Investigator fallout clouds MIST follow-up results

“POSITIVE” RESULTS from the Migraine Intervention with STARflex Technology (MIST) I trial have been overshadowed following a very public fallout between the former, ‘co-principal investigator’ Dr Peter Wilmshurst, Royal Shrewsbury Hospital, UK), and NMT Medical, the company behind the STARflex Technology. MIST, which was conducted in the UK, is the first prospective, randomised, double-blinded study to evaluate the effect of patent foramen ovale (PFO) closure on migraine headaches. NMT’s proprietary PFO closure technology, STARflex, was exclusively used in the study. BioSTAR is designed to provide a bioabsorbable option and incorporates a collagen matrix on the proven STARflex alloy framework. Over time, 90-95% of the implant is absorbed and replaced with the patient’s native tissue providing a more natural, biological closure. The BioSTAR collagen also is a platform for adding biological response modifiers (genes, cells, proteins and drugs). The study results were first presented at the American College of Cardiology (ACC) in March 2006, screened 432 migraine with aura patients for a PFO, enrolled 147 patients into the study. A significant finding in the MIST study was that over 60% of those screened had a right to left shunt. Of those patients, almost 40% had a moderate or large PFO, six times greater than the general population. Although the preliminary analysis of MIST data did not satisfy the study endpoints, the MIST results indicated an approximate 37% reduction in migraine burden (number of headaches multiplied by the length, in hours of headache) in those patients who received a STARflex implant and a 17% reduction in those who received the sham procedure and no implant. At the Transcather Cardiovascular Therapeutics 2007 meeting, Dr Andrew Dowson, Kings College Hospital, London, UK, presented MIST I follow-up results (so-called MIST III) and claimed 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. It was proposed that the trial’s failure was due to the high rate of residual shunts among patients who had had their PFOs closed. According to heartwire.org, Wilmshurst has alleged that NMT has attempted to marginalise his role in the trial including claiming that he was never a co-PI for MIST I and has barred his hospital from participating in MIST III. Indeed, the website quotes an NMT spokesperson, as saying Wilmshurst is “on a warpath,” was never really the coprincipal investigator for MIST, and has been dropped from the trial for committing protocol violations. He also asserts that NMT has repeatedly prevented him from viewing the complete MIST I data set and have failed to disclose whether echocardiograms from the MIST patients have been independently reviewed. Challenged if the residual-shunt data have or have not been reviewed by an expert at a single centre, Dowson denied that such a review had taken place. “We did not collect data in a form that would enable someone to do a proper review of the data set. …We haven’t got data on all these patients in a way that can be reviewed.” Dr Jonathan Tobis, University of California, Los Angeles, the discussant for the MIST presentation, said that questions are being raised: “Why was MIST I less impressive than the observational studies? Is it due to the fact that the patients in the observational studies are somehow different from the migraine populations in MIST and in the US clinical trials? Or because of concerns about reporting of the echocardiographic follow-up? . . . There should be complete transparency of the MIST echo data with an independent core lab review of the studies that have already been done,” he said.