BBI Contributing Editor

ATLANTA, Georgia — Characterized by a rapid pace of innovation and continued emergence of new competitors, the cardiology products market remains one of the most dynamic sectors of the medical device market (Table 1). The competitive landscape continues to evolve, as innovations in product design along with intellectual property issues drive rapid changes in market share. The major new development expected to rekindle growth in the market is drug-eluting stents, which promise to essentially eliminate restenosis, the primary drawback of minimally invasive therapy at present. But a number of new product segments also are emerging, including the use of interventional techniques to perform tissue engineering on damaged hearts, addressing the approximately 5 million patients in the U.S. alone suffering from congestive heart failure. Stents for use in peripheral vessels are another growth segment of the market. Carotid stents represent a major emerging target for suppliers of coronary stents, and significant progress is occurring as second-generation devices enter clinical trials, along with devices to guard against distal embolization during stent implantation.

The market for intravascular brachytherapy products emerged as a major segment in 2001, with worldwide sales exceeding $90 million in the first full year. The future of that segment is uncertain, however, since drug-eluting stents now also are showing promise for treatment of in-stent restenosis, the primary indication for vascular brachytherapy. So far, results in early clinical studies indicate that drug-eluting stents may prove to be the more effective modality. Developers are also focusing more attention on uses of intravascular brachytherapy in the peripheral vessels. Another segment of the market, and one that has now reached a level estimated at more than $300 million worldwide, is vascular sealing devices for closure of the puncture site following a diagnostic or interventional catheterization procedure. Although the market is already quite competitive, with three major suppliers having established strong positions, new suppliers continue to emerge in this segment, competing both on the basis of price and by offering new and improved product features. The opportunity remains substantial, since fewer than 20% of procedures now use the devices. Growth in that segment has slowed as compared to the rapid rate that characterized the early stages of market development, but forecasts indicate that the sector will remain attractive for suppliers.

Major advances are occurring in interventional treatments for cardiac arrhythmia. Use of ablation techniques to treat atrial fibrillation appears increasingly feasible, and a number of companies, including some that are new to the electrophysiology segment, are pursuing that opportunity. Cardiac assist devices represent yet another rapidly developing segment, with new technologies continuing to emerge for temporary support, and long-term cardiac support with artificial devices now a reality. The use of information technology is also increasingly pervading the cardiology products arena. For example, at the annual scientific sessions of the American College of Cardiology (ACC; Bethesda, Maryland), held here in March, Medtronic (Minneapolis, Minnesota) introduced the CareLink system, which allows physicians to view data from implantable cardiac devices such as defibrillators and pacemakers over a standard telephone line, and to remotely consult with other physicians viewing the data via a PC link. Similarly, the use of telecommunications technology to monitor patients with heart failure continues to be a promising area, although the market remains small at present.

Advances in cell transplantation technology

The use of cell transplants to regenerate cardiac muscle that has been lost due to myocardial infarction represents a significant market opportunity. There are more than 4.6 million patients with congestive heart failure in the U.S., according to the American Heart Association (Dallas, Texas), and an estimated 22.5 million worldwide. Another 2.5 million new cases are diagnosed each year worldwide. Development of cell transplant therapy to treat heart failure is at an early stage, although some patients have already received successful transplants. Another application of cell transplantation in cardiology is revascularization by stimulating the creation of new blood vessels. As shown in Table 2, a number of technologies are under development for delivery of cells to the heart tissue, both for restoration of the heart's ability to pump blood as well as for revascularization. It already is recognized, based on prior studies, that only those cells implanted at the border of an infracted region will survive and proliferate; cells implanted in dead tissue typically die. Consequently, investigators are attempting to localize delivery of cells to regions that will allow proliferation to occur and that also will promote tissue regeneration to restore heart function, or result in the sprouting of new blood vessels.

