Comparison of the Effect of Medication Therapy in Alleviating Migraine With Patent Foramen Ovale (COMPETE)

COMParison of the EffecT of mEdication Therapy: Anticoagulation Versus Anti-platelet Versus Migraine Therapy in Alleviating Migraine With Patent Foramen Ovale

Migraine attack is an episodic disorder that affects approximately 12% of the population. Previous studies have shown that 41-48% of migraineur have a combination of patent foramen ovale (PFO). Clinical observational studies have been linking medication therapies which include anticoagulation and anti-platelet therapy with the effectiveness in improving migraine symptoms and reducing the frequency of attacks in patients combined with a PFO. However, it has been unclear whether the effectiveness of anticoagulation or anti-platelet therapy outweigh the conventional migraine medication therapy, as a result, we designed a multi-center randomized clinical trial aiming to examine the effectiveness of anticoagulation versus anti-platelet versus migraine medication therapy in migraine patients with PFO and provide a clinical guidance for migraineur.

Study Overview

• Status: Completed
• Conditions: Migraine; Patent Foramen Ovale
• Intervention / Treatment: Drug: Metoprolol 25mg; Drug: Aspirin 300mg; Drug: Clopidogrel 75mg; Drug: Rivaroxaban 20mg

• Study Type: Interventional
• Enrollment (Actual): 1000
• Phase: Phase 2

Contacts and Locations

Study Locations

• China
  • Anhui
    • Hefei, Anhui, China
      • The First Affiliated Hospital of Anhui Medical University
    • Hefei, Anhui, China
      • The First Affiliated hospital of USTC
    • Suzhou, Anhui, China
      • Suzhou Hospital of Anhui Medical University
  • Beijing Municipality
    • Beijing, Beijing Municipality, China
      • Beijing Tiantan Hospital, Capital Medical University
    • Beijing, Beijing Municipality, China
      • National Clinical Research Center for Cardiovascular Diseases, Fuwai Hospital, Chinese Academy of Medical Sciences
  • Gansu
    • Lanzhou, Gansu, China
      • Gansu Provincial Hospital
    • Lanzhou, Gansu, China
      • The Second Affiliated Hospital of Lanzhou University
  • Guangdong
    • Guangzhou, Guangdong, China
      • Guangdong Provincial People's Hospital
    • Shenzhen, Guangdong, China
      • Fuwai Hospital, Chinese Academy of Medical Sciences, Shenzhen Hospital
    • Shenzhen, Guangdong, China
      • The Seventh Affiliated Hospital of Sun Yat-sen University
  • Guangxi
    • Nanning, Guangxi, China
      • The First Affiliated Hospital, Guangxi Medical University
  • Guizhou
    • Guiyang, Guizhou, China
      • Guizhou Provincial People's Hospital
  • Hebei
    • Shijiazhuang, Hebei, China
      • Hebei General Hospital
    • Shijiazhuang, Hebei, China
      • The Second Hospital of Hebei Medical University
    • Xingtai, Hebei, China
      • Xingtai People's Hospital
    • Zunhua, Hebei, China
      • Affiliated Zunhua People's Hospital of North China University of Science and Technology
  • Heilongjiang
    • Daqing, Heilongjiang, China
      • Daqing Longnan Hospital
  • Henan
    • Nanyang, Henan, China
      • Nanyang Central Hospital
    • Shangqiu, Henan, China
      • Shangqiu First People's Hospital
    • Zhengzhou, Henan, China
      • Zhengzhou Central Hospital Affiliated to Zhengzhou University
    • Zhengzhou, Henan, China
      • Central China Fuwai Hospital of Zhengzhou University
  • Hubei
    • Wuhan, Hubei, China
      • Wuhan Asia Heart Hospital
    • Xiangyang, Hubei, China
      • Xiangyang Central Hospital
  • Jiangxi
    • Nanchang, Jiangxi, China
      • The Second Affiliated Hospital of Nanchang University
    • Nanchang, Jiangxi, China
      • Jiangxi Provincial People's Hospital Affiliated to Nanchang University
  • Liaoning
    • Dalian, Liaoning, China
      • Dalian Municipal Central Hospital
    • Dalian, Liaoning, China
      • Dalian University Affiliated Zhongshan Hospital
    • Shenyang, Liaoning, China
      • The Fourth People's Hospital of Shenyang
  • Ningxia
    • Yinchuan, Ningxia, China
      • People's Hospital of Ningxia Hui Autonomous Region Affiliated to Ningxia Medical University
  • Shandong
    • Jinan, Shandong, China
      • The Second Hospital, Cheeloo College of Medicine, Shandong University
    • Qingdao, Shandong, China
      • Qingdao Fuwai Cardiovascular Hospital
    • Zibo, Shandong, China
      • Zibo Central Hospital Affiliated to Binzhou Medical College
  • Shanxi
    • Taiyuan, Shanxi, China
      • First Hospital of Shanxi Medical University
  • Sichuan
    • Chengdu, Sichuan, China
      • West China Hospital of Sichuan University
    • Chengdu, Sichuan, China
      • The First Affiliated Hospital of Chengdu Medical College
    • Chengdu, Sichuan, China
      • Clinical Medical College and Affiliated Hospital of Chengdu University
  • Xinjiang
    • Ürümqi, Xinjiang, China
      • The Second Affiliated Hospital of Xinjiang Medical University
  • Yunnan
    • Kunming, Yunnan, China
      • The First Affiliated Hospital of Kunming Medical University
    • Kunming, Yunnan, China
      • Fuwai Cardiovascular Hospital of Yunnan Province

