CDU Contributing Editor

KAUAI, Hawaii – The cardiovascular device market remains one of the most attractive segments of the medical products industry, continuing to exhibit above-average growth and attracting significant attention within the investment community. As shown in Table 1, the key segments of the worldwide market, in order of sales volume, include products for percutaneous intervention, pacing devices, surgical products, implantable cardiac defibrillators and angiography products. Whereas the overall worldwide medical device market is growing at only about 4%, the cardiovascular device market is growing at more than twice that rate. Key areas of new product development in the cardiovascular surgery product segment include devices for beating heart surgery, automated devices for performing anastomosis during cardiovascular surgery, devices for improving the efficacy of cardiopulmonary bypass and artificial vascular grafts.

An important trend in the market that will impact the relative growth of the various segments in the future is the evolution of therapeutic modalities for surgical vs. percutaneous intervention. As discussed at a mid-August conference on Emerging Therapies in Cardiovascular Disease, sponsored by ProMedica International (Huntington Beach, California), some experts, such as Dr. Patrick Serruys of the Thoraxcenter (Rotterdam, the Netherlands), have predicted that cardiac surgeons will eventually become obsolete, perhaps within as little as five years due to continued improvements in transcatheter technology. However, surgical techniques also are advancing to become less invasive and continue to hold an edge, at least for now, in lower long-term re-intervention rates.

Use of beating-heart surgery is expanding rapidly, due to patient preference, cost advantages for providers and continued improvements in device technology. The most recent area of innovation is devices for performing anastomosis, which will greatly simplify minimally invasive procedures and reduce procedural invasiveness even further. At least six companies are developing new anastomosis devices for use in cardiac bypass surgery and similar procedures. Other new developments are expanding the range of applications of percutaneous intervention, including stent-grafts for transcatheter thoracic and abdominal aortic aneurysm treatment; new devices to protect against distal embolization during percutaneous procedures; and stents for use in the carotid arteries. Such new techniques are already beginning to replace some surgical procedures, providing an alternative that may be preferred to surgery in spite of the continuing evolution of less invasive surgical techniques.

Emerging therapies discussed at the ProMedica conference may open up entirely different approaches for coronary and peripheral revascularization, including the use of gene therapy for angiogenesis, tissue-engineered bypass grafts, and transcatheter reconditioning of calcified vessels and heart valves to restore tissue compliance and eliminate one of the key causes of poor outcome for both surgical and percutaneous treatment. According to market analysts who presented at the symposium, another area of application that may hold the key to continued above-average growth in the cardiovascular products market is new approaches for the treatment of congestive heart failure, a condition afflicting 4.6 million persons in the U.S. and the cause of about 45,000 deaths per year, according to the American Heart Association (Dallas, Texas).

Integrating surgery, percutaneous intervention

The ProMedica symposium was unique in that it brought together cardiovascular specialists from both surgical and interventional disciplines to discuss not only the emerging developments in each field but also the issues regarding competition between the two. Over the past few years, percutaneous intervention has clearly gained the upper hand if trends in the number of procedures performed are the benchmark. As shown in Table 2, data from a sample of 60,706 patients, treated at 79 community hospitals within the Columbia/HCA network, demonstrates that percutaneous intervention is favored by a wide margin, with a ratio of angioplasty to surgery of 2.4 to 1. The ratio is somewhat higher than for the most recent data published from the National Center for Health Statistics (NCHS), which shows a ratio of 1.7:1 for 1998. However, extrapolation of the NCHS data indicates that the ratio could have been approximately 2:1 in 1999, in closer agreement with the HCA survey data. Furthermore, it is likely that the ratio is in fact higher in community hospitals than for the total set of U.S. hospitals represented in the NCHS data, since many smaller hospitals that perform PTCA may not have high-volume cardiac surgery departments. The trend is clearly in favor of continued growth in PTCA and stent use, with declining usage of CABG. As shown in Table 3 on page 3, these factors have combined to drive continued, although maturing, growth in the coronary stent market in the U.S., with sales expected to reach $1.5 billion this year.

