CDU Contributing Editor

Treatment of coronary artery disease has typically involved a choice among the three primary therapeutic modalities: Medical therapy, percutaneous intervention or coronary artery bypass surgery. Medical therapy, involving lifestyle changes as well as pharmaceutical agents, is prescribed for about 45% of all patients who require treatment, while percutaneous intervention is now selected for about 40% of patients. The remaining 15% of patients are treated with bypass surgery. However, there is some overlap between the treatment groups, since many patients treated with percutaneous intervention and surgery also receive medical therapy to help prevent recurrence of disease. An emerging hybrid form of therapy involves a combination of percutaneous and surgical treatment. That approach may become more widely used in the future as outcomes for percutaneous treatment continue to improve, approaching those achievable with surgery, with bypass reserved for only those lesions that are difficult or impossible to treat with stents or balloon angioplasty.

Another major segment of heart disease treatment involves external and implantable devices for support of failing hearts, such as left ventricular assist devices, bi-ventricular assist devices, temporary right ventricular assist devices, and total artificial hearts. Paracorporeal devices already are available for long-term support of patients with advanced heart failure, and implantable devices for temporary use are also on the market. Advances are continuing in the development of totally implantable long-term support devices, with companies such as Abiomed (Danvers, Massachusetts), World Heart (Ottawa, Ontario), Arrow International (Reading, Pennsylvania), MedQuest Products (Salt Lake City, Utah), MicroMed Technology (Houston, Texas), Thoratec (Pleasanton, California) and A-Med Systems (West Sacramento, California) achieving promising results in clinical trials. The next generation of treatments for heart failure may make such devices obsolete, however, through techniques that allow heart function to be restored via tissue engineering technology. Early-stage trials have shown that muscle cells can survive transplantation into the heart and not be rejected by the body.

In the meantime, the prevalence of heart failure is reaching epidemic proportions, requiring shorter-term measures that, while not promising to cure the condition, may nevertheless allow significant improvements in outcome, perhaps allowing patients to remain alive until newer treatments reach the market. For example, a number of companies are introducing systems that allow heart failure patients to be monitored in the home in real time using audio, video and data transmission links. A number of companies are now offering monitoring services targeted at CHF patients, and the market opportunity is likely to continue to increase as better treatment methods are developed.

Advances in percutaneous intervention are expected to play an increasingly important role in patient treatment. Treatment modalities such as drug-eluting and drug-coated stents, antirestenosis drugs, sonotherapy, cryotherapy and brachytherapy may all play a role in improving patient outcomes and in expanding the applications of interventional therapy. However, experts still predict that about 15% to 20% of patients who cannot be treated with medical therapy alone will require surgical treatment, perhaps in combination with percutaneous intervention.

Hybrid therapy an emerging option

Patients who require intervention to treat occlusive coronary artery disease have commonly been treated with percutaneous therapy (i.e., balloon angioplasty or stents) if their disease is localized and the affected vessels are not completely blocked by a chronic total occlusion. While multiple sites can be treated, percutaneous intervention works best if the lesions are focal, and if they are not located in critical regions such as the left main coronary artery. For patients with more diffuse, complex coronary artery disease, or those who have disease in the left main coronary artery, surgical bypass is typically selected. It is not uncommon for patients to have both surgery and percutaneous intervention over the course of a number of years, since new lesions may develop that require use of different treatment alternatives. Most recently, however, physicians have begun to treat some patients using a hybrid approach, that is, the concerted use of both surgical and percutaneous intervention, to reduce the invasiveness and associated morbidity of bypass surgery while still achieving the maximum degree of revascularization.

Table 1 shows trends in heart surgery procedures over the 1989-1999 period, demonstrating that bypass procedure complexity has decreased somewhat in recent years. For example, quadruple bypass surgery procedures have dropped from 19.3% to 9.8% of the total, while triple bypass procedures have dropped from 21.5% to 18.9%. Quadruple bypass procedures also declined in absolute number over the period, from 71,000 to 56,000, according to the National Center for Health Statistics. Over the same period, single bypass procedures, including single internal mammary-coronary artery bypass procedures, have increased from 36.7% to 48.9% of the total.

