CDU Contributing Editor

CHICAGO, Illinois – The annual conference of the American Heart Association (AHA; Dallas, Texas), held here in mid-November, addressed a wide range of topics related to cardiovascular disease, and it often serves as a forum for presentation of technologies that will shape the future of diagnosis and therapy. At this year's conference, there was strong interest among physicians who treat heart disease in the use of minimally invasive therapies for conditions that, until recently, have been treated exclusively by surgery, and in particular in devices that allow non-surgical treatment of patent foramen ovale, atrial-septal defect and carotid artery stenoses. Diagnosis of coronary artery disease also is beginning to be revolutionized by increasingly powerful non-invasive imaging technologies that promise to reduce or perhaps eliminate the use of diagnostic angiography.

On the other hand, catheter-based methods for vulnerable plaque detection, particularly those employing optical methods, may emerge as a major new segment of the cardiology device market, allowing interventionalists not only to treat identified lesions with high efficacy using drug-eluting stents, but also to find and treat developing lesions in other vessels during the same procedure that otherwise could cause recurrence. Advances in genomic analysis, in vitro testing and physiological monitoring also were described at the AHA conference, promising significant improvements in the ability to identify at-risk patients at an early stage, where disease is most treatable.

Another area attracting considerable interest is the use of biotechnology techniques such as tissue engineering for the treatment of cardiovascular disease. One topic highlighted at the AHA conference was the use of tissue-engineered blood vessels in coronary artery bypass graft procedures, an approach that could prove life-saving for patients who lack suitable autologous vessels and that, if perfected, could potentially reduce the invasiveness and morbidity associated with routine coronary bypass surgery. Such technologies also may prove valuable in the treatment of peripheral vascular disease. Other applications include the replacement of today's prosthetic devices such as pacemakers with bioengineered versions, and repair of failing cardiac tissues with implanted cells to restore the heart's ability to pump blood. The wide range of new developments demonstrates that the market for products used in the management of cardiovascular disease remains one of the most dynamic in the medical device industry.

Tissue engineering, cell transplant therapy

As shown in Table 1, the use of surgical bypass to treat coronary artery disease is declining both because of the expanding capabilities of transcatheter therapy and also because of improved medical therapies, particularly statin drugs, that are helping to prevent the development of advanced coronary artery disease. The number of patients undergoing a CABG procedure dropped almost 3% per year on average from 1995-2000, while the total number of grafts implanted (essentially all of which are autologous grafts derived from the patient) dropped almost 4% a year. A similar declining trend in bypass procedures is occurring for peripheral vascular bypass, although not for grafts implanted for dialysis access. In spite of the decline in procedures, almost 1 million coronary bypass grafts are implanted each year in the U.S. A development-stage device for use as an alternative to autologous grafts for coronary bypass, which also has potential applications in peripheral vascular bypass and dialysis access, was described at the AHA conference by privately held Cytograft Tissue Engineering (Novato, California). According to Cytograft, the market opportunity for prosthetic vascular grafts for those applications totals at least $5 billion in the U.S. alone.

Cytrograft's Todd McAllister, MD, said the company is developing a technique that starts with a postage stamp-sized skin biopsy from the patient. The skin cells are cultured over a period of 14 weeks to create a sheet of cells that is then fitted around a stainless steel cylinder to form a tubular structure. A second layer of cultured endothelial cells derived from animal veins is then formed on the inner lining to make a two-ply structure that can be used as a blood vessel. The use of the patient's own cells plus the lack of use of a scaffold to direct cell growth are key factors in avoiding an immune response when the graft is implanted, according to Cytograft. While animal cells now are used as the endothelial cell source, the long-term strategy is to use cells derived from blood, according to McAllister. So far, grafts implanted in animals have exhibited no clots or occlusions at 90 days, and surgical handling characteristics are positive. The company plans human trials in 12 to 18 months.

The technology clearly would not be applicable to patients requiring immediate surgery but would be appropriate for patients who lack sufficient autologous vessels for bypass who are able to wait for their cells to be cultured. About 20% of all CABG patients have too few or no autologous saphenous veins for use in bypass procedures. Conservatively, the market for such a device is about 200,000 to 250,000 units annually in the U.S.