Most studies are employing autologous cells, i.e., cells derived from the patient, which are first harvested from peripheral blood, skeletal muscle, bone marrow or other sources, then expanded in culture and subsequently implanted at the target site in the heart. Some studies are using cell selection techniques, such as purification of a typically heterogeneous population of harvested cells using separation via antibody markers (e.g., CD34). As discussed by Takayuki Asahara, MD, of St. Elizabeth's Medical Center (Boston, Massachusetts) at the ACC conference, the isolation procedure usually results in harvest of only about 0.01% of the number of cells needed for treatment, making expansion in culture mandatory. One approach to improving the efficiency of the procedure is to transfer genes into the isolated cells that promote growth of the desired cell types. In Asahara's studies, transfection of isolated epithelial progenitor cells with vascular endothelial growth factor (VEGF) gene is being studied. That strategy has been shown to improve the efficiency of cell differentiation to promote vasculogenesis and angiogenesis for revascularization of the heart. The approach could allow treatment of the 20% to 37% of patients with coronary artery disease who are unsuitable for percutaneous intervention or bypass surgery, or who have incomplete revascularization after such procedures.

Bone marrow stem cells are proving to be one good candidate cell type for inducing angiogenesis and vasculogenesis, according to Hung-Fat Tse, MD, of the University of Hong Kong, a presenter at the ACC sessions. Bone marrow contains epithelial progenitor cells that appear well suited to differentiate into vascular cells. Tse has used the Cordis Biosense MyoStar injection catheter to inject cells into the left ventricle of eight patients with severe, untreatable coronary artery disease who had previously failed all other revascularization options (CAGB, percutaneous intervention, and percutaneous myocardial revascularization using laser techniques). The procedure is relatively complex, involving an average of 16 injections per patient and a procedure time of over 200 minutes. Some improvement in ejection fraction has been observed (61% in the treatment group vs. 56% in controls) at 90 days, although the change was not statistically significant. However, the number of angina episodes dropped by more than 50% (from 27 to 12), and nitroglycerin usage also dropped. The improvement did not become evident until after about 30 days, perhaps indicating that an incubation period is needed for the effect to develop.

TransVascular (Menlo Park, California) also is actively pursuing applications of its catheter-based system for cell implantation therapy. The focus of TransVascular's studies is on restoration of contractile units in the heart and also maintaining a favorable ventricular geometry. The technique, called cellular cardiomyoplasty, uses the company's coronary venous catheter technology. Advantages include avoidance of shunting of cells away from the target region by blood flow, which can occur with arterial delivery, and improved access to diseased areas of the heart that may not be readily reached via an arterial catheter. TransVascular has developed a technique for harvesting of progenitor cells from bone marrow, preserving them in bovine collagen gel and then expanding the cells in culture prior to injection. The company's CrossPoint TransAccess Catheter, a 2 Fr device, is then used to perform a transvenous puncture to access the target site, and the MicroLume Catheter, a 27G microinjection device, is used to deploy a network of cells. Animal studies with the TransVascular delivery technology are in progress.

A new approach to delivery of cells for myocardial regeneration was described at the ACC conference by a group led by Keith March, MD, PhD, of Indiana University's Krannert Institute of Cardiology (Indianapolis, Indiana). The technique employs retrograde infusion through the coronary venous system to allow widespread distribution of cells throughout the myocardium. Microspheres manufactured by BioPal (Wellesley Hills, Massachusetts) have been used, along with a neutron activation assay, to assess the distribution obtained with retrograde infusion. An ongoing study is under way to verify via histology that the microsphere distribution pattern correlates with the distribution of infused cells. In animal studies, the company has shown that 36% of the infused particles are retained in the heart, and that one-third of the left ventricle contained microspheres. Viability of infused cells has been demonstrated via BrdU labeling. As opposed to approaches that involve highly targeted delivery of cells to regions of the heart that require regeneration, the retrograde infusion technique provides a more widespread distribution of cells throughout the myocardium, although the distribution is not necessarily uniform. Studies are planned to assess survival of infused cells in infarcted regions of the heart. The procedure requires only a single injection lasting a few seconds, vs. the lengthy procedure needed for targeted injection of cells. A standard diagnostic angiography catheter can be used for the infusion. A limiting factor at present is obtaining a sufficient number of cultured cells for infusion, although the optimum number of cells needed for therapy remains an open question even for targeted injection approaches. The retrograde infusion technique will face a greater challenge in this regard, however, since not all of the infused cells will necessarily localize in the regions requiring regeneration.

