivaroxaban vs metoprolol difference 12.5% (4.1-20.8)
• Safety: total AEs 24.3% aspirin, 21.6% rivaroxaban, 17.3% metoprolol, 13.9% clopidogrel; no major bleeding; GI symptoms in 11.7% aspirin; bradycardia/hypotension in 3.6%/6.9% metoprolol
Clinical Question
In adults with migraine and patent foramen ovale, do antithrombotic agents (aspirin, clopidogrel, or rivaroxaban) achieve better ≥50% migraine responder rates than the standard preventive metoprolol, and is rivaroxaban superior?
Bottom Line
In patients with migraine and PFO, rivaroxaban was superior to metoprolol for migraine responder rate (78.4% vs 61.8%; absolute difference 16.2%, P<0.001), while aspirin and clopidogrel were non-inferior; no major bleeding occurred.
Major Points
- First large randomized head-to-head comparison of anticoagulant, antiplatelets, and beta blocker for migraine prevention in PFO (1000 randomized, 39 Chinese centers).
- Rivaroxaban 20 mg daily produced the highest ≥50% responder rate (78.4%) and was superior to metoprolol; aspirin (61.7%) and clopidogrel (66.8%) were non-inferior but not superior.
- Benefit of rivaroxaban was consistent across subgroups and especially pronounced in migraine with aura and grade 3 right-to-left shunt — groups thought to have the strongest microembolic mechanism.
- No major bleeding; 2 SAEs total. GI symptoms clustered with aspirin; bradycardia/hypotension with metoprolol; clopidogrel had fewest drug-related AEs.
- Open-label PROBE design and a lower-than-Western metoprolol dose (25 mg BID) are important caveats when generalising the rivaroxaban benefit.
Study Design
- Study Type
- Randomized Controlled Trial (investigator-initiated, active-controlled, open-label with blinded endpoint adjudication; hypothesis-generating)
- Randomization
- Yes
- Blinding
- Open-label with blinded outcome assessors (PROBE design)
- Sample Size
- 1000
- Follow-up
- 12 weeks of treatment (post 12-week screening)
- Centers
- 39
- Countries
- China
Primary Outcome
Definition: Proportion of participants achieving ≥50% reduction in monthly migraine days or attacks from baseline to weeks 9-12
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| - | - | - | - |
Limitations & Criticisms
- Open-label design (PROBE) and self-reported headache diaries create risk of reporting bias despite blinded endpoint adjudication.
- Metoprolol dose (25 mg twice daily) at the lower end of the effective range — may have underestimated the active-control effect and magnified rivaroxaban's apparent superiority.
- 12-week treatment period is too short to assess long-term efficacy or cumulative bleeding risk of chronic anticoagulation in a young migraine population.
- Enrolment restricted to Chinese centres, predominantly East Asian participants, limiting generalisability; East Asian pharmacogenomics (CYP2D6) may affect metoprolol exposure.
- Only ~24% of participants had migraine with aura — the subgroup most mechanistically linked to PFO; subgroup analyses underpowered.
- Framed as 'hypothesis generating' with hierarchical testing rather than a confirmatory pivotal trial; requires replication before rivaroxaban can be recommended for migraine prevention.
Citation
BMJ 2026;394:e100103