Atlanta, GA - Regardless of the outcome, results from the first randomized controlled trial of patent foramen ovale (PFO) closure for the treatment of migraine—one of the top-billed late-breaking trials at this year's American College of Cardiology (ACC) 2006 meeting—will have profound spillover effects on stroke prevention and research.

If negative, the Migraine Intervention with STARflex Technology (MIST) study may have the effect of dimming enthusiasm for device development in the divisive field of cryptogenic stroke research, plagued by slow trial enrollment and acrimonious debate between supporters and detractors of the paradoxical embolism hypothesis. If positive, the study will undoubtedly lead to an explosive increase in the number of device-based closure procedures worldwide, while an unintended casualty of success in migraine may be the stroke trials themselves.

Much of the hype over MIST stems from the fact that these results are the first ever from a large, randomized clinical trial of PFO closure, in this case using the STARflex septal-repair implant (NMT Medical, Boston, MA).

"The excitement is that we will have, for the first time, a prospective study in a condition that will tell us whether PFO is actually important for something," co-primary investigator for MIST, Dr Andrew Dowson (King's College Hospital, London, UK), told heartwire. "We haven't even got the results for that in stroke yet."

The public impact of a positive MIST result could be staggering. As Dowson notes, the World Health Organization currently lists migraine in its top 20 causes of years lived with disability. Studies in Europe and the US point to a migraine prevalence of 5% to 15%. As testament to the appetite for a new migraine therapy, the MIST trial received a deluge of patients desperate to be enrolled in the study—a stark contrast to the sluggish enrollment seen in the PFO stroke trials.

I'm sure Ariel Sharon's family wished he had had his PFO closed before he had his second stroke.

In fact, experts interviewed by heartwire believe a positive MIST trial would go far beyond migraine sufferers and directly affect the field of stroke research. Here, enrollment in PFO-closure studies has lagged in part due to the fact that two closure devices—the Amplatzer PFO Occluder (AGA Medical Corp, Golden Valley, MN) and the CardioSEAL septal occlusion system (NMT Medical)—were FDA approved under a humanitarian device exemption (HDE) in 2001. Under the HDE, physicians may close PFOs in cryptogenic stroke patients who fail medical therapy. In practice, however, the number of patients who have undergone PFO closure far exceeds the number who would be expected to meet this exemption.

"If you had a stroke and you were found to have a PFO when they investigated you, would you want to go into a study where you may or may not be closed, or would you find however many thousand dollars is required to just close your PFO so that you don't have another stroke?" Dowson asked. "It's a very emotive area, the stroke area. To take people at risk and monitor them over a long period of time is hard to do."

For example, he added, "I'm sure Ariel Sharon's family wished he had had his PFO closed before he had his second stroke."

Another key difference between the migraine and stroke studies is what's at stake, Dr William Maisel (Beth Israel Deaconess Medical Center, Boston, MA) told heartwire. "What makes the stroke issue challenging is that patients and patients' families are usually dissatisfied with medical therapy and the strategy of 'hoping for the best,' whereas with migraine headaches, patients have often been dealing with them for years and they understand that, while it's affecting their life, it's unlikely that they'll have a devastating consequence. So if they had to wait another year or two for a device to become available, that's not going to be as much of an issue, unlike the stroke patient, who wants immediate intervention so that it never happens again."

Impassioned pleas for stepped-up enrollment in the PFO stroke trials seem to have fallen on deaf ears. During a debate at the 2005 TCT meeting, Dr Paul Kramer (Kramer and Crouse Cardiology, PC, Shawnee Mission, KS) predicted, "If closure devices gain regulatory approval for migraine sufferers, the opportunity to determine their safety and efficacy in cryptogenic stroke will be lost."

Likewise, in a Commentary in the Journal of the American Medical Association last year, Maisel, with Dr Warren K Laskey (University of New Mexico, Albuquerque), called forcefully for equipoise among physicians seeing patients with cryptogenic stroke, completion of the stroke trials of PFO closure, and a halt to the off-label use of the devices [1].

Maisel believes that while a positive MIST trial does not guarantee FDA approval of the STARflex device for a migraine indication, in practice, the impact of the results may preempt an FDA decision and increase off-label use. "What tends to happen is that physicians and patients sometimes get ahead of the curve. I wouldn't be surprised, if the trial results were very positive, if people started using the currently available devices to close PFO for migraine."