The decline in more complex procedures is probably due in part to the growth in utilization of minimally invasive coronary artery bypass surgery, which now accounts for about 20% of all coronary artery bypass procedures. According to surgeons who perform such procedures, about 1 to 1.5 fewer bypass grafts are used in off-pump, beating-heart coronary bypass surgeries, since it can often prove difficult to access all regions of the heart through the smaller incision used in beating-heart surgery. In addition, because of increasing improvement in outcomes for patients treated with advanced coronary stents, some types of lesions can be treated as successfully with stents as with bypass surgery. For example, outcome for stented lesions in the right coronary artery and in the circumflex artery is usually equivalent to that for bypass, and in-stent restenosis is very rare, in the range of 2% to 3%.

As a result, some institutions are using hybrid treatment, wherein a patient is first treated with percutaneous intervention, allowed to recover and possibly improve in status for a few days or weeks, and then return for a minimally invasive bypass procedure to complete the revascularization process. In some cases, a stent procedure may be performed on an emergency basis for a patient suffering a myocardial infarction, followed by bypass a few weeks later. Some centers in Europe are using an opposite hybrid approach, first performing minimally invasive Port-Access surgery, followed by percutaneous intervention at least three days later. Cost of the hybrid approach may not be significantly different from conventional bypass surgery, however. Although length of stay for the surgical procedure is usually about one day less for hybrid treatment, particularly in older patients over the age of 60, the added stay to perform a stent procedure may negate any savings. The hybrid approach is attractive for younger patients with major disease in some vessels and less severe disease in another vessel. In that case, the use of minimally invasive surgery, combined with percutaneous intervention, allows all lesions to be treated while avoiding the potential long-term complications of conventional open-heart surgery.

Some surgeons are continuing to advance the state-of-the-art of off-pump surgery to allow more complete revascularization to be performed. Robotic bypass surgery is one approach that has attracted some interest. As described by Dr. Randall Wolf, MD, of the University of Cincinnati (Cincinnati, Ohio) at a recent conference on Controversies in Cardiac Surgery sponsored by Promedica International (Huntington Beach, California), a variety of new technologies are helping to make robotic surgery more effective. Originally, the goal was to use robotic surgery to allow a bypass procedure to be performed completely via endoscopy. The first totally endoscopic robotic CABG procedure was performed in 1998. However, the introduction of beating heart surgery techniques caused most surgeons to lose interest in endoscopic CABG. More recently, the development of new imaging technologies has greatly improved visualization for robotic surgery, previously an important limitation of the technique. The technique, termed Video-Assisted Coronary Artery Bypass, or VADCAB, also uses a new ultrasonic scalpel that does not risk application of electric currents to the heart, and that can be used for all required incisions, making the procedure more efficient. Suppliers of robotic surgery systems include Intuitive Surgical (Mountain View, California) with the Aesop and Computer Motion (Santa Barbara, California) with the Zeus Telemanipulator System. Computer Motion is now working on a two-robot system that allows even more complex procedures to be performed robotically.

Another important advance that promises to enhance procedural success, improve long-term outcomes and expand the range of procedures that can be performed via minimally invasive CABG techniques is the development of automated anastomosis devices. Companies developing that technology include Jomed AB (Helsingborg, Sweden), St. Jude Medical (St. Paul, Minnesota), the Cardiovations unit of Ethicon/Johnson & Johnson (Somerville, New Jersey), Ventrica (Fremont, California) and Guidant (Indianapolis, Indiana). A related technology using a stent conduit, the VStent, is under development by Pericardia (Merrimack, New Hampshire).

