CDU Contributing Editor

SEATTLE – This year's small but highly regarded "Summer in Seattle" (SIS) conference, whose stated goal is to provide a state-of-the-art perspective on the field of interventional cardiology and vascular therapies, was held here in the latter part of July amidst glorious summertime weather. The conference, now in its fourth year, is sponsored by the Swedish Medical Center (Seattle), whose faculty includes some of the most renowned physicians in the field of interventional medicine.

A session titled "Emerging Technologies Symposium" was very well attended, as physicians, venture capitalists and medical device industry executives were eager to hear about new companies and technologies that heretofore had been below the radar. Much has been written in recent years about the enormous and growing healthcare issues associated with congestive heart failure (CHF), which has been described by the National Institutes of Health (Bethesda, Maryland) as "the new epidemic." The facts and figures for CHF are remarkably bleak.

For example, more than 5 million Americans have heart failure today and it is the cause for at least 20% of all hospital admissions among persons older than 65. Over the past decade, the rate of hospitalizations for heart failure has nearly tripled to almost 3 million per year, with 80% representing readmissions. An estimated $11,000 is now being spent for every hospital-discharge diagnosis of heart failure, and nearly another $2,000 per month was required to care for each patient after discharge. Managing the nation's CHF consumes more resources than does cancer.

Medical management and bi-ventricular pacing have certainly improved the plight of some CHF patients in recent years but yet patients still continue their inexorable slide to disability and death. Thus, it was of great interest to the Summer in Seattle attendees to hear presentations from two private companies that propose potential improvements in the way CHF is managed, with the goal to reducing hospital admissions and improving overall patient care.

Savacor (Los Angeles) was formed in the fall of 2000, based on the premise that current fixed-dose therapies do not adequately adjust for changing clinical conditions and that an implanted sensor that can dynamically optimize medical management and device- based therapies could provide meaningful patient benefit. It is generally accepted in the cardiology community that improper fluid management in CHF patients leads to an increase in left atrial pressure (LAP) of the heart, which in turn, directly forces water into the lungs. Water accumulated in the lungs (pulmonary congestion) causes difficult breathing and necessitates an emergency trip to the hospital. According to the company, it is common for even the best-managed CHF patients to have large swings in their heart pressures and more importantly, more than 90% of CHF-related hospitalizations are due to pulmonary congestion.

Until now there has been no way to proactively manage the ambulatory patient in response to subtle or dramatic changes in their hemodynamics. However, Savacor's technology resolves this dilemma in much the same way daily glucose monitoring has enabled the diabetic to appropriately dose their insulin to maintain their blood glucose in the proper range. By measuring LAP daily, which Savacor believes is an excellent predictor of symptoms and an impending hospital visit and using that measurement to actively titrate the patient's CHF medications, the heart pressures can be maintained in a narrow and safe range, which optimizes the functioning of the heart. Success will be seen in improved symptoms, reduced hospital visits and most importantly, an improvement in the patient's quality and length of life.

According its principal investigator, William Abraham, MD, professor of internal medicine and chief of the division of cardiovascular medicine at the Ohio State University College of Medicine (Columbus, Ohio), "fluid volume in congestive heart failure is as glucose to the diabetic. Whereas diabetics adjust their insulin up to several times a day, heart failure patients are on fixed doses of medications. Heart failure patients need an equivalent approach for homeostatic control of fluid balance. Left atrial pressure is the ideal to which all others will be compared." Abraham also was the principal investigator for the landmark Multicenter InSync Randomized Clinical Evaluation (MIRACLE) bi-ventricular pacing trial that showed significant benefits of pacing for certain CHF patients.

Savacor CEO Neal Eigler, MD, an interventional cardiologist who has practiced at Cedars-Sinai Hospital (Los Angeles) and also is a seasoned and successful medical device entrepreneur, told attendees that the device, trade-named HeartPOD, includes a small sensor that is permanently implanted in the left atrium in a minimally invasive cath lab procedure. It measures left atrial pressure, core body temperature and the cardiac electrogram.

The system also includes a remote, patient advisory module that can receive and store these measurements. This remote device, currently a personal digital assistant, will then instruct the patient, based on the physician's parameter-driven prescription, to change the patient's drug regimen if necessary. The HeartPOD also can serve as the atrial lead for various cardiac rhythm management devices such as bi-ventricular pacemakers and defibrillators.

