PFO Closure for Migraine: Debates Continue as PREMIUM Is Published

Megan Brooks

December 06, 2017

LOS ANGELES, CA – Percutaneous closure of patent foramen ovale (PFO) did not significantly curb migraine-attack frequency in patients with episodic migraine refractory to multiple medications in the PREMIUM randomized sham-controlled trial[1].

However, the trial did meet the secondary end point of a significant reduction in migraine days after PFO closure.

"The end point of migraine-days reduction is now commonly used as an acceptable end point for migraine studies," Dr Jonathan Tobis (University of California, Los Angeles), one of the trial's principal investigators, told theheart.org | Medscape Cardiology. Had this been the primary end point, then PREMIUM would have been a "positive" study, he said.

In addition, a subgroup analysis found that patients with frequent aura (>50% of episodes with aura) had a significant reduction in migraine attacks with PFO closure. "So there is some validity to right-to-left shunt closure if we can identify the subset of patients who are most likely to respond. This should be addressed in future clinical trials of PFO closure in migraine," said Tobis.

PREMIUM was published online December 5, 2017 in the Journal of the American College of Cardiology. It had been presented and covered in June 2015 at the American Headache Society 57th Annual Scientific Meeting.

Multiple studies have reported a significant association between migraine, particularly with aura, and the presence of PFO. Yet this relationship remains controversial, and studies to date have failed to clearly demonstrate that PFO closure can reduce migraine attacks.

The PREMIUM trial enrolled 230 patients with 6 to 14 migraine days per month who had failed at least three migraine preventive medications and had significant right-to-left shunt on transcranial Doppler. Patients were randomly allocated to medical therapy with a sham procedure (right heart catheterization) or medical therapy and PFO closure with the Amplatzer PFO Occluder (St Jude Medical).

The primary efficacy end point—a responder rate defined as a 50% reduction in migraine attacks per month between baseline and months 10 to 12—was achieved in 45 of 117 (38.5%) patients randomized to PFO closure and 33 of 103 (32.0%) randomized to control, which failed to achieve statistical superiority (P=0.32). Of note, 10 patients (8.5%) in the PFO-closure arm had complete cessation of migraine attacks for 1 year vs one patient (1.0%) in the control arm (P=0.01).

"As the point estimate favored the device and the sample size yielded an overall power of 80%, it is possible that a larger sample size may have detected a statistically significant, albeit modest, benefit of PFO closure regarding this primary end point," note Dr Brian Whisenant (Intermountain Heart Institute, Salt Lake City, UT) and Dr Mark Reisman (University of Washington, Seattle) in an editorial[2].

A subgroup analysis of the primary efficacy end point in patients with aura as a consistent feature of their migraine attacks (>50% of attacks) showed a significant difference in the responder rate. For this subgroup, 49% (19 of 39) of device patients responded with a >50% reduction in migraine days compared with 23% (9 of 40) of control patients (P=0.015).

In this subgroup, 15.4% (six of 39) of PFO-closure patients had complete cessation of their migraine attacks vs 2.5% (one of 40) of control patients (P=0.04). "Because this subgroup was not prespecified, these observations can be used only to generate the hypothesis that a future clinical trial of PFO closure might be beneficial in subjects where aura is a frequent component (>50%) of the migraine episodes," Dr Tobis and colleagues write.

For the key secondary end point of reduction in migraine days, PFO-closure patients experienced 3.4 fewer migraine days per month, which represented a 47% reduction from the baseline rate of 7.2 migraine days per month. Control patients had 2 fewer migraine days per month, which represented a 25% reduction from the baseline of 8 monthly migraine days (P=0.25 for the difference between groups).

The PFO-closure procedure was "generally safe," which is consistent with recently published data demonstrating the safety of PFO closure, the investigators report. Except for one patient who developed nonsustained intraprocedural atrial fibrillation, the adverse events were "self-limited mild events that may occur with any right-heart catheterization procedure," they write.

Nonetheless, the fact remains that "PFO closure in PREMIUM failed to significantly reduce headache frequency among patients with episodic migraine refractory to multiple medications and is unlikely to benefit the majority of patients who suffer with migraines," Whisenant told theheart.org | Medscape Cardiology. "Neurologist-directed medications and lifestyle interventions should be the focus of migraine prevention."

However, because PFO closure is a safe procedure and a minority of migraineurs "seem to derive substantial headache relief with PFO closure, additional research is warranted to see if a PFO-closure–responsive subpopulation of migraineurs can be identified," Whisenant said.

St Jude funded PREMIUM. Tobis discloses serving on the trial's steering committee; disclosures for the coauthors are listed in the paper. Whisenant and Reisman report they have no relevant financial relationships.

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