CDU Contributing Editor

SEATTLE – The 5th annual “Summer in Seattle” (SIS) conference, held here in July, once again was well-attended and featured some of the interventional community’s best-known physicians, addressing a wide range of topics of current interest. The co-founders of SIS, Mark Reisman, MD, director of the cardiac catheterization lab at Swedish Heart Institute (Seattle), and William Gray, MD, director of endovascular intervention, center for interventional vascular therapy at Columbia University Medical Center (New York), have been leaders in the emerging field of atrial septal defects (ASD), which has become an area of great interest in the interventional cardiology community in the last few years. Thus, several presentations and sessions were devoted to this area.

The most prevalent and widely known ASD is a patent foramen ovale (PFO), which is a persistent, usually flap-like opening between the atrial septum. Autopsy data has shown that about 25% of all adults have a PFO. For the vast majority, it is clinically insignificant. Although it has never been conclusively proven, many clinicians believe that this pathway may cause an embolic stroke, by allowing blood carrying micro-emboli to flow from the venous system to the arterial system without first being filtered by the lungs. For younger patients who suffer an inexplicable or so-called cryptogenic stroke, it has generally become accepted that a PFO may be the culprit.

An article in the July 20 issue of the Journal of the American Medical Association (JAMA), authored by William Maisel, MD and Warren Laskey, MD, noted that the migration of venous thrombus across the PFO to the systemic circulation, which they termed paradoxical embolus “ ... may be the etiology of stroke in some patients.”

Paradoxical embolism is when some type of matter (e.g., clot, fat or a gas bubble) from the venous circulation enters the right heart, passes through a defect in the heart and enters the systemic circulation, where it occludes a blood vessel, causing an infarction or an ischemic event (i.e., a stroke, a transient ischemic attack or TIA).

Two U.S. companies – NMT Medical (Boston) and AGA Medical (Golden Valley, Minnesota) – currently market their PFO closure devices in the U.S. under a humanitarian device exemption (HDE). These devices have a full CE-mark approval in Europe. Under the FDA’s HDE approval, PFO closure devices are indicated for the closure of a PFO in patients who have had a recurrent cryptogenic stroke due to presumed paradoxical embolus, while being treated with conventional drug therapy. The latter term is defined as a therapeutic international normalized ratio using oral anticoagulants.

Cardiovascular Device Update estimates that some 4,000 to 5,000 PFO closure devices are sold annually in the US by the two HDE-approved companies. Under the FDA’s provisions, each company is allowed to sell a maximum of 4,000 HDE implants annually.

In addition to their HDE programs, both companies have opened an investigational device exemption (IDE), comparing PFO closure to best medical management, in order to gain a full PMA approval. NMT’s trial is called CLOSURE-1 while AGA’s is dubbed RESPECT. Both IDE trials are multi-center, prospective, randomized and are designed to evaluate the safety and efficacy of PFO closure devices vs. best medical management in patients who have had one stroke and/or a TIA due to a presumed paradoxical embolism believed to be due to a PFO.

Unfortunately, enrollment for these trials has proceeded very slowly. At last count, NMT had enrolled about 350 patients, while AGA had enrolled approximately 100. At these levels, they are only 20% toward their full enrollment goals, after which a two-year follow-up period will be required before the data is analyzed and presented.

Thus, it will be several more years before there is data to provide an answer to the question of which is better for a PFO-related stroke: closure or medical management. The authors of the aforementioned JAMA article concluded with the following comments: “expedited evaluation of this potentially beneficial therapy can only occur with a commitment by all stakeholders to subscribe to the fundamental tenets of evidence-based medicine. Absent the acquisition of reliable safety and efficacy data, clinical equipoise will persist. At best, completion of randomized clinical trials may permit expansion of this novel therapy into new patient populations. At worst, additional uncontrolled observational reports will prolong the uncertainty. Physicians, patients, regulators and industry must work together to move beyond equipoise.”

In the midst of this disappointing progress on the stroke front, another potentially huge indication has emerged for PFO closure. Researchers have noted that there is a possible association between PFOs and migraine headaches, especially migraines with aura, which have visual, auditory, sensory or motor abnormalities preceding the migraine attack. Table 1 displays the massive market opportunity available.