The potential market for devices used for cell transplantation therapy in cardiology is potentially quite large. Diacrin (Charlestown, Massachusetts), one of the companies developing technology to regenerate cardiac tissue for the treatment of cardiac disease, estimates a target U.S. patient population of 200,000 per year, representing the number of patients who survive a heart attack annually (about 800,000 of the 1 million total heart attack victims) but die within the following year. Those patients comprise the group most in need of regenerative therapy. Based on costs of comparable existing therapies, a successful cardiac cell regeneration technology could sell for as much as $5,000 per treatment, representing an annual market opportunity of $1 billion in the U.S. alone. Furthermore, use of the technology as a treatment for existing patients with congestive heart failure could greatly expand the potential market.

Expanded peripheral vascular role

While cardiologists have generally confined their practice to treating diseases of the heart and coronary arteries, the technologies employed, particularly vascular stents, are showing increasing promise as modalities that can be used to treat certain forms of peripheral vascular disease. Another relatively new device segment, endovascular grafts used in the treatment of abdominal aortic aneurysm, is also one that has attracted the attention of a growing number of cardiologists. For suppliers of stents, devices for the treatment of peripheral vascular disease represent an opportunity to expand their served market, allowing conversion of a large number of procedures now performed by vascular surgeons to minimally invasive techniques. The treatment of carotid artery stenosis, a condition that can lead to a stroke if not treated, represents a potential market opportunity of approximately 150,000 procedures per year in the U.S., based on the number of carotid endarterectomy surgeries performed annually. As discussed by Kenneth Ouriel, MD, of Cleveland, Ohio, at the ACC sessions, carotid endarterectomy was first performed in the early 1950s, and experience with the technique resulted in halving of the procedural stroke and death rates between the mid-1980s and the mid-1990s. The number of procedures has doubled over the past 10 years, indicating that improved outcomes have stimulated use of carotid endarterectomy. Carotid artery stenting was first attempted in the 1990s to treat patients who were at high risk for adverse events during surgery. However, recent experience with carotid stenting, including studies that include the use of embolic protection devices during the procedure, indicates that stenting is safer than surgery. Ouriel said he now believes that carotid artery stenting is likely to replace carotid endarterectomy within the next 10 years. The primary drawback observed with carotid stenting so far is a possible higher rate for intracranial hemorrhage vs. surgical treatment.

Carotid stents are under development by most of the leading suppliers of coronary stents, including Cordis (Miami Lakes, Florida), Boston Scientific (Natick, Massachusetts), Guidant (Indianapolis, Indiana) and Medtronic (Minneapolis, Minnesota). Carotid stents typically are based on self-expanding stent technology using nitinol or a similar metal, in order to withstand compression forces that are more common in the neck than in the coronary arteries. A key ancillary device needed to ensure the safety of the procedure is an embolic capture system. Those devices are also under development by stent suppliers, as shown in Table 3.

While most trials performed with embolic protection devices have addressed applications in coronary intervention (e.g., for treatment of patients suffering acute myocardial infarction), other versions of the devices are being evaluated for use in carotid interventional procedures. For example, Medtronic obtained FDA clearance for the PercuSurge GuardWire system in January for use in saphenous vein graft interventional procedures, and it is continuing to evaluate the device for use in carotid stenting procedures. There are a total of 26 embolic protection devices under development, according to Gregg Stone, MD, of the Cardiovascular Research Foundation (New York). An important characteristic for embolic protection systems is the crossing profile of the device, since an excessive profile can cause dislodgement of embolic particles from the site to be treated before the capture system can be deployed. Device designs have continued to evolve to lower-profile versions, with profiles of 5 Fr to 5.5 Fr now considered necessary to avoid embolization. MedNova (Galway, Ireland) has now progressed to a third generation design for its NeuroShield system. As described in a poster presentation at the ACC conference by a group of cardiologists from Lenox Hill Heart and Vascular Institute (New York), including Christina Brennan, Gary Roubin, and Martin Leon, use of the newest NeuroShield device in a study of elderly patients (octogenarians) resulted in reduction in the rate of major peri-procedural strokes from 6.8% to zero, and the rate for fatal strokes was reduced from 1.1% to zero. Minor strokes were reduced from a 7.9% rate to 5.1%. The NeuroShield, as well as the Guardian Occlusion Balloon embolic protection system from Rubicon Medical (Salt Lake City, Utah), will be distributed by Abbott Laboratories (Abbott Park, Illinois) once regulatory clearance is obtained.

