Migraine With Aura, Patent Foramen Ovale, Platelet Aggregation, Spontaneous
Conditions
Keywords
Migraine;, PFO, platelet reactivity, aura
Brief summary
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
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?
Interventions
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
Sponsors
Centro Cardiologico Monzino
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Group 1: patients treated with PFO closure Group 2: Healthy subjects on Aspirin therapy
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Migraine Characteristics | The outcome data were evaluated at 6-months and 12-months after PFO closure and compared to baseline | The evaluation in absolute numbers of patients fully responders, non-responders or with a moderate benefit on migraine symptoms after PFO Closure was performed |
| Migraine Assessment by Anzola's Score | Baseline, 6 months and 12-months after PFO closure | 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 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Platelet Activation (III) | baseline and six months after PFO closure | Platelets' endogenous thrombin generation potential in Migraneurs and Healthy subjects |
| Platelet Activation (IV) | Baseline and six-months after PFO closure | Platelets' functional activity measured as the amount of thrombin generation |
| Platelet Activation (I) | baseline and 6 months after PFO closure | Platelet Thrombin generation potential in migraineurs and healthy subjects |
| Clinical Outcomes | In hospital, six and 12 months follow-up | Absence of TIA and stroke recurrences after PFO closure and during the follow-up |
| Platelet Aggregation (I) | baseline and 6 months after PFO Closure | 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. |
| Platelet Activation (II) | Baseline and 6 months after PFO closure | Platelet Thrombin generation Potential in Migraneurs and Healthy subjects |
Countries
Italy
Participant flow
Recruitment details
Patients were enrolled at Centro Cardiologico Monzino, Milan, Italy between February 2018 and April 2020
Pre-assignment details
After screening of 93 consecutive PFO patients suffering from migraine 15 were excluded due to unwillingness to sign the informed consent, absence of patent PFO at the invasive evaluation, intolerance to antiplatelet therapy. Finally, 78 pts were enrolled in the study and assigned to the PFO Arm; another arm included 12healthy subjects on Aspirin treatment
Participants by arm
| Arm | Count |
|---|---|
| PFO Patients Enrolled We enrolled consecutive patients who met the inclusion criteria, symptomatic for migraine alone and Migraine with aura (MHA) patients.
The leading indication to PFO closure was a previous TIA or stroke in 37 patients while an off-label indication was offered to 25 patients. These pts underwent PFO closure with the Occlutech Figulla device and treated with dual antiplatelet therapy (Aspirin 100 mg/day + Clopidogrel 75 mg/day), followed by aspirin 100 mg/day alone. | 78 |
| Healthy Subjects Healthy subjects on aspirin treatment by at least 15 days were the comparative group for platelet aggregation markers and activation markers, platelet procoagulant, circulating serotonin and cell-associated procoagulant potential | 12 |
| Total | 90 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | non compliant to ASA treatment | 8 | 0 |
| Overall Study | Withdrawal by Subject | 8 | 0 |
Baseline characteristics
| Characteristic | Total | PFO Patients Enrolled | Healthy Subjects |
|---|---|---|---|
| Age, Continuous | 40.8 years STANDARD_DEVIATION 10 | 40.6 years STANDARD_DEVIATION 12 | 41 years STANDARD_DEVIATION 10 |
| Migraine | 60 Migraine | 60 Migraine | 0 Migraine |
| Migraine with aura (MHA) | 18 Migraine with aura | 18 Migraine with aura | 0 Migraine with aura |
| Patients finally evaluated | 74 participants | 62 participants | 12 participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 90 Participants | 78 Participants | 12 Participants |
| Region of Enrollment Italy | 90 Participants | 78 Participants | 12 Participants |
| Sex: Female, Male Female | 71 Participants | 63 Participants | 8 Participants |
| Sex: Female, Male Male | 19 Participants | 15 Participants | 4 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 62 | 0 / 12 |
| other Total, other adverse events | 0 / 62 | 0 / 12 |
| serious Total, serious adverse events | 0 / 62 | 0 / 12 |
Outcome results
Primary
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
Time frame: The outcome data were evaluated at 6-months and 12-months after PFO closure and compared to baseline
Population: Analysis performed only in PFO Group patients as not applicable to the control Healthy subjects group
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Migraine Assessment After PFO Closure | Change in Migraine Characteristics | Migraine Symptoms improvement | 17 Participants |
| Migraine Assessment After PFO Closure | Change in Migraine Characteristics | Migraine : Complete Migraine Resolution | 43 Participants |
| Migraine Assessment After PFO Closure | Change in Migraine Characteristics | Migraine : Non-responders | 2 Participants |
Primary
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
Time frame: Baseline, 6 months and 12-months after PFO closure
Population: Analysis performed only in PFO Group patients as not applicable to the control Healthy subjects group