While automatic anastomosis devices appear to hold promise for making bypass procedures safer and more reliable, some surgeons express skepticism regarding the rate at which the technology will be adopted. Cardiac surgeons are typically conservative when adopting new technologies, and may find it difficult to relinquish a part of the CABG procedure that now depends on their highly developed skills. Furthermore, cost may be a barrier to adoption, and in fact the market has already driven prices to lower-than-expected levels of approximately $300. Even this price may cause some surgeons to balk, however, unless studies demonstrate significant improvements in outcome as a result of the elimination of cross-clamping.

Automatic anastomosis devices will be particularly attractive for use with robotic surgery systems now beginning to be used for cardiac surgery. Suppliers of robotic surgery systems include Intuitive Surgical (Mountain View, California), with the Aesop 3000, and Computer Motion (Santa Barbara, California), with the Zeus Telemanipulator System. At present, as described by Friedrich Mohr, MD, PhD, of the University of Leipzig (Leipzig, Germany) at the ProMedica symposium, beating-heart robotic bypass remains a difficult procedure, requiring the surgeon to re-learn many aspects of the operation. So far, Mohr has performed 27 total endoscopic arrested-heart procedures and eight total endoscopic beating-heart procedures. A key need is an endoscopic stabilizer for use in beating heart procedures, but in addition endoscopic anastomosis using conventional sutures is both challenging and time-consuming. With the availability of automatic anastomosis devices, particularly those that can be used endoscopically, the use of robotics could in principle enable a significant step forward in further reducing the invasiveness of OPCAB procedures.

The next generation of bypass technologies, however, may completely eliminate the need for surgical techniques by allowing bypass to be performed entirely via transcatheter methods. The leading company involved in the development of such technology is Transvascular (Menlo Park, California). Transvascular's Percutaneous In Situ Coronary Venous Arterialization (PICVA) technique employs a Transaccess catheter comprised of an intravascular ultrasound imaging catheter combined with a needle-tipped catheter. The IVUS catheter is used to image through the target artery's wall to view the veins surrounding the heart. The nitinol needle is then pushed through, followed by a guidewire. Next, a catheter is placed from the artery into the vein to implant blocking devices that isolate the section of the vein overlying the artery to be bypassed. Finally, the vein and artery are connected together using a stent to complete the anastomosis. The PICVA technique has been shown to provide long term (three- to five-month) patency in animals, and is now undergoing initial human trials to evaluate safety in Germany. A similar technology is under development by Vascular Sciences/St. Jude Medical.

While such approaches appear promising to allow patients who are not candidates for PTCA or stents to undergo non-surgical treatment or less invasive surgery, they will nevertheless continue to face competition from next-generation stents and related technologies. In particular, initial results of recent studies in Brazil with rapamycin-coated stents, being conducted by Cordis/Johnson & Johnson, have demonstrated that restenosis may be completely eliminated. Brachytherapy is also showing promise for reducing restenosis rates to levels of well under 10%. Furthermore, companies such as Intraluminal Therapeutics (Carlsbad, California) are developing devices such as the Safe-Steer catheter, a forward-looking guidance system designed to navigate through total occlusions. Progress also is continuing to be made with laser-based devices for crossing total occlusions or for treating in-stent restenosis, such as the Vitesse-C catheter from Spectranetics (Colorado Springs, Colorado). Such devices promise to further expand the range of applications for percutaneous intervention, narrowing the niche addressed by conventional surgical treatment.

Long-term, some specialists in both the cardiac surgery and interventional cardiology camps expect that there will be an integration of disciplines, with all revascularization procedures performed with a variety of less invasive devices selected based on specific characteristics of individual patients. Clearly, patients would benefit from a less biased approach to treatment that avoids the tendency for specialists to recommend the treatment modality that they themselves use in favor of an approach that results in the optimal modality being used. One possibility is that imaging specialists (i.e., radiologists) will ultimately make the decision on the therapeutic modality to be used, since they are less biased than surgeons or interventionists. Some centers are considering hybrid treatment strategies that enlist both surgeons and interventionists in patient treatment. However, from a practical standpoint, there are significant differences in income for surgeons vs. cardiologists, creating a barrier to cooperative arrangements. In addition, there is a question as to the type of facility that is needed for integrated surgical and interventional therapy, since surgeons are not comfortable in the cath lab, and interventional cardiologists do not require the complexities of a surgical suite.

