Aspirin, clopidogrel, and rivaroxaban may be noninferior to metoprolol in preventing migraine among patients with patent foramen ovale.
Investigators conducted the prospective, multicenter, randomized, active-controlled, open-label COMPETE trial with blinded outcome assessment at 39 centers in China. Eligible patients were aged 18 to 64 years, had migraine for more than 1 year, experienced at least 4 migraine days per month, and had echocardiography-confirmed patent foramen ovale. Migraine diagnoses were verified by site neurologists according to International Classification of Headache Disorders, third edition criteria.
Following a 12-week screening period consisting of an 8-week washout and 4-week prospective baseline period, 1,000 patients were randomly assigned 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. The full analysis included 984 patients.
The primary endpoint was the proportion of patients who achieved at least a 50% reduction from baseline in monthly migraine days or attacks during weeks 9 to 12. The investigators initially tested each antithrombotic agent for noninferiority to metoprolol using a prespecified 15–percentage point margin, followed by sequential superiority and pairwise testing. The primary efficacy analysis used complete cases within the full analysis set, excluding patients without primary endpoint data.
Responder rates were 62% with aspirin, 67% with clopidogrel, 78% with rivaroxaban, and 62% with metoprolol. All 3 antithrombotic agents met criteria for noninferiority to metoprolol. Rivaroxaban had an absolute responder-rate difference of 16 percentage points compared with metoprolol and had higher responder rates compared with aspirin and clopidogrel. The findings were consistent in the per-protocol analysis and remained robust in sensitivity analyses addressing missing data.
In secondary analyses, which were not adjusted for multiplicity, rivaroxaban was associated with greater reductions in migraine days and attacks compared with metoprolol. Complete migraine cessation occurred in a greater proportion of patients receiving rivaroxaban compared with metoprolol. Greater improvements in migraine-specific quality-of-life scores were also observed with rivaroxaban compared with metoprolol.
No major bleeding events occurred. One serious adverse event considered related to rivaroxaban involved corpus luteum rupture with pelvic hemorrhage and resolved following hospitalization. The investigators noted limitations including the open-label design, 12-week treatment duration, lower metoprolol dose, and limited generalizability beyond the predominantly East Asian study population. They characterized the findings as hypothesis generating and cautioned that they should not be interpreted as evidence to replace first-line preventive treatment.
“The numerical advantages seen with rivaroxaban should be interpreted not as evidence to replace first line preventive treatments, but rather as a potential marker that may help identify patients with a more embolic driven migraine phenotype,” wrote lead author Ziping Li of the Chinese Academy of Medical Sciences and Peking Union Medical College, in China, and colleagues.
The trial received support from the 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, and Yunnan Pan Xiangbin Expert Workstation under the Yunnan Provincial Project for Scientific and Technological Talents and Platforms. The study authors reported no conflicts of interest.
Source:The BMJ