pLatelEts And MigRaine iN patEnt foRamen Ovale (LEARNER)

Migraine in Patients Undergoing PFO (Patent Foramen Ovale) Closure: Evaluation of a Platelet-associated Pathophysiologic Linking Mechanism

Migraine is a common, chronic neurovascular disorder characterized by attacks of severe headache, autonomic nervous system dysfunction and, in some patients, aura, and disabling neurological symptoms. Worldwide, migraine prevalence is as high as 18% in the general population. Increased frequency of patent foramen ovale (PFO) in migraineurs was first reported in 1998 in a case-control study. Since then, others have described a 60% prevalence of PFO in patients suffering from migraine with aura. The presence of a right-to-left shunt (RLS) is thought to be a potent trigger of migraine attacks, although the mechanism is unknown. Moreover, PFO closure has correlated with improved migraine symptoms in several retrospective uncontrolled studies. The aim of this single-center, prospective study is to assess the impact of PFO closure on migraine attacks over time together with evaluation of potential predictive risk factors.

Study Overview

• Status: Completed
• Conditions: Patent Foramen Ovale; Migraine With Aura; Platelet Aggregation, Spontaneous
• Intervention / Treatment: Device: patent foramen ovale closure

Detailed Description

The Study will evaluate the results of approximately 100 subjects from a single center study registered in this trial. Subjects who experienced transient ischemic attack (TIA) or stroke with a clinical indication to PFO closure and symptomatic for migraine with/o aura are considered for a migraine score analysis at baseline before PFO closure and during the subsequent follow-up (FU) at 6 and 12-months, together with lab evaluation for platelet reactivity tests (P selectin, Thromboxane B2), Prostaglandin E1 and 2 (PGE1, PGE2), serotonin, cytokines and prostaglandin PGE1 urinary metabolite run under aspirin therapy.

The research questions are as follows:

Does the presence of a large PFO have any impact on migraine with aura?

Do migraineurs with aura and PFO have higher biomarkers of platelet activation than control patients? and are they at higher risk of stroke and TIA recurrences based on high on clopidogrel platelet reactivity?

What is the effect of PFO severity on monthly migraine frequency and aura frequency?

What is the result of PFO closure in migraineur patients with PFO? Do Migraine with aura patients with large PFO have higher platelet activation and better migraine resolution after PFO closure?

• Study Type: Interventional
• Enrollment (Actual): 90
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Italy
  • MI
    • Milan, MI, Italy, 20138
      • Centro Cardiologico Monzino, IRCCS

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Patients older than 18 years with more than 2 criteria:
• Previous Stroke or TIA (transient ischemic attack)
• positive MRI for ischemic events -
• PFO with a baseline R-L shunt > 10 microembolic signals (MES) and > 20 MES during/after Valsalva Manoeuver
• Atrial septal aneurysm (ASA) or residual Chiari network or Eustachian Valve
• positive Thrombophilic screening (MTHFR/prot C/Prot S)
• Ability to sign the informed consent for the study participation

Exclusion Criteria:

• Patients older than 70 years
• Paroxysmal Atrial fibrillation
• Carotid, vertebral or basilar artery stenosis> 50% on duplex imaging
• Inadequate temporal bone windows (signals) for transcranial Doppler insonation
• medication overuse headache
• history of cognitive dysfunction, epilepsy, brain injury
• use of continuous positive airway pressure (CPAP) within 6 months of study enrollment
• Left Ventricular Ejection Fraction (LVEF) < 30%
• Moderate/severe mitral valve regurgitation
• Known Allergy to aspirin
• Known allergy to nickel
• Severe chronic kidney disease (GFR < 30 ml/min)
• Beck depression inventory score > or= 29
• State-trait anxiety inventory score exceeding cut-off for are and sex

Keywords: PFO, migraine, migraine with aura, aura, platelets

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Migraine evaluation in PFO patients; Patients symptomatic for migraine with/o aura and addressed to patent foramen ovale closure (Occlutech Figulla Flex II PFO occluder device) for a previous ischemic event, will receive dual antiplatelet therapy (DAPT) for 2 months after procedure and aspirin alone subsequently. Patients will undergo evaluation of platelet reactivity, serotonin and cytokines before PFO closure with a dedicated device and at 6 months follow-up and these results compared to those of a control, group of healthy subjects treated with aspirin alone	Device: patent foramen ovale closure; Pts undergoing PFO closure will receive 2-months of DAPT and 6 months of aspirin after patent foramen ovale (PFO) closure; they will be compared to healthy subjects on aspirin treatment; Other Names: Occlutech Figulla Flex II PFO device; aspirin
No Intervention: healthy subjects on aspirin treatment; 12 healthy subjects on 100 mg aspirin daily will be compared to PFO patients in terms of platelet reactivity, serotonin and cytokines

