CDU Contributing Editor

SEATTLE, Washington Beginning with the advent of percutaneous transluminal coronary angioplasty (PTCA) about 20 years ago, the interventional cardiology (IC) market has grown rapidly, fueled by relentless and impressive innovation. This has resulted in huge improvements in patient outcomes and fostered a very large and generally very lucrative market for the many competitors in this arena. In a May report titled "Cardiovascular Device Handbook," authored by Michael Weinstein of the investment banking firm J.P. Morgan Securities (New York), the global interventional cardiology (IC) market, as shown in Table 4, was estimated at approximately $4.5 billion in 2002, with growth forecasted at about 30% a year for both 2003 and 2004.

Weinstein projected that the IC market would grow at a robust 30% rate in both 2003 and 2004, propelled by the coronary stent segment, which is benefiting from the conversion of moderately-priced bare metal stents to premium-priced drug-eluting. The lion's share of this conversion will occur in 2003 and 2004 and by 2005 growth of the market will slow to a more sustainable 10% rate.

Drug-eluting coronary stents clearly stand out today in the IC world and will be heavily featured at this month's Transcatheter Cardiovascular Therapeutics (TCT) conference in Washington. While stents will occupy the limelight at TCT, this year's smaller, but highly-regarded "Summer in Seattle" interventional cardiology therapy conference, held here in mid-July, spotlighted emerging interventional cardiology technologies. Indeed, the stated goal of this conference is "to provide a state-of-the-art perspective ... of future technologies and treatments in cardiac and vascular intervention." The conference, now in its third year, was sponsored by the Swedish Medical Center (Seattle, Washington) and the Society for Cardiac Angiography and Interventions (Bethesda, Maryland).

Although numerous topics were discussed at this meeting, there was a heavy focus on percutaneous devices for the prevention of both primary and recurrent ischemic stroke. Numerous live cases and podium lectures by experts presented impressive data and progress on devices that can prevent strokes that are specifically related to cardiac thrombo-embolic sources. Stroke prevention for high-risk patients prior to the availability of minimally invasive catheter devices has relied on either medical management or invasive, expensive open-heart surgery, neither providing the optimum care for the typically young and often active patients.

In the past several years, epidemiological evidence suggests that cardiac structural abnormalities, also referred to as septal defects, may be a significant cause of stroke. The principal type of defect, which is known as a patent foramen ovale (PFO), is a persistent, usually flap-like opening between the atrial septum. Incomplete closure of a patent foramen ovale has been shown to persist in 5% to 35% of the adult population, depending on the study and how the PFO is defined.

According to NMT Medical (Boston, Massachusetts), the market leader in the treatment of "cardiac sources of stroke," the worldwide market potential for septal defect repair approximates 500,000 procedures annually. PFOs are believed to account for at least 90% of this total.

PFO closure has been in the limelight in the past several months as both publicly owned NMT Medical and the other large competitor, privately held AGA Medical (Golden Valley, Minnesota), have reported that they are initiating large PFO clinical trials. The former said in early July that patient enrollment had commenced for its pivotal CLOSURE I trial, which is expected to enroll 1,600 patients at about 100 centers. Half of these patients will be receiving NMT's STARFlex implant, with the other half receiving traditional medical therapy, which is either anticoagulation or antiplatelet drugs alone or in combination with aspirin. Follow-up will measure recurrent events over a period of two years, comparing the two methods in preventing recurrent stroke and transient ischemic attack.

More than 100 leading stroke and interventional cardiology centers in the U.S. have committed to participate exclusively in the study. The principal investigators for the study are two highly-regarded physicians: Anthony Furlan, MD, director of the stroke program at The Cleveland Clinic (Cleveland, Ohio), and Mark Reisman, MD, an interventional cardiologist who is the director of cardiovascular research at Swedish Medical Center.

AGA Medical recently reported that the FDA had approved its Recurrent Stroke comparing PFO Closure to Established Current Standard of Care Treatment (RESPECT) trial, which uses its Amplatzer PFO Occluder. The trial will include a maximum of 45 medical institutions and 500 patients, who will be randomized so that half are implanted with the Occluder device and the other half will receive standard medical therapy. The trial is designed to evaluate whether transcatheter closure of a PFO is superior to medical treatment in preventing recurrent stroke or a TIA in patients with PFO.

A controversy has ensued as the two companies disclosed the details of their respective trials, basically centering around how many patients are required to be enrolled for statistical significance to be achieved in meeting the trial's primary endpoint. Each company has been adamant that its trial size has been optimized to achieve its goal More importantly, however, is that two relatively small companies are simultaneously starting two huge trials, which will hopefully help the neurology community to finally have the data to determine if closure is superior to medical management.