Peter Lamm of the University of Munich (Munich, Germany) described a similar technology to fabricate grafts for use as alternatives to autologous veins or arteries. Lamm's technique uses cryopreserved allografts, available from suppliers such as Cryolife (Kennesaw, Georgia), seeded on the inner lumen with autologous endothelial cells harvested from the patient. The harvesting process uses high-pressure flow through a vein of the donor to extract endothelial cells, which are then cultured for two to three weeks. The resulting construct is equivalent to saphenous veins in burst strength and exhibits a level of platelet activation that is equivalent to normal arteries, vs. synthetic materials such as ePTFE that produce a two-fold higher level of activation. A study involving implants in 23 patients resulted in patency of 87% at three months, vs. 67% for autologous veins. The researchers expect to achieve 60% to 70% patency at one year.

Another application of tissue engineering described at the AHA conference is bioengineered heart valves. Carlos Ruiz, MD, of the University of Illinois-Chicago, described studies using a low-profile valve employing an acellular structure fabricated from small intestinal submucosa (SIS) that can be placed percutaneously. In studies conducted in pigs, the SIS is remodeled in vivo by growth of autologous cells following implant. A stainless steel wire and spring-like coil are used to help form a valve with the proper dimensions with sufficient strength to allow initial implant. Subsequently, cells populate the structure to form a valve that can persist in vivo and that does not generate immune rejection. Other studies using heart valves implanted via transcatheter techniques were described by Eleftherios Sideris, MD, of the Athenian Institute of Pediatric Cardiology (Athens, Greece). The studies have only been conducted in animals so far, with a short (one week) follow-up. However, the principle of the method has been demonstrated in studies using piglets, and future versions will be aimed at demonstrating applications in humans.

Cell transplant therapy for the treatment of heart failure is another emerging application that has now been under investigation for at least two years. Nabil Dib, MD, of the Arizona Heart Institute (Phoenix, Arizona) described the results of a program conducted in the U.S. in collaboration with Diacrin (Charlestown, Massachusetts) to study the safety and feasibility of autologous myoblast transplantation in patients with ischemic cardiomyopathy. The study involved 16 patients with previous myocardial infarction, all with an ejection fraction of less than 30%. Cells were extracted from skeletal muscle, cultured for three to four weeks, and injected into the damaged regions of the patients' hearts. Ten million cells were contained in each injection, and between one and 30 injections were given to each patient. The success rate for cell transplant was 100%, and viable cells were detected in the scar tissue via MRI and PET imaging. Only one patient exhibited an irregular heartbeat. A number of other researchers have also begun to investigate cell transplants for treatment of heart failure, including a group led by Manuel Galinanes, MD, of the University of Leicester (Leicester, UK); a team led by Christof Stamm, MD, of Rostock University (Rostock, Germany); and Philippe Menasche, MD, of Hopital Bichat (Paris).

Menasche began studies using cell implants in animals seven years ago, and was the first to perform human cell implants to treat heart failure. He has continued to achieve promising results with the technique. Using implants of myoblast cells derived from skeletal muscle in the leg, Menasche has achieved a 60% improvement in cardiac function in patients with ischemic heart muscle damage, whereas the improvement that can be obtained using conventional revascularization techniques is only about 30%. The improvement in function is due in part to remodeling of cardiac tissue, but the most important factor is increased contractility that results from engraftment of cardiac myotubes that couple electrochemically with cardiomyocytes. Another aspect of the procedure is use of Insulin Growth Factor 1 (IGF-1) to stimulate recruitment of stem cells which differentiate into cardiomyocytes to supplement the implanted cells. Menasche's team is now conducting a Phase II clinical study in the U.S. and Europe that should be completed in about two years.