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Migraine Characteristics	The evaluation in absolute numbers of patients fully responders, non-responders or with a moderate benefit on migraine symptoms after PFO Closure was performed	The outcome data were evaluated at 6-months and 12-months after PFO closure and compared to baseline
Migraine Assessment by Anzola's Score	The change in migraine severity, incidence and duration with or without aura as measured by the Anzola's score (The score is the expression of the sum of each corresponding value referring to migraine duration, frequency and the presence or absence of aura). The minimum value was 2 and the maximum 9; the higher the value, worse is the migraine classification. Anzola's score: Duration 0=No pain 1=<6 hours 2=6-12 hours 3=>12 hours Frequency 0=No pain 1=1-4/month 2=5-9/month 3=>10/month Aura 0=No aura 1=Aura in ≥1 attack	Baseline, 6 months and 12-months after PFO closure

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Clinical Outcomes	Absence of TIA and stroke recurrences after PFO closure and during the follow-up	In hospital, six and 12 months follow-up
Platelet Activation (I)	Platelet Thrombin generation potential in migraineurs and healthy subjects	baseline and 6 months after PFO closure
Platelet Activation (II)	Platelet Thrombin generation Potential in Migraneurs and Healthy subjects	Baseline and 6 months after PFO closure
Platelet Activation (III)	Platelets' endogenous thrombin generation potential in Migraneurs and Healthy subjects	baseline and six months after PFO closure
Platelet Activation (IV)	Platelets' functional activity measured as the amount of thrombin generation	Baseline and six-months after PFO closure
Platelet Aggregation (I)	Platelet aggregation was measured on PAP-8 aggregometer (BioData). Briefly, PRP aliquots (250µL) were pipetted into a siliconized glass cuvette, stirred at 1200 rpm at 37°C and stimulated with arachidonic acid (1mM), collagen (2µg/ml), ADP (5µM), TRAP-6 (5µM). Light transmission was recorded for 5 min after stimuli addition and platelet aggregation was reported as maximal percentage of light transmission. Aspirin-treated patients were considered drug responders when platelet aggregation was less than 20% after arachidonic acid (1mM) stimulation.	baseline and 6 months after PFO Closure

Collaborators and Investigators

• Sponsor: Centro Cardiologico Monzino
• Investigators: Principal Investigator: Daniela Trabattoni, MD, Centro Cardiologico Monzino, IRCCS

Publications and helpful links

General Publications

• Trabattoni D, Brambilla M, Canzano P, Becchetti A, Teruzzi G, Porro B, Fiorelli S, Muratori M, Tedesco CC, Veglia F, Montorsi P, Bartorelli AL, Tremoli E, Camera M. Migraine in Patients Undergoing PFO Closure: Characterization of a Platelet-Associated Pathophysiological Mechanism: The LEARNER Study. JACC Basic Transl Sci. 2022 Apr 13;7(6):525-540. doi: 10.1016/j.jacbts.2022.02.002. eCollection 2022 Jun.

Study record dates

Study Major Dates

• Study Start (Actual): February 15, 2018
• Primary Completion (Actual): October 31, 2020
• Study Completion (Actual): October 31, 2020

Study Registration Dates

• First Submitted: April 16, 2018
• First Submitted That Met QC Criteria: May 9, 2018
• First Posted (Actual): May 11, 2018

Study Record Updates

• Last Update Posted (Estimated): April 19, 2024
• Last Update Submitted That Met QC Criteria: December 15, 2023
• Last Verified: December 1, 2023

More Information

Terms related to this study

• Keywords: platelet reactivity; aura; PFO; Migraine
• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Congenital Abnormalities; Headache Disorders, Primary; Headache Disorders; Heart Defects, Congenital; Cardiovascular Abnormalities; Heart Septal Defects, Atrial; Heart Septal Defects; Migraine Disorders; Foramen Ovale, Patent; Migraine with Aura; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Peripheral Nervous System Agents; Enzyme Inhibitors; Analgesics; Sensory System Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Fibrinolytic Agents; Fibrin Modulating Agents; Platelet Aggregation Inhibitors; Cyclooxygenase Inhibitors; Antipyretics; Aspirin
• Other Study ID Numbers: CCM769

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No