During this trial, both companies will continue to sell their PFO devices under a humanitarian device exemption (HDE) protocol, which allows up to 4,000 devices to be sold annually by each sponsor. The HDE is an FDA approval to sell their device for patients who have tried and failed medical management and who have had a second ischemic stroke. Cardiovascular Device Update estimates that between 4,000 and 5,000 PFO devices will be implanted under the HDE protocol in 2003 in the U.S., the majority being accounted for by NMT Medical.

Another player in the PFO closure market is privately owned Cardia (Burnsville, Minnesota), which began its own FDA-approved trial comparing PFO closure to medical management about nine months ago. Given the controversy that surrounds trial size and design, it is conceivable that Cardia's trial, which is considerably smaller than the others, will have to be broadened to meet its endpoints and satisfy the FDA. In the international arena, its Cardia PFO device has been marketed for several years, initially by the company but currently by ev3 (Plymouth, Minnesota), which acquired exclusive international distribution rights for this device earlier this year.

There were several sessions at the Summer in Seattle conference devoted to the closure of PFOs and the enthusiasm for this procedure was obvious and vociferous. Last year's meeting discussed both transcranial Doppler (TCD) and intra-cardiac echocardiography (ICE) as emerging tools for PFO diagnosis and device implantation. In the past, the presence of a PFO has been detected non-invasively with either transthoracic echocardiography (TTE) or transesophageal echocardiography (TEE). However, TCD has been gaining in popularity recently, spurred by the fact that it is far more accurate than TTE and considerably less invasive and more patient friendly than TEE. Leading interventional cardiology centers around the U.S. appear to have adopted TCD, along with TEE, as the standard of care for PFO detection. TCD's value-added proposition is that it provides non-invasive diagnosis, monitoring local blood flow in real time and reveals micro-emboli. It does not measure perfusion or assess cardiac anatomy, which TEE does. The two modalities are an ideal combination.

Leading manufacturers of TCD equipment include the Nicolet Vascular (Madison, Wisconsin) division of publicly-owned Viasys Healthcare (Conshohocken, Pennsylvania) and privately owned Spencer Technologies (Seattle, Washington).

On the final day of the program here, an "ICE Workshop," featuring Siemens Medical Solutions Ultrasound Division's (Mountain View, California) intracardiac echocardiography (ICE) technology, was held. Compatible with three Siemens ultrasound system platforms, the AcuNav catheter features four-way, 160 degree steering that enables virtually unlimited views from the near field of the atria to the depth of the ventricular apex, all from the right side of the heart. The single-use catheter, which costs about $2,500, obtains either 2-D gray scale or highly sensitive Doppler modes ultrasonic images from within the heart, not behind the heart as in the case of TEE, and is an excellent tool to monitor the deployment of the PFO device in real time. It provides outstanding information on cardiac anatomy and regional myocardial tissue motion, the great vessels and vascular anatomy and blood flow direction and velocity.

An article titled, "Intracardiac Echocardiography Is Superior to Conventional Monitoring for Guiding Device Closure of Interatrial Communications," authored by Thomas Bartel, MD, et al., from the departments of internal medicine and pediatrics at the University of Essen (Essen, Germany), was published in the February issue of Circulation. The authors concluded that "ICE is a safe tool to guide device closure of PFO ... and (patients) tolerate ICE better than TEE. ICE reduces fluoroscopy time and procedure time and seems to be advantageous, especially when long continuous or repeated echocardiographic viewing is required."

In a presentation on PFO closure, Ziyad Hijazi, MD, professor of pediatrics and medicine and chief of the section of pediatric cardiology at the University of Chicago (Chicago, Illinois), opined that ICE has become the "imaging of choice" for septal defect repair.

As shown in Table 5, aside from septal defect applications, there are numerous uses for ICE in electrophysiology and cardiology. Hijazi also mentioned that he has completed a cost-outcome study comparing ICE to TEE and that these results will be presented at the seventh annual Pediatric Interventional Cardiac Symposium (PICS), which will be held in Orlando, Florida, in the latter part of this month.

Siemens has been the lone player in the domestic ICE market, but competition is expected imminently from EP MedSystems (EPMed; West Berlin, New Jersey). It received the CE mark for its ViewMate imaging system in April and during the same month submitted its 510(k) filing to the FDA. The system, which was displayed at the annual North American Society of Pacing and Electrophysiology (Natick, Massachusetts) meeting held in mid-May, offers excellent imaging quality and will be marketed by EPMed's direct sales force.

A new and intriguing potential application for PFO closure devices is for the treatment of refractory migraine headaches. Migraine is defined as episodic attacks of headache lasting anywhere from four to 72 hours, with two or more of the following symptoms: unilateral pain, throbbing, aggravation on movement, pain of moderate or severe intensity and one of the following symptoms: nausea or vomiting and/or sensitivity to light or noise. The majority of migraines are "common migraines" without aura and less than 20% are "classic migraine" with aura.