Galinanes and Stamm both described techniques using implantation of bone marrow cells into damaged cardiac tissues to restore heart function. In studies conducted by Galinanes at the University of Leicester, autologous bone marrow cells are injected into scar tissue in patients with significant levels of angina. Improvement in heart wall motion is observed, but the improvement is only achieved if the cell transplant is combined with a bypass graft procedure to improve blood circulation to the damaged region of the heart. While the initial studies involving 14 patients have demonstrated safety of the technique, a more comprehensive trial will be needed to demonstrate efficacy. Stamm described similar experiments on a group of 11 patients at Rostock University, but with the addition of a selection process using the C133 cell surface marker to select stem cells from bone marrow. Improved contractile function was observed in eight of the patients, with another patient only treated two weeks prior to the AHA meeting and thus too early to evaluate. Some patients were at 15 months post-treatment with no recurrence of symptoms, and, significantly, no indication of heart rhythm problems as have been observed in some studies (e.g., those conducted by Menasche) using skeletal muscle cell transplants. Stamm theorized that the cell selection process used in his studies could be a factor in helping to avoid arrhythmias, but he also noted that scar tissue is a known risk factor for arrhythmia, and the effect of injecting cells into such tissues has not been extensively studied. An important aspect of cell transplant therapy for the repair of damaged heart tissue is that the technique, particularly when used in conjunction with angiogenesis, may allow treatment of regions of the heart that cannot be accessed via bypass surgery or percutaneous intervention.

Other researchers are exploring the use of engineered cell sheets for implants to treat heart failure. As discussed by Gabriel Amir of Sheba Medical Center of Tel Hashomer, Israel and Tatsuya Shimizu of Tokyo Women's Medical University (Tokyo) at the AHA gathering, tissue-engineered grafts can be produced by seeding cells onto various types of scaffolds, and in animal experiments it has been shown that the grafts can develop contractile properties about four weeks following implant and beat in synchrony with the native heart. Furthermore, the area of the sheet increases over time. Piero Anversa, MD, of New York Medical College (Valhalla, New York), and many other researchers in the field, have recently shown that stimulation with growth factors, and particularly with IGF-1, can augment cell transplant therapy and enhance the repair process.

Another approach to managing patients with ischemia-induced tissue damage is to use tissue preservation technology to prevent or minimize the loss of cell function. As described by Richard Kitsis, MD, of Albert Einstein College of Medicine (New York) at AHA, agents have recently been identified that can inhibit the enzymes, known as caspases, that cause apoptosis or cell death, and that can potentially be used to limit tissue damage in myocardial infarction or to retard the loss of viable myocardium that is characteristic of heart failure. A drug identified as IDN6734 has been used by Ketsis in studies in mice to achieve a 50% reduction in infarct size at seven days, with sustained improvement. In heart failure, a study of a mouse model of virulent cardiomyopathy using the compound to retard cell loss produced a modest to moderate improvement in cardiac function and resulted in no deaths in 20 animals vs. six in the control group. In order to determine if such compounds can prove useful in humans, there is a need to move to a larger animal model.

As a result of the increasingly promising research results with tissue engineering for treatment of heart failure and other cardiovascular diseases, a number of companies are now actively pursuing development of biotechnology products for those applications. As shown in Table 2, programs are underway to develop new types of vascular grafts for coronary bypass at companies including CardioTech International (Woburn, Massachusetts), Cell Lining GmbH (Berlin, Germany), Tepha (Cambridge, Massachusetts) and Cytograft, while studies of cell transplants for treatment of ischemic cardiomyopathy are being pursued by Diacrin. GenVec (Gaithersburg, Maryland) is developing its Biobypass technology, an angiogenesis approach that is showing promise compared to others that have used different vectors or angiogenesis agents. However, according to Duncan Stewart, MD, of St. Michael's Hospital (Toronto, Ontario), who has conducted studies with Biobypass, there are still some adverse events associated with the minimally invasive surgical procedure used to deliver the agent, making it desirable to switch to transcatheter delivery for future development.

While the programs being pursued by such companies look promising at present, the field of tissue engineering faces a number of hurdles in becoming established as a commercially viable segment of the cardiovascular device market. Most importantly, recent bankruptcy filings by Advanced Tissue Sciences (La Jolla, California) and Organogenesis (Canton, Massachusetts), the first companies to introduce tissue-engineered products in the U.S. market, have demonstrated the difficulty of penetrating the emerging market while maintaining financial viability. While sales for both companies were increasing (Organogenesis' sales more than doubled in 2001 to $8.2 million and increased 37% vs. the prior-year quarter in 1Q02), the costs of manufacturing and selling the products resulted in substantial losses, at least under the contract arrangements the companies had established with their respective marketing partners, Smith & Nephew plc (London) and Novartis AG (Basel, Switzerland). Organogenesis subsequently regained those rights from Novartis.