While studies with all of the devices used for embolic capture have found that the devices do capture significant amounts of macroscopic material that could otherwise cross an occlusion, studies have also shown that focal regions of ischemia develop in the brain in spite of the use of a protection device, and that the incidence of such ischemic events does not appear to be device-related. Investigators believe that manipulation of equipment prior to placement of the capture device may be the cause of those events. However, the events do not cause clinical symptoms, so they may not be a practical issue. Some devices, such as the Microvena (White Bear Lake, Minnesota) TRAP filter, contain a hydrophilic coating to facilitate passage through a lesion prior to treatment. So far, the results of clinical trials with carotid stents have not shown that any one device is markedly superior to another, although many companies have changed their designs based on initial experience in the field. The Wallstent is by far the most widely used device so far. In a study conducted at the Cardiovascular Center Berthanien (Frankfurt, Germany) using a wide variety of stent designs, 66% of all carotid stents implanted were Wallstents, while 25% were Cordis Precise stents, and 6% were Cordis Tetra stents.

Stroke prevention, the focus of carotid stent development programs, has also attracted the attention of numerous other companies in the medical device sector. One company, Appriva Medical (Sunnyvale, California) exhibited the X-Caliber System, designed to help prevent thromboembolic strokes in patients with atrial fibrillation who are unable to take coumadin. The system employs an ePTFE plug inserted via transcatheter techniques to block flow in the left atrial appendage, which is the site where clots typically form during atrial fibrillation. The plug is inserted via a transseptal puncture, in a procedure called Percutaneous Left Atrial Appendage Transcatheter Occlusion (PLAATO), and remains in place permanently. At present, Phase I feasibility studies are in progress, and Phase II studies are being planned. According to the American Heart Association, 2 million individuals in the U.S. have atrial fibrillation, and the condition is cited as a principal or contributing cause for over 61,500 deaths annually. About 15% of all strokes occurring each year in the U.S., or about 90,000 strokes, are attributable to atrial fibrillation.

Vascular brachytherapy is another technology finding applications in peripheral vascular therapy as well as in coronary intervention. Three intravascular brachytherapy systems are now available for treatment of in-stent restenosis to help prevent recurrent restenosis, including the Beta-Cath from Novoste (Norcross, Georgia), the CheckMate system from Cordis and the Galileo system from Guidant. All three were initially introduced for use in the coronary vessels. However, in part because of promising results with drug-eluting stents for in-stent restenosis prevention, suppliers of brachytherapy systems are now actively exploring other applications, such as in the peripheral vessels. Novoste, the current leader in intravascular brachytherapy, has recently initiated the MOBILE trial using its Corona system, which investigators find very similar in operation to the coronary Beta-Cath system. The company recently filed an IDE application to conduct the BRAVO trial to study uses of the Corona system in preventing restenosis in dialysis access grafts, an application that could address up to 220,000 patients worldwide.

Additional product segments drive expansion

A number of other growth segments have emerged in the cardiology products market that will help drive long-term growth in the sector. In the electrophysiology arena, devices for the treatment for atrial fibrillation, long recognized as by far the largest potential opportunity in the ablation device segment, now appear to be closer to the market. A key breakthrough is the discovery that circumferential ablation of conduction channels around the orifices of the pulmonary veins is a very effective treatment for atrial fibrillation. AFx (Fremont, California) exhibited a new microwave surgical ablation device at the ACC conference that can be used to treat atrial fibrillation. The existing AFx ablation device is placed on the pericardium using a port access technique. Microwave energy is used to ablate tissue in a pattern that mimics the Maize procedure. A transcatheter version of the device is under development. AFx is a venture-funded company, and received 510(k) clearance for its FLEX 10 Ablation Probe accessory for the AFx Microwave Surgical Ablation system in February, including an indication for use in ablation of cardiac tissue.