In spite of such issues, however, the trend toward increased use of less invasive treatment is clearly established. Surveys of cardiac surgeons indicate that at least 60% of coronary artery bypass procedures will be performed with minimally invasive techniques by 2005, and only 9% of surgeons believe that CABG will be performed using today's conventional methods in 2005. True integration of the surgical and interventional specialties is expected to occur in approximately 10 to 20 years, with a new combined specialty emerging that makes use of the full range of minimally invasive and transcatheter technologies to use the most appropriate modality for a given case. Integration will be facilitated by the development of improved diagnostic methods, including genetic testing, that allow more accurate prediction of outcomes based on the treatment modality used. As a result, therapy selection will be based more on objective, evidence-based factors, and less on factors such as control over referrals or the physical location of the patient when diagnosis is performed.

Stent applications continue to expand

Another important trend in cardiovascular therapy is the expansion of interventional treatment for applications in the peripheral vessels and in bypass grafts, including stent-grafts for thoracic and abdominal aortic aneurysms and for treatment of diseased saphenous vein bypass grafts, and new stents and embolic protection devices for use in the carotid arteries. According to Mark Wholey, MD, of Pittsburgh Vascular Institute (Pittsburgh, Pennsylvania), experts in vascular surgery have recently predicted that 65% of all vascular surgery cases will eventually be converted to use endovascular techniques. One driver of that trend is reduced procedural mortality, which is quoted at 3% to 5% for interventional therapy vs. 8% to 10% for surgery. In addition, morbidity is considerably greater with surgery. Conventional surgery for abdominal aortic aneurysm repair can be almost as invasive as an open-chest CABG procedure, for example, while the use of alternative stent-graft repair is a minimally invasive procedure involving only femoral artery catheterization.

As discussed by Friedrich Mohr, MD, PhD, at the ProMedica symposium, there are significant advantages in using endovascular repair for thoracic aortic aneurysms (TAAs), including lower rates of stroke and paraplegia, particularly as compared to surgery performed on an emergency basis. Because many TAA patients don't present or are not referred until their condition has become serious (one-third present in emergent condition), it is often not possible to perform early surgical intervention when procedural risk is lowest. Consequently, there is strong demand for new stent-graft devices, both from physicians and patients. The current leader in this market, Medtronic (Minneapolis, Minnesota), has trained more than 900 physicians worldwide to use its AneuRx endovascular graft, and more than 5,000 patients worldwide have received implants. The device is priced at about $11,000. The other supplier with an FDA-approved device is Guidant (Indianapolis, Indiana), with the Ancure stent-graft.

Distal embolic protection devices represent another emerging opportunity in the cardiovascular products market. Initially, an important focus of development was for use in conjunction with carotid stenting, to protect against emboli released during the implant procedure that could cause a stroke. However, the potential range of applications is in actuality much broader, and extends to most interventional procedures including PTCA, PTA and stent implantation in both the coronary and peripheral vessels. For example, as discussed by Richard Heuser, MD, of St. Luke's Medical Center (Phoenix, Arizona), up to 21% of patients have no reflow of blood following a PTCA procedure, a problem that could potentially be resolved if plaque debris were captured and not allowed to migrate distally where it can cause a blockage. The new interventional devices in use today, such as stents and high-pressure balloons, have increased rates of embolization, according to Heuser, and new drug therapies, such as ReoPro, have not eliminated the problem. Interventional treatment of saphenous vein grafts, an increasingly common procedure because of the large number of patients now alive with such grafts, results in a 10% to 15% incidence of embolic events, as demonstrated in the SAFE trial of PTCA vs. stenting. Most often, in up to 30% of patients, there is not complete embolic blockage, but rather only slow flow following the procedure. In the SAFE study, use of the GuardWire from PercuSurge (Sunnyvale, California) resulted in a greater than threefold reduction in adverse events. A new randomized trial involving 800 patients is now under way (the SAFER trial) to obtain a true comparison of the benefit of the GuardWire vs. controls. In another study, the CAF trial, employing the PercuSurge device, there were no strokes or deaths reported for patients treated using the GuardWire. Other embolic protection devices are under development by Cordis/J&J (Miami Lakes, Florida); Embolic Protection; MedNova (Galway, Ireland), Microvena (White Bear Lake, Minnesota) and Scion Cardiovascular (Miami, Florida).