As companies move forward to commercialize the products now under development for cardiovascular applications, strategies for manufacturing, marketing and distribution that provide a rapid return on investment will be key to success. A focus on those applications where the technology offers a high degree of added value, such as treatments that help reduce the burdensome high costs of long-term management of heart failure, is likely to prove successful. Conversely, high-cost tissue-engineered solutions for replacing autologous vessels in vascular bypass procedures may find only limited acceptance, being reserved for a relatively small proportion of patients with no other options.

Use of interventional techniques expands

Interventional treatment of cardiovascular disease also attracted considerable attention at the AHA conference. Many companies, including Boston Scientific (Natick, Massachusetts), Avantec Vascular (San Jose, California), Abbott Laboratories (Abbott Park, Illinois), Guidant (Indianapolis, Indiana), Medtronic (Minneapolis, Minnesota) and a number of companies based outside the U.S. continue to pursue Cordis/J&J (Miami Lakes, Florida), the leader in drug-eluting stents, to develop competitive devices.

Avantec is one of the more recent entrants in the race, with a drug-eluting stent using mycophenolic acid (MPA) as the active agent. MPA is the active metabolite of mycophenolate mofetil, a drug approved in 70 countries and sold under the brand name CellCept by Roche Pharmaceuticals (Nutley, New Jersey) for immunosuppressive therapy. The drug is loaded in a proprietary polymer coating less than five microns thick formed on the company's Duraflex coronary stent, a device that is not yet approved for sale in the U.S. In a study involving a total of 132 patients, a group of 50 that received an implant of the high-dose version of the device had no revascularization events at 30 days, although there were two myocardial infarctions in that group. Overall, the initial safety data with the device is promising, according to researchers, with low rates of adverse events and no subacute thrombosis.

Blue Medical Devices (Helmond, the Netherlands) described a stent now undergoing evaluation in the NOBLESSE trial in Brazil that uses a bioabsorbable coating comprised of amino acids and fatty acids that elutes a nitric oxide preserving compound. The goal is to foster normal behavior of the vessel following stent implantation. At 60 days follow-up, the first 18 patients treated with the device were free of major adverse coronary events. The key advance is development of a method to preserve nitric oxide in the tissues, since nitric oxide is impossible to deliver with conventional drug-eluting techniques, according to the company.

Drug-eluting stents will certainly provide a significant advance in the efficacy of minimally invasive therapy for coronary artery disease. However, the products may encounter a barrier to adoption, due to high cost. At an AHA session on drug-eluting stents, David Cohen, MD, of Beth Israel Deaconess Medical Center (Boston, Massachusetts), described a detailed cost/benefit study of the devices. Using 1999 data from the Center for Medicare & Medicaid Services (CMS; Baltimore, Maryland), Cohen calculated that restenosis increases one-year average medical costs for patients who receive a stent by $1,850 per year, which is less than the expected incremental cost for a drug-eluting stent of about $2,000.

Cohen concluded that it is unlikely that drug-eluting stents will prove to save costs except for patients at high risk for restenosis (e.g., diabetics). However, they may prove cost-effective for the majority of the population if all factors are taken into account because of improved quality of life and reduced needs for additional procedures. Cost benefits also may accrue as a result of converting patients to percutaneous intervention who are now treated with bypass surgery. In addition, if the total (not incremental) cost for drug-eluting stents could be reduced to between $2,000 and $2,300, the devices could prove cost-effective for all patients.

While drug-eluting stents for coronary applications, and perhaps for some additional applications in smaller-diameter peripheral vessels, represent the highest-profile market opportunity, a number of other interventional product segments were highlighted at the AHA conference that promise to expand the scope of the market and create opportunities for suppliers. Atritech (Plymouth, Massachusetts) exhibited its development-stage device for performing the Percutaneous Left Atrial Appendage Transcatheter Occlusion (PLAATO) procedure. Appriva Medical (Sunnyvale, California), now part of ev3 (White Bear Lake, Minnesota), already has launched its X-Caliber device in Europe for use in the PLAATO procedure. The Appriva device uses 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, and which can subsequently be released resulting in embolic stroke. The new device from Atritech uses a filter rather than a plug to block the left atrial appendage. It consists of a nitinol frame covered by a PET membrane. Human trials with the device have just been initiated in Germany.