As Dr Bernard Meier (University Hospital, Bern, Switzerland), a staunch advocate for PFO closure to treat cryptogenic stroke, explains, the problem will be compounded if a closure device is approved for migraine. "For people who have a stroke patient and who are anxious to close their PFO, they will have a much easier way to have a solid indication. They will just investigate their patient who has had a cryptogenic stroke for headache, and if you ask the right questions, you get the right answers. They will have an 'indication' based on migraine, and they will close the PFO to prevent cryptogenic stroke under the heading of migraine. This will certainly boost the number of PFO closures worldwide."

A negative MIST result, says Meier, might also have an effect, although to a much lesser degree. "The evolution of the procedure will stagnate, but if you are convinced that a PFO needs to be closed for prevention of recurrent paradoxical embolism and the MIST trial is negative, this will not convince you that you should no longer close PFO for paradoxical embolism. If it is positive, there will be an explosion of cases, but there will be no decrease in cases if the MIST trial is negative."

A positive or negative outcome for MIST, as for stroke trials, will also be device specific, experts point out.

"There are both theoretical and practical reasons why individual devices may or may not be better," Maisel points out. "Some may close a PFO more completely or more reliably, the safety of deployment may differ between devices, and the long-term structural reliability may vary. So the evidence that one device is successful does not necessarily translate to other devices. . . . Certainly [the MIST trial] will be the best data available when it's released, but there are a couple important things that still need to be determined."

Part of the uncertainty stems from the fact that the etiological link between PFO and migraine is not fully understood. As Dowson explained to heartwire, a PFO is, on average, 7 mm across, while a blood clot believed to cause stroke is an average of 3 mm across. "So is it a blood clot causing a migraine? Or is it something smaller than a blood clot, something in the blood?" Dowson asked rhetorically. "We know in decompression illness that it is something as small as gas going through the PFO that's important. If you have a hole in your table, you can get a baseball through that, but you can also get a table-tennis ball through that, you can get water through that, and you can get air through that."

I think MIST will be positive. For some reason or another migraine is positively influenced by closing the PFO.

One way to investigate migraine and PFO, he said, would be to measure "every blood-borne factor known to man" in people who've had a stroke, or migraine, or another index condition hypothesized to relate to PFO. "But what we've done in this case is we've closed these things and looked to see whether there is a difference. Now, I don't know the results—I haven't seen them yet—but if it comes back that closure is better than sham, that will tell us that there is something about PFO that is important to migraine. If it is positive, then the next scientific questions will be, do we need to do larger studies to confirm this? Second, can we work out why closing a PFO makes a difference?"

Maisel declined to speculate on the MIST trial's outcome but also pointed to unanswered questions. "I don't have a prediction, other than to say that I think there are a lot of things other than PFO closure that can affect incidence of migraine."

Meier, however, who has closed untold numbers of PFOs, went out on a limb, saying, "I think MIST will be positive. For some reason or another migraine is positively influenced by closing the PFO. And I also think that probably quite a few of the sham patients will have found out that they were sham patients, which will further enhance the positivity of the trial."

As for PFO and stroke, experts predict the trials will continue, even if impeded by a positive MIST result. Whether they will meet their target enrollment is difficult to say, Maisel observed. "Longer enrollment and fewer patients may ultimately supply the answer," he told heartwire, but he emphasized that the trials must be completed before more off-label use of the devices occurs.

"I think it would be a mistake to not get the definitive answer on stroke from randomized controlled trials, because there are hundreds of thousands of patients who are potentially candidates for this device, so even a small unrecognized incidence of severe complication would have major implications."

For his part, Meier is unconcerned with procedural risks and has already made up his mind. "We know that paradoxical embolism exists, and if it exists, it is doing harm. And it can only be doing harm when the PFO is open. So you will find a benefit in closing the PFO, providing you're not killing patients by closing the PFO or causing strokes. And we know now after closing thousands of PFOS worldwide, that it is a harmless procedure, with very little in the way of side effects. So the PFO is more dangerous than closing the PFO, that's for sure; we just need time to prove it. Even if no further patients are randomized, the ones already randomized will bring out the truth."