A.G. Edwards (St. Louis, Missouri) sees atrial fibrillation (AF) as very much a coming thing that those who invest through the brokerage house should know more about. To that end, AF was the focal point of what the company billed as its "inaugural panel and interactive discussion on emerging medical technology" last month.
Jan Wald, PhD, vice president and health care analyst at A.G. Edwards, said the program was organized in order to help investors understand the clinical issues as well as the diagnostic and therapeutic possibilities for new treatment options for AF in what is estimated as a $5 billion annual market.
"Atrial fibrillation is, just as congestive heart failure and drug-eluting stents were two years ago, at the point where we believe new technologies and products will begin to enter the clinical practice within a year or two," Wald said in introducing the panel.
AF is an increasingly common cardiovascular problem in a society where many people now survive an initial heart attack, only to have secondary problems. During AF, abnormal electrical impulses fire randomly in the atria, causing the heart to beat in an irregular manner. As a result, the chambers are inadequately filled, causing less blood to be pumped to the rest of the body. Left untreated, AF can lead to severe complications such as stroke and death, though it is generally regarded at first as primarily only affecting a patient's quality of life.
Current AF treatments are primarily directed at trying to reestablish a normal heartbeat and prevent stroke, and are primarily supportive and palliative, rather than curative. These treatments focus primarily on the use of antiarrhythmic and anticoagulant drugs, therapies to which approximately half of all patients eventually develop a resistance. Some severe side effects also are associated with antiarrhythmic drugs, including pulmonary fibrosis and impaired liver function.
The first part of the mini-conference, held at the tony Le Meridien Hotel in Boston, Massachusetts, and also carried by webcast, was given over to a lengthy panel overview and discussion by several prominent physicians involved in new treatment options for the condition. They discussed these new approaches to the treatment of AF as well as what they think is a timetable for approval of these groundbreaking new treatments.
"I think that all of you know that atrial fibrillation is the most common heart rhythm problem that we as clinicians deal with," said Jeremy Ruskin, MD, director of cardiac arrhythmia service at Massachusetts General Hospital and associate professor of medicine at Harvard Medical School (both Boston). "It affects close to two-and-a-half million people in the U.S." He said that because it is an age-related disease, "it is, therefore, the only arrhythmia that's actually increasing because the population is aging." He cited the "baby boomer" generation as a primary reason for this as they head into their late 50s and early 60s. He added that the number of patients with AF is expected to double by 2020.
In the treatment of AF, "one of the major challenges that we face is trying to understand the mechanisms of this arrhythmia," Ruskin said. He added that if one were to look at where physicians have been successful in therapeutics, "it's almost always been in areas where we understand the mechanism, whether it's the development of drugs around that mechanism, or an ablation strategy or a surgical strategy." He said that currently, doctors don't have an understanding of that mechanism as it concerns AF, "although we have some insights."
According to Ruskin, electrophysiologists are on the cutting edge of new technology and techniques in the AF field, though they currently only treat a very small percentage of all patients with this disease. He said that general cardiologists, internists and the primary care physician "who take care of 95% to 99% of patients with atrial fibrillation, they either do nothing but anticoagulation and rate control or they use drugs."
He said that the first responsibility of any health care provider taking care of AF is to prevent stroke. Once that's done, what happens afterwards "is kind of dealer's choice." And he said that many of these providers then assume an "if it isn't broken, don't fix it" attitude rather than trying to eliminate the problem altogether. That being said, he noted it is important for investors and industry to realize "that this enormous population out there is not being optimally managed." He added that the small percentage of people he sees for ablation therapy are only the "tip of the iceberg."
Other treatment options that Ruskin termed either "unpredictable" or "very drastic" include the destruction of the AV node, followed by the implantation of a pacemaker or the pacemaker alone as a primary mode of therapy.
Discussing some of the breakthrough technologies was Warren Jackman, MD, professor of medicine and director of clinical electrophysiology at the University of Oklahoma Health Sciences Center (Oklahoma City, Oklahoma). He agreed with Ruskin that drug therapy has been disappointing and hopefully "20 to 25 years from now, drug therapy will be something that we'll tell medical students that we used to do."