CardiacAssist (Pittsburgh, Pennsylvania) exhibited its new temporary cardiac support system, the TandemHeart Percutaneous Ventricular Assist Device (pVAD), at the ACC conference. The company also is developing an implantable version, the AB-180 iVAD. Both devices are intended for use in treating patients with heart failure, primarily due to cardiogenic shock. The pVAD device has received a CE mark in Europe, and is in Phase II clinical trials in the U.S. A registry of patients treated with the device has been started in Europe, and some patients have survived for up to 14 days on the device and bridged to definitive therapy or recovery. The CardiacAssist pVAD can serve as an alternative to an intra-aortic balloon pump, according to the company, but can support up to 60% of the heart's pumping ability vs. only about 20% for existing IAPB systems. It provides continuous flow using a two-catheter system (one placed in the femoral artery, and a second in the left atrium), although there is still some dampened level of pulsatile flow since the patient's heart is still beating. The device is particularly useful for patients in cardiogenic shock after an acute myocardial infarction, allowing them to survive until a long-term ventricular assist device can be implanted. About 100 patients have now been treated worldwide using the device. The company believes that some portion of the estimated 70,000 patients who develop cardiogenic shock each year comprise the target market for the product. Pricing is similar to that for an IABP. The pVAD device also can serve as an alternative to a surgically implanted VAD at a fraction of the cost, avoiding the need for two invasive surgical procedures.

Another segment of the cardiology device market that continues to attract new entrants is arterial closure devices used to seal the puncture wound following a diagnostic or interventional procedure. The market for such products is well established, and is estimated at over $300 million worldwide for 2001. The average unit selling price in the U.S. is about $250, according to suppliers, which include St. Jude Medical (St. Paul, Minnesota), Abbott's Perclose unit, Datascope (Montvale, New Jersey), and Vascular Solutions (Minneapolis, Minnesota). New closure devices exhibited at the ACC meeting include the D-Stat from Vascular Solutions, the QuickSeal from Sub-Q (San Clemente, California), and the EVS Vascular Closure System from AngioLink (Taunton, Massachusetts). The D-STAT is a flowable hemostat, employing an injectable solution containing components that have been shown to achieve hemostasis. The same chemical components are used in the company's Duett closure device. The Sub-Q QuickSeal is an over-the-wire closure system employing a plug of bovine gelatin sponge (Gelfoam) that is applied in an extravascular fashion to achieve hemostasis in about five minutes. An advantage of the device is its ability to work in patients with severe peripheral arterial disease, including those with calcified arteries. The QuickSeal is undergoing 510(k) review and will be distributed worldwide by Boston Scientific when cleared for marketing. Sub-Q expects the pricing for QuickSeal to be very competitive with existing closure devices. The EVS device from AngioLink is to be introduced this summer. It employs a miniature square titanium staple along with a device equipped with mechanical tines that approximate the media and adventitia to be sealed. Like the QuickSeal, the EVS can be used on patients with calcified arteries, and automatically adjusts for variation in artery dimensions. Pricing will be competitive with existing closure devices. AngioLink is a privately held medical device company formed in 1999.

The use of telecommunications technology in cardiology represents yet another expanding area of the market, with applications in cardiac rhythm management, management of heart failure and management of hypertension. Medtronic introduced the CareLink programmer at the ACC exhibition, a newly approved system that allows clinicians to review data on implantable cardiac defibrillators remotely in real time. The system brings telemedicine technology into the cardiac rhythm management arena by allowing consulting cardiologists to view the data over a PC link. A key factor that will determine the success of such systems is the level of reimbursement that is available for physicians who provide remote consultation services, and for referring physicians, as well as the rules governing reimbursement. Reimbursement policy is not yet determined for the Medtronic CareLink system. Trends in related areas such as home telemonitoring of heart failure patients indicate that policies will evolve slowly, with agencies such as the Center for Medicare & Medicaid Services (Washington) as well as private insurers allowing reimbursement on a very limited basis initially to allow them to determine if such services actually benefit patients and lead to more cost-effective health care.

Another new service now being offered to cardiologists is telephonic monitoring of blood pressure. Wellness Monitoring (San Ramon, California) demonstrated its BPfone system at the ACC meeting. The system already is in use by thousands of patients in the UK and Australia, according to the company. BPfone provides a patient-directed alternative to ambulatory blood pressure monitoring, and has been preferred by patients for that reason. Reports showing blood pressure trends over time are generated from data recorded over the phone line, and can be mailed or faxed to the physician from the Wellness Monitoring data center. Physicians in turn can share the data with the patient. Eventually, the company plans to add monitoring of glucose, body weight, and other parameters, as has been done in Australia.

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