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria

Participants must meet all of the following criteria:

1. Aged 18 to 64 years at Visit 1.
2. Diagnosis of migraine with or without aura confirmed by a neurologist, according to the International Classification of Headache Disorders, 3rd edition (ICHD-3) criteria.
3. History of migraine for more than 1 year, with an average of at least 4 migraine days per month during the 12-week screening period, as recorded in a headache diary and confirmed by the investigator at Visit 2.
4. Patent foramen ovale (PFO) diagnosed by transcranial Doppler (TCD), transthoracic echocardiography (TTE), or transesophageal echocardiography (TEE), with a right-to-left shunt at the atrial level.
5. Provision of written informed consent and willingness to comply with follow-up procedures.

Exclusion Criteria

Participants will be excluded if any of the following apply:

1. Secondary headache attributable to other causes.
2. History of transient ischemic attack, stroke, or intracranial hemorrhage.
3. History of pacemaker implantation, atrial septal defect closure, or left atrial appendage closure.
4. Right-to-left intracardiac shunt due to causes other than PFO.
5. Contraindications to antiplatelet or anticoagulant therapy, including thrombocytopenia, major trauma, active bleeding, decompensated cirrhosis, or drug allergy.
6. Contraindications to beta-blocker therapy, including hypotension, severe bradycardia, atrioventricular block, asthma, or drug allergy.
7. Poorly controlled atrial fibrillation at Visit 1.
8. Poorly controlled hypertension at Visit 1, defined as blood pressure >160/90 mmHg despite regular medication.
9. Inability to maintain a headache diary or to reliably report headache symptoms.
10. Use of anticoagulants (e.g., warfarin, rivaroxaban) or antiplatelet agents (e.g., aspirin, clopidogrel, ticagrelor) within 12 weeks prior to Visit 2.
11. Use of metoprolol within 12 weeks prior to Visit 2.
12. Pregnancy, intention to become pregnant during the study period, or planned elective surgery during the study period.
13. Any condition that, in the investigator's opinion, may pose significant risk, confound study results, or interfere with participation.
14. Any other reasons (e.g., likely non-adherence, inability to attend follow-up visits, or planned relocation) that render the participant unsuitable for the study in the investigator's judgment.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Migraine Medication Group - Metoprolol Group; Participants randomized to the active comparator group received metoprolol 25 mg orally twice daily for 12 weeks.	Drug: Metoprolol 25mg; Metoprolol 25 mg was administered twice daily for 12 weeks.
Experimental: Anticoagulation or anti-platelet medication Group 1 - Aspirin Group; Participants randomized to this group received aspirin 300 mg orally once daily for 12 weeks.	Drug: Aspirin 300mg; Aspirin 300 mg was administered once daily for 12 weeks.
Experimental: Anticoagulation or anti-platelet medication Group 2 - Clopidogrel Group; Participants randomized to this group received clopidogrel 75 mg orally once daily for 12 weeks.	Drug: Clopidogrel 75mg; Clopidogrel 75 mg was administered once daily for 12 weeks.
Experimental: Anticoagulation or anti-platelet medication Group 3 - Rivaroxaban Group; Participants randomized to this group received rivaroxaban 20 mg orally once daily for 12 weeks.	Drug: Rivaroxaban 20mg; Rivaroxaban 20 mg was administered once daily for 12 weeks.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Responder rate	Defined as the proportion of participants achieving a ≥50% reduction in the mean number of monthly migraine days or migraine attacks at 12 weeks post-randomization compared to baseline.	Baseline to 12 weeks post-randomization

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in monthly migraine days	Change in the mean number of migraine days at 12 weeks post-randomization compared to baseline.	Baseline to 12 weeks post-randomization
Change in monthly migraine attacks	Change in the mean number of migraine attacks at 12 weeks post-randomization compared to baseline.	Baseline to 12 weeks post-randomization
Reduction rate of migraine days	Percentage reduction in the mean number of migraine days at 12 weeks post-randomization compared to baseline.	Baseline to 12 weeks post-randomization
Reduction rate of migraine attacks	Percentage reduction in the mean number of migraine attacks at 12 weeks post-randomization compared to baseline.	Baseline to 12 weeks post-randomization
Complete migraine cessation	Percentage of participants achieving complete migraine cessation during the 12-week treatment period.	Weeks 9-12 post-randomization
Migraine-specific quality of life (MSQ v2.1)	Change in Migraine-Specific Quality of Life Questionnaire (MSQ version 2.1) scores at 12 weeks post-randomization compared to baseline.	Baseline to 12 weeks post-randomization