The Jomed Solem GraftConnector is intended for use during beating-heart procedures, and allows a sutureless anastomosis to be completed off-pump in less than one minute. Human clinical trials with the Solem device were initiated in August in Finland. Jomed also is developing a catheter-based device for performing percutaneous valve repair. St. Jude's Symmetry Aortic Connector was originally developed by Vascular Sciences, a company that was acquired by St. Jude in September 1999. The Aortic Connector is the first component in the Symmetry family of minimally invasive surgical devices and provides sutureless anastomosis between a saphenous vein graft and the aorta with no cross-clamping or side-biting during deployment. The Aortic Connector features an arrow tip that is used to mechanically puncture the aorta. A rotating shaft then is driven in along the path of the arrow tip to create a clean opening. The harvested graft is then everted over a second shaft, and the assembly is pushed in to force the Connector in where it locks into the aorta, completing the anastomosis.

The Cardiovations device does not require placement of the entire graft over a shaft as do other devices. Clips are used to attach the graft to the aorta, and a punch is used to puncture the aorta and create an opening. Ventrica's connector employs perhaps the most innovative design. The Ventrica system is designed to shunt blood directly from the left ventricle. Two magnets are attached to each vessel, with a total of four magnets used to perform a typical anastomosis. One magnet is attached to the inside of a vessel, and a second is attached to the outside, with the vessel wall sandwiched between the two. For example, a magnet pair can be attached to both the aorta and to the saphenous vein or internal mammary artery graft. The graft can then be locked in place by positioning its magnetic rings over the opposing rings on the aorta. The unique shape of the rings and the magnetic properties of the material automatically ensure exact alignment. An anastomosis can be completed in less than two minutes. More than 200 procedures have already been performed in animals, and clinical trials are now under way in Europe.

The market opportunity for anastomosis devices is substantial: An estimated 5.1 million anastomoses are performed annually worldwide in coronary artery bypass patients. The total number of grafts implanted per year is stable or perhaps declining slightly in the U.S., but worldwide the expected growth in the older segments of the population, along with increasing incidence of coronary artery disease as well as the growing availability of surgical treatment in developing countries, is expected to drive continued increases in demand. In fact, by 2020, statistics presented at the September conference of the European Society of Cardiology (Sophia Antipolis, France) in Stockholm, Sweden, indicate that 80% of deaths from cardiovascular diseases will occur in low- and middle-income countries. Though ability to pay will continue to limit the dollar volume market opportunity in many regions, strong growth in unit volume should create an attractive long-term market opportunity.

A related opportunity exists for artificial vascular grafts for use in coronary artery bypass, since one of the most invasive aspects of bypass procedures is graft harvesting. The current leader in development of such devices is Thoratec (Pleasanton, California), now in clinical trials in the U.S. with the Aria coronary artery bypass endoprosthesis. CardioTech International (Woburn, Massachusetts), acquired by Thoratec this year, also has been pursuing the development of artificial vascular grafts for coronary applications. A total of 19 patients have received implants of one or more Aria grafts in a Phase I study conducted at six centers, and the company has submitted a supplement to its approved IDE to enroll an additional 91 patients in a Phase II study in a total of 20 centers. According to Thoratec, the Phase I data was encouraging and demonstrated safety and effectiveness of the Aria device.

Use of bypass surgery, however, is increasingly being challenged by advances in percutaneous interventional technology. Major new developments in coronary stenting, most importantly drug-eluting stents, are expected to allow an even higher percentage of patients to be treated percutaneously. Not only are major suppliers such as Cordis (Miami Lakes, Florida), Boston Scientific (Natick, Massachusetts) and Guidant making progress with drug-eluting and drug-coated stents, but many emerging suppliers are developing advanced stents, particularly in Europe. Key emerging suppliers of coronary stents include Clearstream Technologies Ltd. (Wexford, Ireland), Terumo Medical (Tokyo), Translumina GmbH (Hechingen, Germany), AMG GmbH (Raesfeld-Erle, Germany) and Orbus International BV (An Hoevelaken, the Netherlands). Clearstream has developed a new coronary stent that the company believes is equivalent to the Cordis BX Velocity in terms of trackability, flexibility, and conformity, but that will be priced at about $500 to end users. The stent is supplied premounted on the TrackForce high pressure semi-compliant catheter, and offers a low crossing profile of 1.1 millimeters. Terumo has recently developed the Tsunami Coronary Stent System that uses a coating, similar to that used in the company's Glidewire, to reduce friction at the catheter tip, along the distal shaft and at the interface between the balloon and the stent in the undeployed configuration, allowing improved access in tortuous lesions.

