ObjectiveWe retrospectively reviewed our clinical experience using off-label thienopyridine agents in patients with migraine headache (MHA) and patent foramen ovale (PFO).MethodsBetween 2011 and 2017, MHA/PFO patients referred to our practice were clinically treated with clopidogrel specifically for MHA. Those with ≥50% reduction in monthly MHA days compared with baseline were deemed MHA responders. MHA nonresponders with inadequate platelet inhibition by PRU testing were offered prasugrel. Thienopyridine-responsive patients were then offered PFO closure.ResultsOf 136 patients (86% female, mean age 37.9 years, mean MHA burden 14.7 days/month), 80 (59%) were MHA responders to clopidogrel. The clopidogrel responder rate was equivalent in episodic, chronic, aura, and nonaura subgroups. A total of 19/45 (40%) MHA nonresponders had inadequate platelet inhibition by PRU testing on clopidogrel. Sixteen of those patients received prasugrel, were adequately platelet inhibited by PRU, and 10/16 (62%) converted to MHA responders. A total of 56/90 thienopyridine-responsive patients underwent subsequent PFO closure with thienopyridine discontinuation after 3 months. Ninety-four percent had ongoing MHA relief. A total of 8/8 responders who stopped thienopyridine without PFO closure had resumption of MHA symptoms.ConclusionSuccessful P2Y12 platelet inhibition seemed to reduce MHA symptoms in some patients with PFO, suggesting a platelet-based mechanism/trigger. The nearly parallel response to PFO closure may mechanistically link venous platelet activation with the right-to-left shunt of PFO. Thienopyridine responsiveness could be used to enrich the study population for a new MHA/PFO trial.Classification of evidenceThis study provides Class IV evidence that in patients with PFO, P2Y12 inhibition improved MHA symptoms.

ObjectiveAfter finding that the thienopyridines clopidogrel and prasugrel reduced migraine headache (MHA) symptoms in some patients with patent foramen ovale (PFO), this small pilot study was undertaken to determine whether ticagrelor, a nonthienopyridine P2Y12 inhibitor, would have similar MHA effects and might be better suited for a future randomized trial.MethodsMHA patients were screened for PFO. Participants with documented right to left shunt (RLS) and ≥6 monthly MHA days received ticagrelor therapy for 28 days. Those with ≥50% reduction in monthly MHA days were deemed responders and completed 2 additional treatment months.ResultsThe 40 participants had a mean age of 36.2 years and mean MHA frequency of 17.4 d/mo. A total of 39/40 were female. A total of 14/40 met criteria for episodic MHA, 26/40 for chronic MHA, 14/40 had migraine with aura, and 22/40 had a moderate–large RLS (Spencer grade ≥4). Seventeen of 40 participants (43%) were responders. MHA reduction continued through 3 treatment months in all responders. MHA responder rates were not statistically different in participants with episodic or chronic MHA, with or without aura, or with small/larger RLS shunt magnitude. Thirteen (32%) patients had medication side effects, without serious adverse events.ConclusionP2Y12 inhibition with ticagrelor reduced MHA symptoms similarly to our previous thienopyridine experience, but participants seemed to have a less robust MHA benefit and more frequent side effects than with the thienopyridines, making it an inferior choice for a randomized trial.Classification of evidenceThis study provides Class IV evidence that ticagrelor reduced MHA symptoms in patients with PFO.