Susan Lipscombe

Migraine Intervention With STARFlex Technology (MIST) Trial A Prospective, Multicenter, Double-Blind, Sham-Controlled Trial to Evaluate the Effectiveness of Patent Foramen Ovale Closure With STARFlex Septal Repair Implant to Resolve Refractory Migraine Headache

Background— Patent foramen ovale (PFO) is prevalent in patients with migraine with aura. Observational studies show that PFO closure resulted in migraine cessation or improvement in ≈80% of such patients. We investigated the effects of PFO closure for migraine in a randomized, double-blind, sham-controlled trial. Methods and Results— Patients who suffered from migraine with aura, experienced frequent migraine attacks, had previously failed ≥2 classes of prophylactic treatments, and had moderate or large right-to-left shunts consistent with the presence of a PFO were randomized to transcatheter PFO closure with the STARFlex implant or to a sham procedure. Patients were followed up for 6 months. The primary efficacy end point was cessation of migraine headache 91 to 180 days after the procedure. In total, 163 of 432 patients (38%) had right-to-left shunts consistent with a moderate or large PFO. One hundred forty-seven patients were randomized. No significant difference was observed in the primary end point of migraine headache cessation between implant and sham groups (3 of 74 versus 3 of 73, respectively; P=0.51). Secondary end points also were not achieved. On exploratory analysis, excluding 2 outliers, the implant group demonstrated a greater reduction in total migraine headache days (P=0.027). As expected, the implant arm experienced more procedural serious adverse events. All events were transient. Conclusions— This trial confirmed the high prevalence of right-to-left shunts in patients with migraine with aura. Although no significant effect was found for primary or secondary end points, the exploratory analysis supports further investigation. The robust design of this study has served as the model for larger trials that are currently underway in the United States and Europe.

Response to Letter Regarding Article, “Migraine Intervention With STARFlex Technology (MIST) Trial”

Jo-hannson et al wonder whether residual migraine burden might berelated to residual right-to-left shunting. The MIST trial was notpowered to assess this and was fully focused through its primary andsecondary end points on the possibility of migraine cessation orreduction in the implanted cohort. The degree of residual shuntingwas a tertiary end point of the study; however, moderate or largeresidual shunts were found in only 6% of patients.The real question arising from the MIST trial is why did PFOclosure for migraine alone prove relatively ineffective if PFO closurefor stroke routinely abolishes incidental migraine? First, manytreatments considered useful in observational registries become lessimpressive when tested in randomized, controlled trials. Second,migraine is a syndrome with no diagnostic test. Patients who havemigraine in the context of stroke normally have migraine of onlymodest severity. By comparison, the patients in the MIST trial werea cohort of severe long-term migraineurs who had failed to improveafter taking at least 2 prophylactic medications. For a sufferer withmoderate migraine, as typically seen in the stroke trials, PFO closuremight reduce the overall risk burden to below the average thresholdto trigger migraine. In the case of an intractable migraineur,however, other factors for migraine headache may be present. If weremove 1 of these factors by PFO closure, it is not surprising thatmigraine resolution after this intervention is rare.The best time to design a clinical trial has always been after thetrial has been completed, and in the case of the MIST trial, the useof a core echocardiographic laboratory would have prevented someof the conjecture surrounding the trial. It must be stressed, however,that the MIST trial was designed and powered to determine whetherPFO closure could effectively eradicate migraine headache, not todetermine whether residual shunts could be matched to residualmigraine. In this primary aspiration, it was ambitious, and ultimatelyunsuccessful, but the trial itself, with its unique sham-controlleddesign, was a success. The MIST trial will be remembered as the firstrandomized trial of PFO closure for migraine and the trial that pavedthe way for others to refine the patient group for whom this treatmentmight be most effective.