Transluminal's Curare stent system employs a 316 LVM stainless steel stent that features bends in each strut to enhance mechanical flexibility while retaining high radial force. Use of a PTFE-coated hypotube catheter enhances vessel access, and a polyamide semi-compliant balloon is employed. The company was founded in the fall of 2000, and released its first products in May. The premounted Curare stent system is priced at DM 1,300 (about $650) in Germany. Orbus has established a significant position in the stent market in Europe and Latin America with the R Stent. The device is priced at about $1,000 in Europe (for a premounted version) and more than 20,000 have been implanted worldwide. AMG has developed the Arthos Inert stent system, a coronary stent that is fabricated using a special process that blocks ion diffusion at the stent surface, specifically addressing the problem of nickel, chromium and molybdenum elution, which the company believes may help to avoid inflammatory or allergic reactions to the device.

The combination of continued improvements in stent design, coupled with major recent advances in anti-restenosis drugs that can be used in conjunction with stents, portends continued expansion in the use of percutaneous intervention. While surgical bypass techniques are also advancing, for now the conversion to less-invasive surgical methods for coronary bypass appears to have stalled at around 20% to 25% of total CABG patients in the U.S. Some centers, such as the Washington Hospital Center (Washington), have seen a significant decline in the use of minimally invasive coronary artery bypass surgery recently, due to disappointing results with the technology. The number of off-pump procedures performed at Washington Hospital Center increased from 1,500 in 1996 to 1,800 in 1998, but procedure volume has since dropped steadily to a projected level of 1,200 for 2001. That trend is not universal throughout the U.S., but nevertheless indicates that minimally invasive CABG may not completely displace open-heart bypass. Overall, current trends indicate that an increasing proportion of patients will be treated with percutaneous intervention, including a number that will be treated with hybrid percutaneous/surgical therapy.

Advances in heart replacement, augmentation

Another segment of the cardiovascular device market attracting considerable investment is devices for support or replacement of failing hearts. The growing prevalence of congestive heart failure, now affecting an estimated 22.5 million worldwide as shown in Table 2, is driving increased demand for devices and new methods to treat the condition.

External and combination external/implanted support devices are now marketed by a number of companies, and considerable progress has been made in artificial heart technology. Leading suppliers of left ventricular assist devices include Thoratec, World Heart and Abiomed. The Thoratec HeartMate Left Ventricular Assist System is the leading device, with more than 2,800 implants in 22 countries. The Thoratec Ventricular Assist Device, which can be used for left, right and bi-ventricular support, is used in over 190 centers worldwide. World Heart now markets the Novacor Left Ventricular Assist system, acquired from Baxter Healthcare (Deerfield, Illinois). 1,200 patients have received implants of the Novacor LVAS. World Heart also is developing the HeartSaver Ventricular Assist Device, a completely implantable system for long-term ventricular support. About half of the 900 hospitals in the U.S. that perform open-heart surgery have purchased the Abiomed BVS5000 cardiac assist system.

The market opportunity for heart support and heart replacement devices is substantial, both in the U.S. and worldwide, based on the number of patients in need of treatment. One of the most promising approaches is to combine left ventricular assist devices (LVADs) with agents such as beta blockers and catecholamines, and possibly with newer drugs such as vasopeptidase inhibitors, cytokine modulators and endothelin antagonists. Two other circulatory support devices, the A-Med PARAFlow and A-Syst Systems, are used for right heart support and have proven particularly valuable in patients undergoing beating heart surgery. The A-Med devices have been used in more than 1,000 patients worldwide. One surgeon, Dr. Jerry Kelley, of South Texas Cardiothoracic Surgical Associates (San Antonio, Texas), was able to increase the percentage of patients who could be treated with beating-heart surgery from the 50%-55% range up to 95% by using the PARAFlow system.