Embolic protection remains essential in the opinion of most experts for the implementation of carotid stenting, particularly in lower-risk patients. Although there are as yet no FDA-approved stents for carotid use, carotid stenting is already a reality for high surgical risk patients, according to Wholey. For such patients, stenting is the only available option. However, a randomized trial will be needed in order to obtain FDA approval for carotid stents and drive more widespread acceptance. Two trials, the CREST and SAPPHIRE studies, are being organized, and the CARESS registry is comparing outcomes for surgery versus carotid stent procedures performed in independent medical centers. SAPPHIRE will study high-risk patients and will employ the AngioGuard protection device, while CREST will attempt to compare stenting with carotid endarterectomy. Wholey anticipates that patient enrollment may be difficult in CREST because surgeons may be reluctant to refer patients. Nevertheless, the number of centers performing carotid stenting is growing at a 21% rate, indicating that the procedure is already being more widely employed. According to Wholey, the stents of choice at present for carotid applications include the Cordis S.M.A.R.T. and Precise stents; the Guidant AccuLink; the Wallstent from Boston Scientific (Natick, Massachusetts); and the NEXT-STENT from EndoTEX (Cupertino, California). All of those devices are constructed of nitinol, which is preferred because of its combination of crush resistance and mechanical flexibility that facilitates placement around bends in the target vessel.

Emerging therapies promise market growth

A number of new therapies are under development that promise to expand the market for cardiovascular products and to create opportunities for both established players and start-up firms. One area of major focus is the treatment of congestive heart failure (CHF). Laser-based transmyocardial revascularization (TMR) technology has already been introduced for CHF, and provides symptomatic improvement of angina although long-term benefit is not demonstrated. As described by Todd Rosengart, MD, of Northwestern University School of Medicine (Evanston, Illinois), at the ProMedica conference, recent studies using TMR by his group have shown a dose-response effect based on the number of laser channels created, leading them to conclude that angiogenesis is the mechanism responsible for the improvements observed in patients. However, a potentially more effective treatment may involve the use of gene therapy to promote angiogenesis, perhaps in combination with TMR or percutaneous TMR (PTMR). Studies conducted by Dr. Jeff Isner at Beth Israel Hospital (Boston, Massachusetts) using vascular endothelial growth factor (VEGF) gene therapy to treat chronic angina have shown recent promising results, although on a small group of only 13 patients as reported in the most recent issue of the journal Circulation. Rosengart has performed studies of VEGF delivery using an adenovirus vector with promising results, although the use of such vectors has since been called into questions because of a death of a patient in a Pennsylvania study who was treated with adenovirus vector gene therapy. Rosengart believes the use of adeno-associated virus vectors could avoid the problems with adenovirus immune response. Another possibility is to use promoters that would activate genes when desired, to allow long term, non-invasive delivery of gene therapy, as is likely to be required for successful treatment of CHF.

The treatment of CHF represents a major opportunity for the medical device industry, according to market analyst Kurt Kruger of Banc of America Securities. The commercialization of a successful technology for CHF treatment could add as much as $25 billion in market valuation to the industry, which at present is valued at approximately $100 billion in market capitalization. Kruger views the development of CHF therapy as a major priority for the industry, since most other major segments are mature and will not generate sufficient growth in the future to match the trend of the past four years. Since 1996, market capitalization for the medical device industry has ballooned from $40 billion to $100 billion, representing a 26% compound annual growth rate.