Jackman said that one of the most promising new therapies that he has been involved with is the catheter ablation of AF, specifically pulmonary vein isolation. Electrophysiologists are experimenting with this new treatment technique, which mimics a more highly invasive surgical operation called a maze procedure already used in the most hopeless AF cases. However, it is performed in a much more minimally invasive procedure using catheters. He added that a reliable product that can thoroughly map the pulmonary vein is also essential for use prior to most AF procedures.
Ruskin said that up until recently, surgical treatment of AF via catheter ablation "has been very uncommon." He said this is because it is a very difficult and time-consuming procedure and cardiac surgeons have not done it. However, he said recent advances in catheters that can be manipulated surgically have reduced left-sided lesion procedures times to between 10 and 20 minutes. "Now there's enormous interest, and I would guess that a majority of cardiac surgeons will do some sort of ablation procedure in the coming two or three years."
The key here, according to the physicians, is being able to perform an ablation procedure in a rapid and economic fashion, a challenge that has still not been completely met.
"If you're an electrophysiologist in practice, and there is a viable option for atrial fibrillation, there is no choice but to do it," said A. Marc Gillinov, a staff physician in the department of thoracic and cardiovascular surgery at the Cleveland Clinic Foundation (Cleveland, Ohio). Patients will be "knocking the doors down" for such a procedure. He said that the large numbers of potential patients for such a system would "dictate that you would not be able to survive in an electrophysiology practice if there's a technique that's feasible and economically viable and you're not doing it."
On the regulatory front, Jackman estimated a timeframe for premarket approval for a new AF device "as probably on the order of two to three years." He added that the systems that win would probably have vigorous sales within a year of approval.
An industry representative on the physicians' panel, Bob Mittleman, MD, associate medical director at Boston Scientific (Natick, Massachusetts), said the device industry would like the FDA to spell out what it will take for AF devices to gain approval. He said the FDA has been mostly silent about its requirements since the whole pulmonary vein technology came along. "I think a lot of people in the industry would like to see the FDA offer more guidance in terms of the approval process for the newer technologies for atrial fibrillation." He said he thinks that the FDA wants to move the technology along, but in a safe manner, since this is virtually uncharted territory. Finally, he spoke to the need for industry to step up to the plate. "The infrastructure [via numerous EP labs] is there, but the time-limiting step in setting this thing on fire is the enabling technology."
With an eye toward shining the spotlight on some of the companies developing technology to diagnose and treat the condition, A.G. Edwards also invited seven companies to make presentations. Wald said the intent to focus on clinical indications. "We did not hesitate to invite private, foreign or small and large public companies to this forum," he said. "Nor did we hesitate to invite diagnostic as well as therapeutic companies to the meeting." He added that the companies on the panel had a "good representation of innovative products that are likely to be entering the market."
One company using an interesting technology to treat AF is CryoCath Technologies (Kirkland, Quebec). The company is developing cryotherapy – the use of extremely low temperatures, as low as -75 C – to treat diseased tissue while leaving underlying connective tissue largely unaffected. It uses its catheter-based cryotherapy products to treat cardiovascular disease across three broad indications: tachyarrhythmia, ischemia and restenosis.
The company has already successfully launched its first product, the Freezor CryoAblation system in Europe and is developing additional products to expand its pipeline of systems to treat tachyarrhythmia. CryoCath also is working to develop a system called the SurgiFrost, a cryosurgical probe specifically designed to treat cardiac arrhythmias.
"We are a therapeutic medical technology company with our initial focus primarily in the field of EP ablation," said Steve Arless, president and CEO. "Longer term, we believe that the technology has merits in other fields of interventional cardiology." While the company has broader aspirations, "right now, our primary focus and about 90% of our energy, effort and money goes into the electrophysiology field."
Arless said he believes that the energy and catheter technologies that his company is developing have application across all the fronts of EP ablation, including atrial fibrillation, "the Holy Grail of ablation right now." He said the company's ultimate goal is to develop a cryotherapy catheter tip that would provide efficacy rates of close to 90%, comparable to current maze procedure levels.
The company also has two other new AF products in development that are being used in clinical settings – the Arctic Circular and the Frost Line. It expects FDA approval, via a PMA, for the Freezor AF system sometime in 2004, with an initial filing by July of this year.