Preliminary data suggests that patients with migraines appear to have a higher incidence of PFOs than the general population. Far more importantly, these patients have about a six-fold higher prevalence of a large inter-atrial shunt than patients without migraine. This information was presented in late-May at a late-breaking clinical trial session at the EuroPCR conference in Paris by Peter Wilmshurst, MD, consultant cardiologist at the Royal Shrewsbury Hospital (Shrewsbury, UK).

In a press conference after his presentation, Wilmshurst, who also is co-primary investigator for the trial, said, “In our evaluation of 370 migraine patients, we found that 50% of them had a PFO, which allows a right to left shunt, or flow, of venous blood into the arterial circulation. This important finding is consistent with earlier observational data and is twice what one would expect to find in the general population.” In addition to PFOs, he said researchers found other shunts, predominately pulmonary, “in another 10% of the migraine patients studied, which again is greater than what one would expect.”

What is remarkable, Wilmshurst said, is that more than 40% of the migraine patients studied had a large shunt “which is six times greater than what would be expected in the general population. By far, the PFO was the most prevalent large shunt we saw in the migraine patients, accounting for over 85% of all large shunts detected.” Interestingly, he said this unusually high incidence was found in a group of people who have frequent migraine attacks with aura, but are otherwise healthy and have no symptoms to indicate a heart defect.

The mechanism for how PFOs could cause migraine is not yet fully understood, although two theories predominate. Some believe that particulate matter from the venous system undergoes paradoxical embolization, causing migraine in a manner similar to that which is thought to cause PFO-related cryptogenic stroke. Other experts have suggested that vasoactive chemicals in the venous blood, typically filtered out by the lungs, bypass the lungs via the PFO. These chemicals could exert their effects on the brain vasculature to cause vasodilation, leading to migraines.

Although no conclusive evidence has been developed to date, several trials, which are summarized in Table 2 suggests that there is an indeed a strong relationship between PFO closure and the improvement or full resolution of migraines.

NMT initiated a UK-based randomized, prospective, multi-center clinical trial in early 2005 that should provide some crucial information. Full enrollment of the Migraine Intervention with STARFlex Therapy (MIST) trial, which compares its STARFlex closure device to a sham procedure, was very rapidly accomplished and was completed in early July. Final data, which is eagerly anticipated, is expected to be reported in 1Q06.

NMT has publicly stated that it is in discussions with the FDA to commence a U.S.-based, “MIST-like” IDE trial and hopes to begin that study in the second half of this year. Through industry sources, CDU has learned that the FDA will require a fully blinded sham arm, in order to eliminate any possible placebo effect. This will essentially mirror the protocol of the MIST trial.

Several other companies also are pursuing a PFO-migraine IDE. The most prominent is AGA, which already is a strong player in the ASD space, especially in atrial septal occlusion devices.

In late July, a three-year battle over the ownership of AGA ended in a settlement that returned two of the three founders to the company and bought out the third through a $300 million recapitalization in which Welsh, Carson, Anderson & Stowe (WCAS; New York City) became a minority owner. WCAS is the largest private equity investor in information and business services, healthcare and communications, with more than $12 billion invested. Franck Gougeon has become a majority owner in AGA and is restored as CEO, and Tommy Thompson, former secretary of Department of Health and Human Services, was appointed chairman of the board.

Other new competitors have recently emerged, particularly as the PFO-migraine opportunity has surfaced. These include Velocimed (Minneapolis), which was acquired by St. Jude Medical (St. Paul, Minnesota) in early April for $74 million in cash, with further contingent payments due upon achievement of regulatory and other milestones. Velocimed’s Premere PFO device already has attained the CE mark and soon will commence broad-scale European marketing.

Privately financed, venture capital-backed Cierra (Redwood City, California) has recently received a Series C preferred $21 million venture capital investment and performed its first human trials in Europe in April. Cierra’s proprietary system utilizes a suction device to hold the tissue in place, followed by radio frequency (RF) heat to seal the PFO pathway. A key attribute of its procedure, according to the company’s CEO, Erik Engelson, is that it does not leave a device behind in the patient.