Another new therapeutic approach unveiled at the ProMedica symposium uses a technology for decalcification of vascular tissues, including blood vessels and heart valves. Such treatments could have major benefits since tissue calcification is significant problem in coronary artery disease, peripheral vascular disease, and valve disease. About 75% of PTCA/stent patients exhibit vessel calcification, and 25% are untreatable due to the severity of the condition. In addition, about 10% of patients, or about 128,000 annually worldwide, have chronic total occlusions due in part to calcification, and about 25% of the 800,000 patients treated with CABG worldwide each year also have significant calcification. Finally, one-fourth of the 269,000 patients treated for valve disease each year have serious calcification. Calcification leads to reduced elasticity in heart valves, impairing their function. Calcification of valves can disqualify a patient for valvuloplasty, a transcatheter approach to treating some forms of valvular disease. The condition also results in poorer outcomes for PTCA or stent procedures since calcified tissues are less able to remodel. Finally, the presence of calcification tends to result in non-optimal healing of vascular tissues following interventional procedures.

As described by Michael Mack, MD, at the ProMedica symposium, Corazon Technologies (Menlo Park, California) is developing the decalcification technology, which uses protonated saline that mimics the bone resorption process of osteoclasts. A two-lumen catheter is used to infuse the protonated saline, which dissolves calcium crystals by ionic exchange. Total exposure time is 10 to 15 minutes. The treated tissue is then flushed with buffer to remove the calcium crystals, leaving the original tissue intact. One potential application would be the in situ reconditioning of heart valves to remove calcification and restore elasticity. The technology could also be used to dissolve total occlusions and to enhance conventional revascularization procedures by debulking distal arterial lesions. Treatment could in principle be used for early-stage atherosclerotic disease, reversing the calcification process before major structural deterioration occurs. Key principals of Corazon include Paul Yock, MD, and Thomas Fogarty, MD.

Another new development with significant market potential was described by Friedrich Mohr, MD, PhD, that offers a new approach to myocardial ablation for the treatment of atrial fibrillation. The procedure, known as intraoperative radiofrequency ablation of atrial fibrillation, or IRAAF, is derived from the Maze procedure, a surgical technique that has a 100% success rate in curing atrial fibrillation. That rate compares to about 40% for pharmacological therapy and 70% at best for catheter ablation. While highly effective, the Maze procedure is difficult to perform and very time-consuming, and as a result is not widely used. IRAAF combines the surgical approach to treatment with RF ablation. Minimally invasive Port Access techniques using devices from Heartport (Palo Alto, California) are used to access the atrium, and a non-contact probe (the En Site 3000) is used for mapping. Ablation is then performed in a manner that mimics the Maze procedure. While the minimally invasive procedure is somewhat time consuming (requiring about one hour and twenty minutes), cure rates of 80% have been achieved. Drawbacks include the need for partial resection of the left atrium with the current format for the procedure, leading to left atrial flutter post-treatment, and some issues in early studies with interaction of the ablation probe with a TEE probe used for imaging. However, those drawbacks can or have been eliminated. Atrial fibrillation is a major medical problem worldwide. There are approximately 353,000 patients discharged in the U.S. annually and 200,000 in Germany presenting with symptomatic atrial fibrillation each year. Total prevalence in the U.S. is 2 million persons, according to the American Heart Association.

Assessing both recent developments in cardiovascular therapy and anticipated new developments in the future, the moderators of the ProMedica symposium were asked to identify the top three recent developments in cardiovascular therapy, and the anticipated top three over the next few years. Table 5 on page 6 lists the developments and technologies that were most often mentioned. Other emerging developments are expected to impact both surgeons and interventional cardiologists over the next three years. One of the biggest challenges for cardiac surgery over the next few years will be to develop methods to prevent post-operative adverse neurological outcomes. As compared with PTCA and stent patients, surgical patients continue to experience a higher rate of neurological deficits, creating a preference among patients for interventional treatment in spite of its proven higher re-intervention rate. The continued development of less-invasive surgical techniques, such as beating heart bypass, aided by the introduction of new technologies (e.g., automatic anastomosis devices), will help reduce adverse outcomes for surgery and improve patient acceptance.