By Jeffrey Zimmet, MD, PhD

Associate Professor of Medicine, University of California, San Francisco; Director, Cardiac Catheterization Laboratory San Francisco VA Medical Center

SYNOPSIS: A meta-analysis of two randomized trials of patent foramen ovale closure in resistant migraine showed a significant benefit in three of four clinical endpoints.

SOURCE: 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;77:667-676.

There is a suspected association between right-to-left cardiac shunts and migraine. The first report of migraine improvement after patent foramen ovale (PFO) closure, based on a retrospective review of just 37 patients who had undergone a closure procedure, was published in 2000.1 Since then, at least four small, randomized trials have been performed to assess the efficacy of PFO closure in reducing migraine symptoms. Of those, two were recent and performed with currently available closure devices: Percutaneous Closure of PFO in Migraine with Aura (PRIMA) and Prospective, Randomized Investigation to Evaluate Incidence of Headache Reduction in Subjects With Migraine and PFO Using the AMPLATZER PFO Occluder to Medical Management (PREMIUM).2,3 Each failed to meet their primary endpoints, in part because of limited study size. However, multiple secondary endpoints were positive, with a minority of subjects reporting significant reductions in headache frequency.

In an unusual-but-thoughtful meta-analysis, Mojadidi et al obtained patient-level data from just these two studies and redefined the endpoints to re-evaluate the potential benefit to PFO closure. A total of 337 subjects were included: 176 who had undergone closure with the Amplatzer PFO occluder and 161 who were treated with medical therapy alone. Since there were different primary endpoints in PRIMA and PREMIUM, Mojadidi et al defined four endpoints for the combined data: mean reduction in monthly migraine days, mean reduction in monthly migraine attacks, responder rate, and complete migraine cessation. The responder rate matched the primary endpoint of the PREMIUM trial and was defined as a 50% reduction in migraine attacks and adverse events.

Of the four endpoints, only the responder rate did not achieve statistical significance. PFO closure patients showed a greater reduction in migraine days vs. those on medical therapy (-3.1 ± 4.5 days vs. -1.9 ± 4.2 days; P = 0.02). The mean reduction in migraine attacks also declined significantly among PFO closure patients (-2.0 ± 2.0 vs. -1.4 ± 1.9 days; P = 0.01). Fourteen of 157 PFO closure patients showed complete resolution of migraines vs. one of 146 in the control group (P < 0.001). Mojadidi et al also attempted to assess the gradations of response to PFO closure in migraine patients with and without aura. Subjects with migraine with aura experienced a significant reduction in migraine days after PFO closure that was not seen in those without aura. In addition, those with migraine with frequent aura (defined as aura in > 50% of migraine attacks) showed a significant change with PFO closure in all four defined endpoints, including the elusive responder rate (there also were more subjects with complete headache cessation). The authors concluded PFO closure was associated with significant reductions in monthly migraine days and attacks and led to a greater likelihood of complete migraine cessation vs. medical therapy alone.

COMMENTARY

Some migraine sufferers with PFO may benefit from closure. Each trial included in the Mojadidi et al study included significant numbers of subjects who appeared to respond to treatment, and each showed significant treatment effects in secondary outcomes. The strong suggestion of benefit here is not new.

Migraines and PFOs are common. Should clinicians start closing PFOs in all patients where the two coexist? The answer is no. The more useful piece of the Mojadidi et al study is in making some headway, albeit small, in determining which subsets of patients are most likely to benefit. Specifically, it appears patients with migraine with aura are more likely to see a response from PFO closure. Among these, those with frequent aura are most likely to respond. But this does not tell the whole story, as some patients without aura also seemed to respond to the procedure. Unfortunately, there is no clear pathophysiologic understanding of the link between PFO and migraine. More data are needed. An additional randomized study, the RELIEF trial, will use migraine responsiveness to P2Y12 inhibition as an additional criterion for entry. Investigators plan to begin enrolling later this year. The key point over time will be separating those migraine patients where PFO is causative from those where it is incidental. Only then will the rational use of PFO closure in treatment of migraine become a reality.

REFERENCES

  1. Wilmshurst PT, Nightingale S, Walsh KP, Morrison WL. Effect on migraine of closure of cardiac right-to-left shunts to prevent recurrence of decompression illness or stroke or for haemodynamic reasons. Lancet 2000;356:1648-1651.
  2. 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;37:2029-2036.
  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;70:2766-2774.