There has been considerable progress recently in the development of totally implantable artificial hearts and support devices. Leaders in that race include Abiomed, Arrow International, MicroMed Technology (Houston, Texas) and World Heart. Good results have been obtained so far with Abiomed's AbioCor heart. The fourth implant of the AbioCor implantable replacement heart was completed last month (see Business Developmentss, page 10), and all patients continue to survive. Another device, the World Heart HeartSaver VAD, continues to perform well in initial studies. The Arrow LionHeart, a completely implantable device, has been used in 12 patients. Two primary types of devices are in development: Pulsatile systems that mimic the natural pumping function of the heart and non-pulsatile systems, exemplified by the Jarvik 2000, Thoratec's Heartmate II and the DeBakey VAD from MicroMed Technology. The latter firm recently received a CE mark for the DeBakey VAD for use in Europe as a bridge to transplant for CHF patients. Pulsatile systems include the LionHeart and the HeartSaver.

A new approach to restoring heart function, cardiac cell transplantation, also is beginning to show promise. Sources of cells include skeletal muscle, used in the first human transplants to be performed; human embryos (a very controversial source in the U.S.); umbilical cord blood; peripheral blood; and bone marrow. Myocytes from bone marrow have been shown to respond when exposed to environmental stimulus, and to become functional cardiac cells, while embryo cells do not. One company that is actively pursuing cell transplant therapy for the treatment of heart failure is Bioheart (Weston, Florida). Bioheart's MyoCellCF treatment for congestive heart failure is in preclinical development in partnership with Dr. Daniel Burkhoff at Columbia University (New York). The company also is developing cell-based therapies for the treatment of myocardial infarction and angina. In addition, a product called MyoGene, which uses growth factors and other additives to enhance efficacy, is in preclinical development in partnership with Dr. Stephen Ellis of the Cleveland Clinic Foundation (Cleveland, Ohio). The Bioheart myocardial implant procedure starts with autologous cells derived from the patient, either in the form of myoblasts or bone marrow-derived stromal cells. The cells are then cultured and expanded, followed by delivery to the damaged portion of the heart using surgical and percutaneous endovascular techniques.

Other companies developing cell transplantation techniques for treating damaged myocardium include Diacrin (Charlestown, Massachusetts), now in Phase I trials with a technique using skeletal muscle cells for cardiac transplant; Genzyme Biosurgery (Cambridge, Massachusetts), in early-stage development with a ventricular restoration product using cell implants; Osiris Therapeutics (Baltimore, Maryland), in animal studies with a technique featuring human mesenchymal stem cells; Geron (Menlo Park, California), in early stage development with human embryonic stem cell therapy; and Collateral Therapeutics (San Diego, California), in preclinical research with gene therapy technology for heart muscle regeneration.

Improved outcome in CHF

New technologies for diagnosis and monitoring also promise improved outcomes for CHF patients. A new venture created by Agilent Technologies (Palo Alto, California), now part of Philips Medical Systems (Best, the Netherlands), uses remote monitoring technology to allow CHF patients to be tracked in their own homes so that changes in disease status can be detected sooner and corrected before hospitalization becomes necessary. The technology is being implemented in the U.S. as well as in Europe.

As of September, about 300 patients were involved in a trial program using the Agilent home monitoring system in Germany, the UK, and the Netherlands, with plans to expand the trial to 500 patients. The system uses an electronic scale to monitor body weight, along with monitors for blood pressure, pulse rate and single-lead ECG. The monitoring devices connect to a Home Hub via a wireless interface, and data is transmitted from the home to a clinician in a central facility via regular telephone lines. Agilent plans to offer the service for a fee of about Euro 150 per month. The current trial is intended to generate cost-effectiveness data showing savings due to reduced hospitalization costs, convincing insurers to provide coverage for the technology.