The company has raised nearly $6 million from its founders and angels to complete its animal trials. It is now on the verge of closing a larger financing round that will fund the first human clinical trials, which were scheduled to commence in both Australia and New Zealand in either later summer or early fall. Eigler said that the U.S. feasibility trial should commence sometime in 2005, while a full-blown U.S. pivotal trial could begin in 2006.

Looking down the road, he said "there are numerous exciting opportunities to build on our technology." For example, he cited two possible combination devices, the HeartPOD and a low-voltage pacemaker and the HeartPOD and a cardiac rhythm device and/or ICD. Eigler said that these devices, which could leverage off of the basic atrial lead design of the first stand-alone device, will "substantially broaden the company's revenue potential and strategic value to a potential acquirer."

Another private company, CardioMetrix (Bothell, Washington), also is targeting the management of CHF, using minimally invasive endovascular technologies. Its CEO, Vern Dahl, also noted that CHF is primarily managed by physicians based on subjective evaluations of their symptoms and that "specific, reliable and quantitative methods for applying and determining therapies simply do not exist."

The company is developing highly sophisticated sensor technologies aimed at providing endovascular measurement of hemodynamic parameters such as blood pressure and flow. Using endovascular access, physicians will place in a location like the pulmonary artery a stent-like structure that will hold permanent sensors. These sensors will be powered with radio frequency (RF) and magnetic coupling technologies, enabling two-way communication and providing physicians with non-invasive access to real-time, beat-to-beat hemodynamic information. This accurate data will then improve patient management and provide an early detection of an impending CHF episode.

One important point emphasized by Dahl is that the use of wireless RF and magnetic coupling will provide power to the sensors and eliminate the need for battery maintenance, enabling a single device to last the life of the patient. The Savacor HeartPOD also uses these same technologies to provide physicians with non-invasive access to real-time information.

CardioMetrix is in its preclinical phase and hopes to shortly conclude a venture capital-led round of financing and accelerate its clinical development.

PFO links with strokes, migraines

Atrial septal defects, of which patent foramen ovale (PFO) is the most widely known, has been an area of great interest to the interventional cardiology community in the last five years, as evidence has mounted that this defect is a significant contributor to ischemic stroke, especially in the younger patient. A PFO, defined as a persistent, usually flap-like opening between the atrial septum, may be a pathway to a stroke, by allowing blood to flow from the venous system to the arterial system without being filtered by the lungs. If micro-emboli seep through the PFO pathway, it can be a cause of an ischemic event, such as a transient ischemic attack or an embolic stroke.

Two U.S. companies – NMT Medical (Boston) and AGA Medical (Golden Valley, Minnesota) – currently address this market. Both companies market their PFO closure devices, which are essentially tiny umbrella-like devices that are delivered percutaneously and cover up the pathway. Patients who have suffered a recurrent stroke (i.e., a second stroke) and previously were managed with medications are eligible to be treated under a humanitarian device exemption and can receive a PFO closure procedure.

In addition, both companies are in the midst of investigational device exemption clinical trials to randomize patients who have incurred only one PFO-related stroke to either best medical management or a closure procedure. NMT's trial, called CLOSURE-1, seeks to enroll 1,600 patients using its Starflex device, while the AGA Medical trial, dubbed RESPECT, will enroll 500 patients using its Amplatzer PFO Occluder.

At an AGA Medical-sponsored evening symposium during the Summer in Seattle gathering, Jeffrey Saver, MD, professor of neurology at the University of California, Los Angeles and the principal investigator of RESPECT, disclosed that only 23 patients had been enrolled to date in the trial. He expressed frustration with this dismal performance and pleaded with the audience to make sure that patients are randomized to a trial rather than being treated off-label in the HDE protocol. "If we do not change, two years from now we will not know any more about the appropriate treatment for PFOs than we know now," Saver said.

While the exact numbers for NMT's CLOSURE-1 enrollment are not known, it is accepted that its enrollment also is severely lagging and is very frustrating to the company and its investigators. Additionally, international trials aimed at shedding more light on which approach to post-PFO stroke is optimal also have lagged well behind their enrollment targets and are still not completed, years after their debut.

