COMPETE
Antithrombotic treatment for migraine in patients with patent foramen ovale: multicentre, randomised, active controlled, open label trial (COMPETE)
Study Overview
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
- Responder rates (โฅ50% reduction in monthly migraine days/attacks at weeks 9-12): rivaroxaban 78.4% (185/236), clopidogrel 66.8% (157/235), aspirin 61.7% (148/240), metoprolol 61.8% (144/233)
- 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.
Patients per Arm
โ246 per arm (984 total in full analysis set; 1000 randomized)
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 โฅ50% 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 โ 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.
Design
Study Type: Randomized Controlled Trial (investigator-initiated, active-controlled, open-label with blinded endpoint adjudication; hypothesis-generating)
Randomization: 1
Blinding: Open-label with blinded outcome assessors (PROBE design)
Enrollment Period: Registered NCT05546320
Follow-up Duration: 12 weeks of treatment (post 12-week screening)
Centers: 39
Countries: China
Sample Size: 1000
Analysis: Full analysis set (n=984); hierarchical hypothesis testing (non-inferiority โ superiority โ pairwise); LOCF and multiple imputation sensitivity analyses
Inclusion Criteria
- Age 18-64 years
- Migraine (with or without aura) diagnosed by ICHD-3 criteria for >1 year
- โฅ4 migraine days per month on average
- PFO confirmed by transthoracic or transesophageal echocardiography
- Right-to-left shunt verified by contrast echocardiography or transcranial Doppler
- Completed 12-week prospective screening/diary period
Exclusion Criteria
- Prior transient ischaemic attack, stroke, or intracranial haemorrhage
- Right-to-left shunt from a source other than PFO
- Contraindications to antiplatelet, anticoagulant, or beta blocker treatment
- Previous use of any of the four investigational medicinal products
- Any condition rendering the patient unsuitable per investigator
Arms
| Field | Aspirin | Clopidogrel | Rivaroxaban | Control |
|---|---|---|---|---|
| Intervention | Aspirin 300 mg once daily | Clopidogrel 75 mg once daily | Rivaroxaban 20 mg once daily | Metoprolol 25 mg twice daily |
| Duration | 12 weeks | 12 weeks | 12 weeks | 12 weeks |
Outcomes
| Outcome | Type | Control | Intervention | HR / OR / RR | P-value |
|---|---|---|---|---|---|
| Proportion of participants achieving โฅ50% reduction in monthly migraine days or attacks from baseline to weeks 9-12 | Primary | Metoprolol: 61.8% (144/233) · Aspirin: 61.7% (148/240) โ non-inferior vs metoprolol · Clopidogrel: 66.8% (157/235) โ non-inferior vs metoprolol · Rivaroxaban: 78.4% (185/236) โ non-inferior AND superior vs metoprolol (difference 16.2%, 98.33% CI 6.0-26.4; P<0.001) | |||
| Reduction in monthly migraine days (rivaroxaban vs metoprolol) | Secondary | Effect: Difference 1.0 (95% CI 0-2.0) | |||
| Reduction in monthly migraine attacks (rivaroxaban vs metoprolol) | Secondary | Effect: Difference 1.0 (95% CI 0-2.0) | |||
| Reduction rate in migraine days (rivaroxaban vs metoprolol) | Secondary | Effect: ฮ 12.5% (95% CI 3.3-20.0) | |||
| Complete migraine cessation at 12 weeks (rivaroxaban vs metoprolol) | Secondary | Effect: ฮ 12.5% (95% CI 4.1-20.8) | |||
| MSQ role-restrictive change (rivaroxaban vs metoprolol) | Secondary | Effect: Difference 6.4 (95% CI 2.9-11.4) | |||
| MSQ total score change (rivaroxaban vs metoprolol) | Secondary | Effect: Difference 18.7 (95% CI 7.9-30.0) | |||
| Rivaroxaban vs aspirin (responder rate) | Secondary | Effect: ฮ 16.6% (6.7-26.4) | |||
| Rivaroxaban vs clopidogrel (responder rate) | Secondary | Effect: ฮ 11.6% (1.6-21.6) | |||
| Clopidogrel vs aspirin (responder rate) | Secondary | Effect: ฮ 4.9% (-5.7 to 15.5), NS | |||
| Any adverse event (participants) | Adverse | Metoprolol 43 (17.3%) | Aspirin 60 (24.3%) | Clopidogrel 34 (13.9%) | Rivaroxaban 53 (21.6%) | |||
| IMP-related adverse events | Adverse | Metoprolol โ | Aspirin 48 (19.4%) | Clopidogrel 23 (9.4%) | Rivaroxaban โ | |||
| Serious adverse events | Adverse | 2 total โ 1 corpus luteum rupture/pelvic haemorrhage (rivaroxaban, IMP-related, resolved); 1 acute cholecystitis (metoprolol, unrelated, recovered) | |||
| Major bleeding | Adverse | 0 in all four groups | |||
| Discontinuation due to AE | Adverse | Metoprolol 7 | Aspirin 0 | Clopidogrel 1 | Rivaroxaban 2 | |||
| Gastrointestinal symptoms | Adverse | Aspirin 29 (11.7%) โ highest | |||
| Bradycardia (metoprolol) | Adverse | 9 (3.6%) | |||
| Hypotension (metoprolol) | Adverse | 17 (6.9%) | |||
Subgroup Analysis
Rivaroxaban vs metoprolol responder-rate benefit largest in participants with migraine aura (ฮ 27.3%, 98.33% CI 5.3-49.4) and grade 3 right-to-left shunt (ฮ 18.8%, 5.8-31.8); direction of benefit consistent across other subgroups.
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 โ 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 โ 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.
Funding
CAMS Innovation Fund for Medical Sciences; National Natural Science Foundation of China; Noncommunicable Chronic Diseases-National Science and Technology Major Project; National High Level Hospital Clinical Research Funding; National Key R&D Programme of China; CAMS Clinical and Translational Medicine Research Fund; Yunnan Pan Xiangbin Expert Workstation. No industry funding declared.
Based on: COMPETE (BMJ, 2026)
Authors: Li Z, Wang C, Tang Y, et al.; COMPETE Investigators
Citation: BMJ 2026;394:e100103
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