Ension (Pittsburgh, Pennsylvania) is developing another new device for performing the PLAATO procedure. The device is placed percutaneously using a port access device from Guidant married to an endoscope. A study to assess ease of placement of the device in pigs was described by David Schwartzman, MD, of the University of Pittsburgh (Pittsburgh, Pennsylvania). Deployment was easy, with consistent occlusion observed. While the device needs to be downsized for human use according to Schwartzman, it shows promise for use in percutaneous occlusion.

A number of companies exhibited development-stage devices for closure of atrial-septal defects. NMT Medical (Boston, Massachusetts), developer of the CardioSEAL and STARFlex septal occlusion systems, is performing studies comparing drug therapy with device therapy, as part of its program to obtain FDA approval for use of the devices in closure of atrial-septal defects and PFOs. The FDA already has approved the CardioSEAL for non-surgical closure of ventricular septal defects. W.L. Gore (Flagstaff, Arizona) is developing the HELEX Septal Occluder, and is in the process of completing clinical studies with the device. Microvena (White Bear Lake, Minnesota) is developing a next-generation version of its Angel Wings Atrial Septal Defect Occluder, the Guardian Angel.

Carotid artery stents represent another segment of the interventional device market that appears very promising, based on the results of recent studies described at the AHA conference. Companies developing carotid stents include Cordis (the PRECISE stent), Guidant (the AccuLink Carotid Stent) and Boston Scientific (the NexStent). MedNova Ltd. (Galway, Ireland) is developing the Exact stent and a nitinol stent is being developed by Medtronic for carotid applications. Jay Yadav, MD, of the Cleveland Clinic Foundation (Cleveland, Ohio), described results of the Stenting and Angioplasty with Protection in Patients at High Risk for Endarterectomy (SAPPHIRE) trial, which enrolled 749 patients over three years at 30 institutions. The trial used embolic protection filters (the AngioGuard from Cordis) and the Cordis PRECISE stent. According to Yadav, emboli occur during 80% of all carotid stenting procedures, making protection devices mandatory for treatment. The trial showed a clear benefit in reducing death, strokes and myocardial infarction for patients treated with stenting vs. carotid endarterectomy (5.8% vs. 12.6% at 30 days). About 200,000 patients per year undergo carotid endarterectomy in the U.S. In addition, patients who do not undergo surgery but who have carotid stenosis could benefit from stent treatment, including those at high risk for surgery as well as those with less severe lesions for whom the risk of surgery cannot be justified.

Major revolution in diagnostic techniques

Although significant advances clearly are being made in therapy for cardiovascular disease, diagnostic techniques also play an important role and are similarly undergoing rapid evolution. Non-invasive imaging technologies such as X-ray computed tomography (CT) and MRI are advancing in capability, and are now poised to begin replacing angiography for initial diagnosis. According to GE Medical Systems (Waukesha, Wisconsin), 30% to 50% of catheterization procedures are for diagnosis. As shown in Table 3, about 1.6 million diagnostic coronary angiography procedures were performed on hospital inpatients in the U.S. in 2000. There are also a significant number of outpatient procedures performed: for the most recent year for which data is available (1996), 605,000 procedures, or about 28% of all coronary angiography procedures, were performed on outpatients. Furthermore, more than 1 million PTCA/stent procedures are performed annually on hospital inpatients, although as shown in the table the number of patients who undergo a procedure is less.

In total, the number of cardiac catheterization procedures performed annually in the U.S. is estimated at 3.4 million by suppliers of radiology equipment. There is some degree (about 1%) of risk of an adverse event associated with angiography, and reimbursement levels are low. GE Medical reported advances in cardiac CT at the AHA sessions that promise to allow diagnosis of coronary artery disease to be performed non-invasively using its eSpeed EBT Scanner as well as its LightSpeed CT System. The key advance is the development of high-speed CT imaging, allowing an image to be acquired in 30 milliseconds vs. 100 to 250 milliseconds for other CT systems. As a result, the eSpeed system can eliminate blurring of the image due to the heart's motion, even for patients with rapid or irregular heartbeats.

