This week's Circulation (on-line version) released the much anticipated MIST trial (Migraine Intervention With STARFlex Technology) results which randomized 147 patients with a moderate to large PFOs between implantation of a STARFlex PFO closure device and a sham (or placebo) procedure.
The study's primary efficacy end point was migraine headache cessation during the analysis phase. It was derived from diary data.
Secondary efficacy comparisons were incidence of migraine during the healing phase; change in the severity of migraine attacks based on MIDAS (over a 3-month retrospective period) and headache impact test (HIT-6) (over a 1-month retrospective period) scores; change in the frequency of migraine attacks other than elimination of attacks; change in the characteristics of migraine (with or without aura and change thereof); change in the severity, frequency, and character of migraine relative to effective closure rate or presence of residual leak; and change in quality of life based on the SF-36v2 questionnaire (over a 1-month retrospective period).
The bottom line? The authors concluded that "no significant effect was found for primary or secondary end points."
To be fair, this was a tough group to fix: all had lots and lots of migraine headaches that were refractory to multiple medical therapies. The authors also note that the study was "underpowered" to show such a difference (do I sense backpedaling??) and the there was a trend toward fewer hours of headache experienced in the treatment group. The investigators want us to wait for the longer-term MIST-III trial results.
But the scuttlebutt doesn't stop there with this trial. Oh, no.
It is interesting that the study's prior "co-principle investigator's" name does not appear on the author list for this manuscript. Wow.
Last year at TCT 2007, Peter Wilmshurst,MD claimed there was data mismanagement over this trial and that perhaps the reason the study was negative was because of the poor performance of the device:
At the TCT 2007 meeting last week, Dowson reported that the closure success rate was 94%, according to the implanting physician--in other words, a residual shunt rate of just 6% for the trial. Wilmshurst's review of the echocardiograms, however, suggested that the residual shunt rate was far higher--approximately one-third of the echocardiograms--a number he says was rejected by NMT, which then had the echocardiograms reviewed again, by the data monitor, Dr Luke Missault (St Jan Hospital, Brugges, Belgium). That second review, says Wilmshurst, who also sits on the steering committee for MIST, was statistically consistent with his own review. Wilmshurst states that all communications with NMT ground to a halt after he told the company the results of his review of the residual shunts. Ironically, while a higher rate of residual shunts would help explain the negative outcome in MIST, it has much larger implications for a device already marketed in Europe for the treatment of cryptogenic stroke.The author's and manufacturer's decision not to report the effectiveness of residual interatrial shunt data following ASD closure is troubling, given the controversy.
Clearly, the definitive jury about migraines and PFO closure is still out, but there are still many other trials (including MIST-III, PREMIUM and ESCAPE) pending with other companies devices, so hopefully more data will be forthcoming soon.
One thing's for sure, though, the MIST-I results will be a headache for gaining FDA approval of future devices without a clear headache improvement and more comprehensive residual interatrial shunt data to back up the observations.
12 Mar 08 Addendum: More analysis on the MIST trial is available from theHeart.org (registration required).