Cierra’s early cases, under the auspices of renown interventional cardiologist Horst Sievert, MD, of the CardioVascular Center, Sankt Katharinen (Frankfurt Germany), have gone well and the company is targeting a European market launch in mid-2006, following CE mark approval.

Another RF-based approach is being developed by CoAptus Medical (Redmond, Washington), which has been financed to date by medical device giant Boston Scientific (Natick, Massachusetts). Its approach involves the coaptation, or joining together of tissue, followed by RF heating. The company has not yet performed any human cases, but told CDU that it hopes to do so before year-end.

Two relatively new privately financed companies presented here during the “Emerging Technologies Symposium.” Steve Kleshinski, CEO of MD3 (Scituate, Massachusetts), discussed the SeptRx device, which is being co-developed as a three-pronged effort that includes MD3, Secant Medical (Perkasie, Pennsylvania) and Nitinol Devices and Components (Fremont, California), a Johnson & Johnson (New Brunswick, New Jersey) subsidiary.

Kleshinski described its device as a “fundamentally different approach to PFO closure.” It utilizes several different design concepts, including nitinol mesh to promote tissue adhesion and an immediate barrier to emboli migration, a sizing device to enable better conformity to the PFO geometry and a retrieval device in cases of improper placement.

Kleshinski recently told CDU that the joint venture hopes to initiate its first human implants in Germany at the end of this year or early in 2006.

Brian Whisenant, MD, an interventional cardiologist and assistant professor of medicine at the University of Utah (Salt Lake City), presented on Proximare (also Salt Lake City), a company he founded. Without describing his device in detail, he noted that the core concepts of his device are that tissue growth is preferable to mechanical obstruction, that a foreign body in apposition to tissue induces growth that should be along the lines of separation of the pathway, that the device needs to correspond to the PFO anatomy and that it should be easy and intuitive to implant.

Proximare is currently conducting animal trials and will likely begin human trials later this year or in 2006.

The typical migraine patient is young and female. While PFO closure may dramatically improve the patient’s quality of life, it does not represent a potentially life-saving technology if performed solely for migraine relief. As such, the long-term safety profile of PFO closure will be very important.

This idea was reinforced by Peter Fitzgerald, MD, co-director of the Center for Research in Cardiovascular Interventions at Stanford University Medical School (Palo Alto, California), who noted during a question-and-answer period following some PFO presentations that “safety is of paramount importance because these are young patients.”

Based upon industry contacts, CDU believes that several companies, including NMT, AGA, Cierra and St. Jude, are actively negotiating with the FDA to open a PFO-migraine IDE. These sources believe that most, if not all of these companies, could be granted approval later this year. Conversely, the skeptics believe that the FDA will await the results of the MIST trial before allowing any U.S. trials to commence.

At an evening session titled “PFO: Bystander or Culprit in Stroke and Migraine,” clinicians debated the potential link between PFOs, stroke and migraine. Lawrence Wechsler, MD, professor of neurology and neurosurgery at the University of Pittsburgh, took a cautionary position regarding the benefits of PFO closure vs. best medical management, as he noted that “there is no strong evidence to date that closing a PFO is better than using medical management.”

However, he is a strong supporter of the RESPECT and CLOSURE-1 trials because when these trails are completed “we’ll finally have good data and lots of answers.”

Wechsler was similarly circumspect on the PFO-migraine connection, indicating that it is impossible to draw any firm conclusions based on anecdotal data or retrospective studies. He did say that “if the MIST trial shows that there is indeed a relationship, this will be very important to the neurology community.”

Jonathan Tobis, MD, professor of medicine and director of interventional cardiology research at the David Geffen School of Medicine at the University of California at Los Angeles, was decidedly more up-beat. “We are going to be closing millions of PFOs,” he said. He strongly believes that the PFO and migraine link is real and that “these trials will demonstrate significant benefit.”

Tobis, who is slated to be the principal investigator for AGA Medical’s PFO-migraine trial, reported on the results of 110 patients treated for a PFO at his institution, noting that closure was successful in all cases, that none of the patients had a recurring stroke or transient ischemic attack and that 75% of the patients who had migraines before PFO closure had been cured.

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