An evaluation of 25 patients who had a stenosis detected via the eSpeed scanner showed that all had a detectable lesion when examined by conventional angiography. The eSpeed system costs more than $2 million, compared with somewhat more than $1 million for an angiography system. However, the hospital can realize an offsetting benefit by replacing low-paying diagnostic catheterization procedures with interventional procedures in the cath lab. Another advantage of the eSpeed system is that the X-rays can be triggered from the patient's ECG so that they are only produced during a portion of the cardiac cycle, lowering the X-ray dose to the patient.

Other suppliers of non-invasive imaging systems also described technological advances at the AHA meeting. Siemens Medical Solutions (Forchheim, Germany) exhibited the Somatom Sensation cardiac CT system, a 16-slice unit that can produce a 0.5 mm resolution coronary image in less than 20 seconds. A study published in the Oct. 15 issue of the journal Circulation showed that the Sensation produces results that are essentially equivalent to diagnostic angiography. The results are also comparable to those that can be achieved with IVUS, according to Siemens. Some 150 of Siemens' 16-slice CT systems have now been installed worldwide at an average selling price of $1.4 million.

Vulnerable plaque detection technologies were also an area of focus at the AHA conference. A number of companies, including Volcano Therapeutics (Laguna Hills, California), Medispes (Zugi, Switzerland), Thermacore Medical Systems (Leuven, Belgium) and LightLab, a unit of ev3, are developing devices for vulnerable plaque detection. In addition, promising results using a miniaturized beta probe to detect vulnerable plaques were described by Ahmed Tawakoi of Massachusetts General Hospital (Boston, Massachusetts). The beta probe, manufactured by IntraMedical Imaging (Los Angeles, California), detects 18F-deoxyglucose, which preferentially deposits in inflamed atherosclerotic plaques. The compound is infused into arteries prior to the imaging procedure. A 1.6 mm-diameter catheter consisting of an optical fiber coupled to a miniature scintillator is used to image plaques. Studies of lesions induced in rabbit arteries demonstrated that the system could accurately detect macrophage-rich plaques.

However, perhaps the most promising technology for vulnerable plaque detection is optical coherence tomography (OCT). The technology can detect and identify macrophages, and can localize them in a high-resolution image. Image resolution is 10 microns, about 10-fold better than IVUS, according to developers of the technology. A study described by Ik-Kyung Jang, MD, of Massachusetts General Hospital and sponsored in part by Guidant used an IVUS catheter modified to perform OCT imaging in 80 patients. The researchers were able to determine the thickness of fibrous caps in arterial lesions, and could also segment plaques into types they classified as stable, lipid-rich and ruptured. There were no complications related to use of the OCT device. LightLab's OCT imaging system is about to be launched in Japan, and will feature a .014" imaging wire. The device uses infrared light, and will cost about the same as an IVUS catheter. The system also includes the capability to fill the lumen to be imaged with saline. LightLab also is pursuing applications in cancer detection and microscopy.

Mark Webster, MD, of Green Lane Hospital (Auckland, New Zealand) described a study using the Volcano Therapeutics thermography catheter for vulnerable plaque detection. The catheter uses five thermocouples to map the temperature of the vessel wall to detect local hot spots that are believed to be indicative of vulnerable plaque. In Webster's studies, conducted in nine patients undergoing PCI, both local and diffuse temperature elevations were observed, perhaps reflecting the presence of both local and diffuse inflammation. Higher temperature was often not associated with angiographic lesion sites. There were no adverse events associated with the thermography catheter.

Glenn Van Langenhove, MD, of Middelheim Hospital (Antwerp, Belgium) described another study using a thermography catheter, the ThermoSense catheter from Thermacore Medical Systems. The device has four nitinol arms that expand when a sheath is removed to force thermocouples against the vessel wall. An automatic pullback feature insures that the tips of the arms are not forced to penetrate the tissue. A total of 33 patients were studied with the catheter. As with the Volcano device, no correlation was observed between angiographic features and thermography. The device proved safe to use, however, and the company plans to apply for a CE mark.