PFOs are present in a higher proportion of patients with migraines than in the general population. Multiple studies of PFO closure for stroke showed a high rate of migraine sufferers among participants, many of whom experienced a reduction of migraine days. Two randomized trials were conducted that specifically examined PFO closure for migraine. These studies did not meet their primary endpoints but did meet secondary endpoints. It was felt by pooling the two studies, there may be sufficient power to demonstrate efficacy.

Study Cohort
This study's cohort comprised patients who were enrolled in either PRIMA (Percutaneous Closure of Patent Foramen Ovale In Migraine With Aura - A Randomized Prospective Study) or PREMIUM (Prospective, Randomized Investigation to Evaluate Incidence of Headache Reduction in Subjects With Migraine and PFO Using the AMPLATZER PFO Occluder to Medical Management).

Study Design
This study was a pooled subject-level data analysis of two randomized trials.

Study Endpoints
The endpoints were mean reduction in migraine days, responder rate (≥50 reduction in monthly migraine attacks), mean reduction in migraine attacks, and complete migraine cessation. The 4 endpoints were given the same importance.

Table 1: PRIMA and PREMIUM

	PRIMA	PREMIUM
Subjects	107	230
Ages	21-61 years	18-65 years
Migraine Type	With aura	With and without aura
Failed Preventive Medications	2	3
Screening	PFO on transesophageal echocardiography with bubble study	Transcranial Doppler bubble study with grade 4 or 5 right to left shunt, confirmed by wire crossing during procedure
Blinding	Unblinded	Neurologist- and patient-blinded, sham-control procedure
Antithrombotic Regimen	3 months clopidogrel 6 months low-dose aspirin	1 month clopidogrel 6 months 325 mg aspirin
Closure Completeness	Transesophageal echocardiography at 6 and 12 months if grade 2 or higher shunting remained	Transcranial Doppler at 12 months, grade 2 or less
Primary Endpoint	Reduction in migraine days per month	Responder rate (≥50% reduction in migraine attacks)

Statistical Analysis
Patient characteristics were compared between the two trials. An intention-to-treat analysis was used for the efficacy outcomes. Sub-group analyses were performed looking at age, gender, history of head trauma, mood disorder, palpitations, snoring, steroid use, migraine with aura, and Migraine Disability Assessment and Beck Depression Inventory scores. Safety outcomes were reported for procedural complications for all subjects who received devices (both randomized subjects as well subjects from PREMIUM who had PFO closed after blinding was removed). This analysis was performed "as-treated."

Results

• No significant differences were observed in patient characteristics in the 2 treatment arms.
• Mean reduction in monthly migraine days was 3.1 with PFO closure versus 1.9 with medical therapy alone (p = 0.02).
• Responder rate was 38% with device versus 29% in the control arm (p = 0.13).
• Mean reduction in monthly migraine attacks was -2.0 with device versus 1.4 in the control arm (p = 0.01).
• Complete cessation rate overall was 9% with device versus 0.7 in the control arm (p < 0.001).
• Migraineurs with aura had significant reduction in migraine days and headache cessation (3.2 vs. 1.8 and 11% vs. 1%).
• Migraineurs with frequent aura (aura with >50% of attacks) had significant reductions in all 4 endpoints.
• Procedural complication rates were <1%. There were 4 device-related complications: 1 fatigue, 2 with non-sustained atrial fibrillation, and 1 with syncope.

Limitations

• The 2 trials had different primary endpoints, so there is inherent bias in interpreting their results together.
• The 2 trials had different populations with respect to minimum number of failed preventive medications (2 vs. 3) and significant differences in multiple characteristics: head trauma, mood disorders, palpitations, steroid use, Migraine Disability Assessment score were all higher in PREMIUM; PRIMA included only migraineurs with aura.
• This was limited to 1-year follow-up; therefore, it is hard to say whether this is durable.
• It is possible that PFOs that were not the cause of the neurovascular event were included because PFOs frequently occur in the general population.

References

1. Mojadidi MK, Kumar P, Mahmoud AN, et al. Pooled Analysis of PFO Occluder Device Trials in Patients With PFO and Migraine. J Am Coll Cardiol 2021;77:667-76.
2. Serrano D, Lipton RB, Scher AI, et al. Fluctuations in episodic and chronic migraine status over the course of 1 year: implications for diagnosis, treatment and clinical trial design. J Headache Pain 2017;18:101.
3. Tobis JM, Charles A, Silberstein SD, et al. Percutaneous Closure of Patent Foramen Ovale in Patients With Migraine: The PREMIUM Trial. J Am Coll Cardiol 2017;70:2766-74.
4. Mattle HP, Evers S, Hildick-Smith D, et al. Percutaneous closure of patent foramen ovale in migraine with aura, a randomized controlled trial. Eur Heart J 2016;37:2029-36.

Clinical Topics: Arrhythmias and Clinical EP, Congenital Heart Disease and Pediatric Cardiology, Noninvasive Imaging, Atrial Fibrillation/Supraventricular Arrhythmias, Congenital Heart Disease, CHD and Pediatrics and Arrhythmias, CHD and Pediatrics and Imaging, CHD and Pediatrics and Quality Improvement, Echocardiography/Ultrasound, Invasive Cardiovascular Angiography and Intervention

Keywords: Prospective Studies, Fibrinolytic Agents, Foramen Ovale, Patent, Echocardiography, Transesophageal, Intention to Treat Analysis, Atrial Fibrillation, Migraine with Aura, Aspirin, Data Interpretation, Statistical, Follow-Up Studies, Migraine Disorders, Stroke, Headache, Syncope, Epilepsy, Fatigue, Craniocerebral Trauma, Steroids

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