pLatelEts And MigRaine iN patEnt foRamen Ovale

Study Overview
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Brief Summary
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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.

Detailed Description
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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?

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

Conditions
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Platelet Aggregation, Spontaneous, Migraine With Aura, Patent Foramen Ovale

Intervention / Treatment
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* Device: patent foramen ovale closure


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Group 1: patients treated with PFO closure Group 2: Healthy subjects on Aspirin therapy
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Migraine evaluation in PFO patients<br>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<br>* 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<br>* Other names: Occlutech Figulla Flex II PFO device; aspirin;|
| No Intervention: healthy subjects on aspirin treatment<br>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?
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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 |
| --- | --- | --- |
| Platelet Activation | Platelet poor plasma levels of P selectin and serum concentration of B2-thromboxane (TXB2). (Plasma levels of P-selectin: ng/ml; Serum TXB2: ng/ml) | baseline and 6 months | 
| Platelet Reactivity Tests | Verify-now Platelet Reactivity Unit (PRU): measures the P2Y12 platelet receptor blockade and platelet response to aspirin by an arachidonic acid initiated reaction. Verify-Now P2Y12 (PRU): Cut off: 208; -Verify-Now Aspirin (Aspirin Reactivity Unit (ARU): Cut off: 550 | baseline and 6 months | 
| Clinical Outcomes | Absence of TIA and stroke recurrences after PFO closure and during the follow-up | In hospital, six and 12 months follow-up | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Migraine;, PFO, platelet reactivity, aura