Response to Letter Regarding Article, “Migraine Intervention With STARFlex Technology (MIST) Trial”
We thank Johansson et al for their letter on the MIST trial, a double-blind, randomized, controlled trial of patent foramen ovale (PFO) closure versus sham control for migraine headache.1 Johannson et al wonder whether residual migraine burden might be related to residual right-to-left shunting. The MIST trial was not powered to assess this and was fully focused through its primary and secondary end points on the possibility of migraine cessation or reduction in the implanted cohort. The degree of residual shunting was a tertiary end point of the study; however, moderate or large residual shunts were found in only 6% of patients.
The real question arising from the MIST trial is why did PFO closure for migraine alone prove relatively ineffective if PFO closure for stroke routinely abolishes incidental migraine? First, many treatments considered useful in observational registries become less impressive when tested in randomized, controlled trials. Second, migraine is a syndrome with no diagnostic test. Patients who have migraine in the context of stroke normally have migraine of only modest severity. By comparison, the patients in the MIST trial were a cohort of severe long-term migraineurs who had failed to improve after taking at least 2 prophylactic medications. For a sufferer with moderate migraine, as typically seen in the stroke trials, PFO closure might reduce the overall risk burden to below the average threshold to trigger migraine. In the case of an intractable migraineur, however, other factors for migraine headache may be present. If we remove 1 of these factors by PFO closure, it is not surprising that migraine resolution after this intervention is rare.
The best time to design a clinical trial has always been after the trial has been completed, and in the case of the MIST trial, the use of a core echocardiographic laboratory would have prevented some of the conjecture surrounding the trial. It must be stressed, however, that the MIST trial was designed and powered to determine whether PFO closure could effectively eradicate migraine headache, not to determine whether residual shunts could be matched to residual migraine. In this primary aspiration, it was ambitious, and ultimately unsuccessful, but the trial itself, with its unique sham-controlled design, was a success. The MIST trial will be remembered as the first randomized trial of PFO closure for migraine and the trial that paved the way for others to refine the patient group for whom this treatment might be most effective.
Dowson A, Mullen MJ, Peatfield R, Muir K, Khan AA, Wells C, Lipscombe SL, Rees T, De Giovanni JV, Morrison WL, Hildick-Smith D, Elrington G, Hillis WS, Malik IS, Rickards A. 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. Circulation. 2008; 117: 1397–1404.