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety Outcome Measures - Any adverse events	Any undesirable medical condition occurring in a participant after initiation of the investigational medicinal products, regardless of its causal relationship with the investigational medicinal products, assessed by investigators and adjudicated by the clinical event committee.	Baseline to 12 weeks post-randomization
Safety Outcome Measures - Adverse events related to investigational medicinal products	Adverse events assessed by investigators as having a definite, probable, or possible causal relationship with the investigational medicinal products, assessed by investigators and adjudicated by the clinical event committee.	Baseline to 12 weeks post-randomization
Safety Outcome Measures - Serious adverse events	Events including death, life-threatening events, hospitalization or prolongation of hospitalization, permanent disability or damage, congenital anomaly or birth defect, or other medically significant events, assessed by investigators and adjudicated by the clinical event committee.	Baseline to 12 weeks post-randomization
Safety Outcome Measures - Serious adverse events related to investigational medicinal products	Serious adverse events assessed by investigators as having a definite, probable, or possible causal relationship with the investigational medicinal products, assessed by investigators and adjudicated by the clinical event committee.	Baseline to 12 weeks post-randomization
Safety Outcome Measures - Any bleeding events	Bleeding events classified according to the Bleeding Academic Research Consortium criteria (types 1 to 5), assessed by investigators and adjudicated by the clinical event committee.	Baseline to 12 weeks post-randomization
Safety Outcome Measures - Major bleeding events	Bleeding events classified as Bleeding Academic Research Consortium type 3b, type 3c, or type 5, assessed by investigators and adjudicated by the clinical event committee.	Baseline to 12 weeks post-randomization
Safety Outcome Measures - Gastrointestinal symptoms	Any discomfort or symptoms involving the gastrointestinal tract occurring after administration of the investigational medicinal products, assessed by investigators and adjudicated by the clinical event committee.	Baseline to 12 weeks post-randomization
Safety Outcome Measures - Bradycardia	Symptomatic reduction in heart rate occurring after administration of the investigational medicinal products, assessed by investigators and adjudicated by the clinical event committee.	Baseline to 12 weeks post-randomization
Safety Outcome Measures - Hypotension	Symptomatic reduction in blood pressure occurring after administration of the investigational medicinal products, assessed by investigators and adjudicated by the clinical event committee.	Baseline to 12 weeks post-randomization

Collaborators and Investigators

• Sponsor: Chinese Academy of Medical Sciences, Fuwai Hospital
• Investigators: Principal Investigator: Xiangbin Pan, National Center for Cardiovascular Disease, China & Fuwai Hospital

Publications and helpful links

General Publications

• Li Z, Dong J, Yan Y, Fang F, Wang C, Zhang F, Ouyang W, Wang S, Pan X. Study design and rationale of COMPETE: Comparison of the effect of medication therapy in alleviating migraine with patent foramen ovale. Am Heart J. 2024 Mar;269:1-7. doi: 10.1016/j.ahj.2023.12.011. Epub 2023 Dec 16.

Study record dates

Study Major Dates

• Study Start (Actual): October 15, 2022
• Primary Completion (Actual): March 26, 2025
• Study Completion (Actual): March 26, 2025

Study Registration Dates

• First Submitted: September 15, 2022
• First Submitted That Met QC Criteria: September 15, 2022
• First Posted (Actual): September 19, 2022

Study Record Updates

• Last Update Posted (Actual): April 22, 2026
• Last Update Submitted That Met QC Criteria: April 17, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Keywords: Migraine; Patent Foramen Ovale; Medication therapy
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Cardiovascular Diseases; Heart Diseases; Headache Disorders, Primary; Headache Disorders; Congenital Abnormalities; Cardiovascular Abnormalities; Heart Defects, Congenital; Heart Septal Defects, Atrial; Heart Septal Defects; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Migraine Disorders; Foramen Ovale, Patent; Sulfur Compounds; Organic Chemicals; Pyridines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Hydrocarbons; Hydrocarbons, Cyclic; Hydrocarbons, Aromatic; Amines; Phenols; Benzene Derivatives; Alcohols; Phenoxypropanolamines; Propanolamines; Amino Alcohols; Propanols; Morpholines; Oxazines; Thiophenes; Salicylates; Hydroxybenzoates; Ticlopidine; Thienopyridines; Clopidogrel; Rivaroxaban; Aspirin; Metoprolol
• Other Study ID Numbers: 2022-1758

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Deidentified individual participant data underlying the results reported in this study will be made available upon the publication of the study.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No