Migraines have a significant prevalence in the U.S., with 6% of males (5.6 million), and 15% to 18% of females (18 million) afflicted. The typical patient has 1.5 attacks per month that last 24 hours, while 1% have one day of migraine per week. Those who suffer from migraines or know those who do are keenly aware of how devastating migraine headaches can be. The World Health Organization (Geneva, Switzerland) has stated that "severe migraine, along with quadriplegia, psychosis and dementia, is one of the most disabling chronic disorders."

The specific causes of migraines are complex and still somewhat controversial. It is very interesting to note that there have been many articles in the literature over the past few decades linking migraine headaches and cerebrovascular events such as stroke. For example, an article in the Nov. 27, 2001, issue of Neurology, titled "Ischemic Stroke and Active Migraine," authored by Didier Milhaud, MD, et al. from the department of neurology at Centre Hospitalier Universitaire Vaudois (Lausanne, Switzerland), concluded from a multi-factorial analysis of ischemic stroke patients that a PFO is characteristic of young patients with migraine and ischemic stroke. Many of these patients have non-specific dense white matter revealed by neurological imaging that is consistent with chronic brain injury from an ischemic stroke.

After many years of anecdotal reports of PFO closure eliminating or reducing migraines, Swedish Medical Center initiated a non-randomized hospital-driven IRB registry in January of this year, with the first patients approaching their six-month follow-up. These patients all have undergone a standard PFO closure using the NMT Medical CardioSEAL device. Follow-up occurs at 30 days, six months and 12 months and includes an exam with a neurologist, a review of their medications and headache diary, along with a TCD or a TEE exam.

This trial, which is called the RELIEF registry, intends to enroll 100 patients in the 18 to 65 year old category with refractory migraines. All patients will be screened by a neurologist, suffer from four headaches a month or six per day on medication and are positively proven to have a PFO via a TCD or TEE exam. As of early September, a total of 20 patients had been treated, and the results of the first 14 patients of this trial are detailed in Table 6. It also is noteworthy that a secondary endpoint of the CLOSURE I trial is whether the PFO closure provides relief for migraine headaches.

Sherman Sorenson, MD, professor of medicine and an interventional cardiologist at LDS Hospital (Salt Lake City, Utah), has been one of the most active physicians in the field of PFO closure, performing about 400 procedures in the past three years. He told CDU in Seattle that "I am convinced that there is a positive association between PFOs and migraines." Sorenson's assertion is based on his experience with numerous patients, who had their PFO closed but were unaware of any potential impact on their migraines. A significant number of these patients reported that following their PFO closure, their migraines had either completely disappeared or substantially diminished in frequency and intensity. Sorenson's comments have been echoed by a number of other physicians around the world, including those directly involved with the RELIEF registry.

In his summary and concluding comments on the RELIEF trial, John Olsen, MD, an interventional cardiologist at the Seattle Heart Clinic (Seattle), had several interesting observations. First, migraine, especially "classic" migraine with aura, and the existence of a PFO, can be a risk for stroke. Second, young patients, especially women under the age of 45 who have had an ischemic stroke, should be evaluated for a PFO, particularly if they have migraine headaches. Third, PFO closure in selected migraine patients can result in successful control of some migraine events as well as reduced stroke risk. Finally, and most importantly if the early results of the RELIEF trial are borne out, large numbers of migraine patients could become candidates for PFO closure.

William Gray, MD, another interventional cardiologist from the Seattle Heart Clinic who is closely involved with the RELIEF registry, acknowledged the speculative aspect of this trial. He noted, however, that large PFOs are seen with increased frequency (approximately 50%) in severe, young migraine patients refractory to medical management. Noting that "PFO closure may allow new insight into the mechanism(s) of some migraine headaches," Gray ended his presentation on the potential association of PFOs and migraines with a quote from the English composer Samuel Butler, that "Life is the drawing of sufficient conclusions from insufficient premises."

At this year's recently concluded European Society of Cardiology (Sophia Antipolos, France) congress, a paper titled "Percutaneous Closure of Patent Foramen Ovale Reduces Migraine Frequency," based on research conducted at the Swiss Cardiovascular Center (Bern, Switzerland), was presented. The lead investigator, Markus Schwerzmann, MD, and his team questioned 215 patients of migraine attacks with presumed PFO-mediated paradoxical embolism about their headache characteristics and frequency during the year before and after their PFO closure.

The team found that migraines were twice as frequent (22% vs. 10% to 12%) in patients with a PFO compared to the general population. In patients with migraine with aura, the difference was even more striking, (17% for PFO patients compared to just 3% to 5% for the general population). After percutaneous PFO closure, 80% of the patients who suffered from migraines before intervention reported improvements.

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