The FDA is unhappy as well. Donna Buckley, a biomedical engineer at the agency's Center for Devices and Radiological Health (Rockville, Maryland), recently said that off-label use of PFO devices is "rampant ... and is delaying enrollment in these trials." She went on to say that "given the extraordinarily slow enrollment, it follows that approval is significantly delayed."

This situation has escalated to the point where the FDA has begun to exhort each hospital's institutional review board to restrict off-label use of these devices.

Support for the FDA's position was contained in the April issue of Neurology, which is published by the American Academy of Neurology (AAN; St. Paul, Minnesota). That article concluded that "there is insufficient evidence regarding the effectiveness of either surgical or percutaneous closure of PFO." Moreover, the AAN urged support of the randomized trial, saying "clinicians ... should encourage patients to consider participating in research protocols."

Frustration also is being felt by the medical community. Ziyad Hijazi, MD, professor of pediatrics & medicine and chief, section of pediatric cardiology at the University of Chicago (Chicago) and a prominent supporter for PFO closure, told Cardiovascular Device Update that these patients are well-informed and are demanding closure rather than accepting a lifelong regimen of anti-coagulation therapy. "It makes it hard to convince them to enter a randomized trial," he said.

In the midst of this quagmire, another significant clinical trial for PFO closure is on the verge of starting. Over the past several years, there has been an increasing and intriguing possible link between a PFO and the incidence of migraine headaches. Numerous abstracts in various journals have speculated on the possible mechanism whereby a patient with a PFO would be more prone to migraine headaches. While no definitive mechanism or link has been established, several theories have been proposed.

William Gray, MD, an interventional cardiologist at Swedish Medical Center, told attendees that he believes that "right-to-left shunting allows embolic material and vasoactive chemicals into the cerebral venous circulation, which causes migraines." Gray noted that the possible link of migraine to PFO was simply the result of "dumb observation," that is, listening to the anecdotal feedback from patients who reported complete remission or significant reduction in their migraines following closure of their PFO.

In a talk titled "Migraines and PFO: What is the Connection," Sheena Aurora, MD, a neurologist and headache specialist at Swedish Medical Center, indicated that epidemiological studies have shown that a PFO is found in about half of patients who suffer from the most severe migraines (i.e., with aura), compared to only 20% to 25% of patients who do not have a PFO. While admitting that a study would be required to prove this hypothesis, Aurora noted that the potential link between migraine and PFO is an "exciting concept." She concluded her remarks by saying that all patients under 45, especially women who suffer from debilitating migraines with aura, should be evaluated for a PFO.

In mid-2003, Swedish Medical Center initiated a non-randomized hospital-driven IRB registry to test the link between PFOs and severe migraines, enrolling a small group of patients who were refractory to all other treatment options and were also found to have a PFO, to undergo a closure procedure.

Known as the RELIEF registry, the trial had intended to enroll 100 patients with refractory migraines. However, after enrolling about 25 patients, with very impressive initial results, the trial was halted, without any official explanation provided. CDU has learned through industry sources that the FDA, unhappy that the trial was not being conducted under an IDE and concerned about the long-term safety of PFO closure products, asked that the trial be stopped. Gray indicated that the relatively sparse RELIEF trial data has been submitted to the Journal of the American College of Cardiology and could be published sometime over the next several months.

During the conference, CDU learned from unidentified sources that a prospective, randomized trial with several hundred patients will commence shortly under the auspices of Peter Wilmshurst, MD, an interventional cardiologist at the Royal Shrewsbury Hospital (Shrewsbury, UK). Wilmshurst has written extensively on this topic, concluding an oft-quoted article in the Nov. 11, 2000, issue of The Lancet that "there may be a subgroup of patients who have severe migraines with a large right-to-left shunt in whom closure of the atrial defect may improve or abolish migraine."

According to these sources, in this trial half the patients will be implanted with the NMT Medical device and the other half will be placed in a placebo group, receiving a "sham" procedure. The results of the trial will be eagerly awaited by the interventional cardiology and neurology communities. If the results of the Swedish Medical Center pilot trial are borne out, a huge potential new market for PFO closure devices could develop.

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