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Migraine Assessment After PFO Closure | Migraine Assessment by Anzola's Score | Anzola's score @12-mos post PFO closure | 1.1 score on a scale | Standard Deviation 1.57 |
| Migraine Assessment After PFO Closure | Migraine Assessment by Anzola's Score | Anzola's score @Baseline | 7.2 score on a scale | Standard Deviation 1.68 |
| Migraine Assessment After PFO Closure | Migraine Assessment by Anzola's Score | Anzola's score@6-mos post PFO Closure | 1.09 score on a scale | Standard Deviation 1.47 |
Secondary
Clinical Outcomes
Absence of TIA and stroke recurrences after PFO closure and during the follow-up
Time frame: In hospital, six and 12 months follow-up
Population: Clinical evaluation of neurologic recurrences or death was performed during in-hospital stay and subsequent follow-up; Analysis performed only in PFO Group patients as not applicable to the control Healthy subjects group
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Migraine Assessment After PFO Closure | Clinical Outcomes | In -hospital vascular complications | 1 Participants |
| Migraine Assessment After PFO Closure | Clinical Outcomes | device malpositioning/embolization | 0 Participants |
| Migraine Assessment After PFO Closure | Clinical Outcomes | Transient atrial fibrillation | 5 Participants |
| Migraine Assessment After PFO Closure | Clinical Outcomes | TIA/stroke post PFO Closure | 0 Participants |
| Migraine Assessment After PFO Closure | Clinical Outcomes | Recurrent TIAs /stroke @6 months FU | 0 Participants |
| Migraine Assessment After PFO Closure | Clinical Outcomes | Recurrent TIAs /stroke @12 months FU | 0 Participants |
Secondary
Platelet Activation (I)
Platelet Thrombin generation potential in migraineurs and healthy subjects
Time frame: baseline and 6 months after PFO closure
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Migraine Assessment After PFO Closure | Platelet Activation (I) | Time to peak | 32.1 min | Standard Deviation 9.5 |
| Migraine Assessment After PFO Closure | Platelet Activation (I) | Lag Time | 26.9 min | Standard Deviation 8.9 |
| Healthy Subjects | Platelet Activation (I) | Lag Time | 30.6 min | Standard Deviation 7.2 |
| Healthy Subjects | Platelet Activation (I) | Time to peak | 37.6 min | Standard Deviation 10.2 |
| PFO Patients at T1 (6 Mos) | Platelet Activation (I) | Time to peak | 37.8 min | Standard Deviation 13 |
| PFO Patients at T1 (6 Mos) | Platelet Activation (I) | Lag Time | 32.2 min | Standard Deviation 12.4 |
Secondary
Platelet Activation (II)
Platelet Thrombin generation Potential in Migraneurs and Healthy subjects
Time frame: Baseline and 6 months after PFO closure
Population: Analysis of platelets' intrinsic characteristics including thrombin-formation capacity, the amount of thrombin and the kinetic rate (peak velocity)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Migraine Assessment After PFO Closure | Platelet Activation (II) | 29.1 nMol/L/min | Standard Deviation 29 |
| Healthy Subjects | Platelet Activation (II) | 12.3 nMol/L/min | Standard Deviation 10.9 |
| PFO Patients at T1 (6 Mos) | Platelet Activation (II) | 17.9 nMol/L/min | Standard Deviation 19.9 |
Secondary
Platelet Activation (III)
Platelets' endogenous thrombin generation potential in Migraneurs and Healthy subjects
Time frame: baseline and six months after PFO closure
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Migraine Assessment After PFO Closure | Platelet Activation (III) | 1038 nmol/L x min | Standard Deviation 352 |
| Healthy Subjects | Platelet Activation (III) | 781 nmol/L x min | Standard Deviation 319 |
| PFO Patients at T1 (6 Mos) | Platelet Activation (III) | 797 nmol/L x min | Standard Deviation 373 |
Secondary
Platelet Activation (IV)
Platelets' functional activity measured as the amount of thrombin generation
Time frame: Baseline and six-months after PFO closure
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Migraine Assessment After PFO Closure | Platelet Activation (IV) | 115.2 nmol/L | Standard Deviation 81.2 |
| Healthy Subjects | Platelet Activation (IV) | 63.4 nmol/L | Standard Deviation 41.8 |
| PFO Patients at T1 (6 Mos) | Platelet Activation (IV) | 77.2 nmol/L | Standard Deviation 59.2 |
Secondary
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.
Time frame: baseline and 6 months after PFO Closure
Population: Patients were analysed at baseline before PFO closure, six months after procedure and compared to healthy subjects
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Migraine Assessment After PFO Closure | Platelet Aggregation (I) | TRAP-6 (5µM) | 8.5 AUC (AU x min) |
| Migraine Assessment After PFO Closure | Platelet Aggregation (I) | ADP (5µM) | 153 AUC (AU x min) |
| Migraine Assessment After PFO Closure | Platelet Aggregation (I) | Collagen (2µg/ml) | 62 AUC (AU x min) |
| Healthy Subjects | Platelet Aggregation (I) | TRAP-6 (5µM) | 8 AUC (AU x min) |
| Healthy Subjects | Platelet Aggregation (I) | ADP (5µM) | 157 AUC (AU x min) |
| Healthy Subjects | Platelet Aggregation (I) | Collagen (2µg/ml) | 76.5 AUC (AU x min) |
| PFO Patients at T1 (6 Mos) | Platelet Aggregation (I) | ADP (5µM) | 187 AUC (AU x min) |
| PFO Patients at T1 (6 Mos) | Platelet Aggregation (I) | Collagen (2µg/ml) | 104 AUC (AU x min) |
| PFO Patients at T1 (6 Mos) | Platelet Aggregation (I) | TRAP-6 (5µM) | 11 AUC (AU x min) |