A company developing laser products for the treatment of cardiovascular disease, with a focus on AF, is CardioFocus (Norton, Massachusetts), a private, venture capital-backed company. The company's photonic ablation technology involves the use of fiber optic catheters, called Lightstics, and a diode laser system designed to make precise lesions, photothermally, at pre-determined locations. CardioFocus received its first round of financing in 1997 and already has 42 patents under its belt.
"We see the surgical market opportunity as a good one," said Jon McIntyre, vice president, product development, "but we see the blockbuster opportunity really in a catheter treatment of atrial fibrillation." He said such a system approaches almost $2 billion in market value and importantly, he thinks such a system will be easily reimbursable.
According to McIntyre, photonic energy penetrates tissue, "so you're getting uniform, simultaneous heating at the surface, as well as at depth." He said such a system makes it possible to make full-thickness lesions without having to bring the surface tissue up to a high temperature, thus preventing potential charring which would damage the tissue. The company says that it can achieve between an 80% and 90% acute success rate with high energy levels and one or two energy deliveries per vein.
AFx Technologies (Fremont, California) has developed a microwave ablation treatment that offers what it said is a two-hour cure for all types of AF. The company said its system creates a curative alternative to the maze procedure, which is often complex and risky. The company's ablation system is comprised of a microwave generator and an attachable, single-use, disposable catheter, resembling a miniature golf club, that is powered by the generator.
Doctors pass the "club," a silicon-encased microwave reflector, over the areas where bad cells impair the heart's function. The company said that killing these cells eliminates aberrant pathways that transport electrical impulses, leaving behind only normal electrical pathways.
"Microwave energy has more control and it's faster to use on patients," said Dinesh Mody, the company's president and CEO, during his presentation. Importantly, he noted, the procedure can be performed in a minimally invasive fashion without stopping the heart and with very little risk of tissue charring, which could cause a stroke.
Microwave radiation has been used for killing tumors since the 1970s. It also is used to treat heart tissue through the femoral vein in the leg. The company is shooting for FDA approval of a percutaneous AF catheter by 2005.
A potential powerhouse company in the AF market is Cardima (Fremont, California), a maker of catheter-based systems to improve the diagnosis and therapy of electrophysiologic disorders. Currently, its systems are used for the mapping and ablation of the two most common forms of cardiac arrhythmias, atrial fibrillation and ventricular tachycardia.
These catheter-based systems under development are designed to provide enhanced access to arrhythmia causing tissue, to diagnose the arrhythmia by locating its origin and to restore normal heart rhythms by isolating and destroying the arrhythmia-causing sites by using radiofrequency (RF) energy.
The company has an interesting approach to its design. Its catheters including the Revelation Tx and Revelation Helix, are being developed to incorporate multiple electrodes in their tips. These catheters will be able to receive electrical signals for mapping and to emit RF energy for ablation. This would allow physicians to map and ablate using a single catheter.
"Cardima can be looked upon as a pioneer of AF," said William Wheeler, president and COO. The company should be one of the first to have a product on the market in the AF arena, with an initial FDA premarket approval of the Revelation Tx by the end of this year, and approval of the Revelation Helix by 4Q03.
Cardiac mapping company Endocardial Solutions (St. Paul, Minnesota) presented information on its EnSite 3000 system. The system is designed to provide electrophysiologists with a real-time 3-D image of the electrical activity of the heart, what A.G. Edwards termed "an important adjunctive tool" of any ablation procedure. "We are a mapping company enabling ablation that through the technology could vastly improve on the speed and the density of the information," said James Bollock, company president and CEO. The system is designed to deliver high-resolution images. It displays more than 3,000 virtual points of electrical activity using patented algorithms.
Bullock compared the imaging abilities of the system to waves of sound. "If someone in the back of the room were to talk to me, the sound would come to my ear as the probe in an amplitude lower than it was delivered." He said that if he were able to compute the distance between the source and his ear, "I could effectively re-compute the amplitude of that sound, much like we do with electricity." He said the company's EnSite system is able to do this "in a very elegant way, such that we are computing more than 3,000 electrograms at over 1,200 times a second."
In addition, the locator function of the EnSite system enhances diagnosis and treatment by providing electrophysiologists with real-time feedback of the precise location of auxiliary catheters introduced into the heart so proper and accurate treatment can be provided.