CDU Contributing Editor

Synthetic vascular grafts, used as alternatives to autologous vessels in bypass procedures and for dialysis access, represent an established, although relatively small, market worldwide. According to Alan Tuchman, MD, of Oscar Gruss & Son (New York), an analyst who follows the segment, the worldwide market for artificial vascular grafts totals between $110 million and $120 million. At present, synthetic grafts are employed only in peripheral vascular applications, and are used in about 60% of dialysis access procedures and about half of all peripheral vascular bypass procedures, according to product suppliers. In patients with arterial stenosis, synthetic bypass grafts are employed for patients who lack suitable autologous vessels, or in cases where it is desired to avoid the increased invasiveness and potential morbidity associated with harvesting of autologous vessels.

Recently, there has been a revived interest in development of artificial bypass grafts for coronary applications, driven in part by promising results of initial clinical studies using a new device from Thoratec Laboratories (Pleasanton, California). Another company that has recently announced initiation of development of a new synthetic graft for coronary applications is CardioTech International (Woburn, Massachusetts). In addition, a number of companies are conducting early-stage research with tissue-engineered vascular grafts with potential applications in coronary artery bypass. A successful graft would address a potential market valued at $1.2 billion to $1.5 billion worldwide by participants in the field, and could revolutionize cardiac bypass surgery if long-term patency actually exceeded that of autologous tissue grafts.

Another revascularization alternative that may find application in treatment of failed autologous bypass grafts or as a less-invasive option for peripheral vascular therapy is endovascular grafts, comprised of synthetic grafts combined with stents to allow transcatheter, rather than open surgical treatment. Such devices are being evaluated in treatment of femoro-popliteal and carotid artery stenosis; for salvage of diseased saphenous vein coronary bypass grafts and treatment of perforation, rupture, aneurysm, and fistula in the coronary circulation; for treatment of aneurysms in the iliac, carotid, and subclavian arteries; and for treatment of diseased aortas. Such devices may be particularly valuable for patients who are poor surgical candidates, or those who desire less-invasive treatment.

New technologies for coronary bypass grafts

In spite of the continued growth in use of stents and angioplasty for coronary revascularization, a substantial number of coronary artery bypass procedures are performed, although the number appears to be declining. As shown in Table 1, 367,000 patients were discharged with a coronary artery bypass graft (CABG) procedure in 1996 according to the National Center for Health Statistics. But the total number of patients has dropped somewhat since then. On average, each procedure requires 3.2 grafts, for a total of perhaps one million grafts placed each year in the U.S. at present. Based on pricing for existing grafts and stents, most suppliers estimate that synthetic coronary bypass grafts would sell for about $2,500. If, as developers anticipate, 20% of all bypass patients are potential candidates for use of a synthetic graft, the market opportunity in the U.S. is $500 million, and the worldwide opportunity is at least twice that size.

In May, Thoratec reported that it had received investigational device exemption approval from the FDA to begin the AEGIS/U.S. clinical trial for the ARIA coronary graft device, a synthetic graft based on the company's Thoralon biomaterials technology. Thoratec had previously received approval for a similar clinical study in Canada, the AEGIS/Canada trial that will enroll up to 330 patients at 10 Canadian hospitals. The first implant in the Canadian trial was completed in November 1999, and a two-month assessment of the first patient performed by perfusion scan was normal. During the past six years, the ARIA graft has been used in 27 patients in Canada and Europe on a compassionate use basis, and to the company's knowledge all surviving patients have remained symptom-free during that time. The U.S. trial will include up to 150 patients recruited at up to 15 centers. Thoratec hopes to pool data from the U.S. and Canadian trials to reduce the total number of patients required in each trial.

The Thoralon technology employed in the ARIA graft uses a base polymer of BPS-215 polyurethaneurea and a proprietary surface modifying additive that is blended with the polymer during fabrication. After fabrication, the additive migrates to the surface to create a surface that is compatible with blood and body tissues. As compared with other synthetic materials, clot formation has been shown to decrease from 45 mm to zero using Thoralon. Another key aspect of the use of synthetic vascular grafts is the thrombogenicity of the anastomosis between the graft and the native tissue. In animal studies using the Thoralon graft, the anastomosis has remained clear, indicating that clot formation at the anastomosis may not be an issue with the ARIA device. Thoratec is pursuing a phased approach in the AEGIS trials, beginning the studies at only two centers in the U.S. and assessing patients at two months, and then using the two-month data to file an amendment to the IDE for the remaining enrollment at up to 15 centers. Patients will be followed up with angiography at one year after receiving the graft, and the company hopes to receive an expedited six-month review by the FDA.

The CardioTech graft, trade-named CardioPass, will be constructed of the company's patented ChronoFlex polyurethane, which has been shown to be biodurable after three years of canine implantation. The device also exhibits compliance similar to that of human saphenous vein, and serves as a scaffold that is populated with endothelial cells after implantation, providing improved biocompatibility. In April of this year, CardioTech announced an initiative to develop CardioPass, and has already begun recruiting patients for clinical studies in Europe and Asia. That same month, CardioTech introduced a line of peripheral vascular products in Europe, the VascuLink grafts, primarily for use in dialysis access. Distributors have been appointed in most countries in Europe, as well as in Turkey and Australia.

Other companies involved in the development of new synthetic coronary artery bypass grafts, according to analysts, include W.L. Gore (Flagstaff, Arizona) and C.R. Bard (Billerica, Massachusetts). However, Thoratec is the only company that has progressed to clinical trials in the U.S. There also are a number of companies that hope to use tissue engineering technology for coronary bypass devices, with the goal of achieving further improvements in long-term biocompatibility. With synthetic grafts, most suppliers are aiming to show performance equivalent to autologous bypass grafts. Studies have shown that 12% to 20% of saphenous vein grafts used in coronary artery bypass typically occlude within the first year, and about 2% to 4% occlude each year thereafter. For the internal mammary artery, patency rates are significantly better, at approximately 91% at one year and 88% at eleven years. Since, as suggested by the data in Table 1, a larger proportion of CABG procedures are employing IMA grafts, performance requirements are increasing on average. However, if tissue-engineered grafts could show better performance than autologous vessels, the opportunity could be perhaps five times greater than for synthetic grafts now under development, or as much as $2.5 billion in the U.S. Clearly, if engineered grafts allowed the patient to avoid graft harvest, while also providing improved long-term patency, there would be no reason not to switch to the use of engineered devices for all coronary bypass procedures.

Companies developing tissue-engineered grafts for coronary applications include Advanced Tissue Sciences (La Jolla, California), Organogenesis (Canton, Massachusetts), Cell-Lining GmbH (Berlin, Germany), BioNova International (North Melbourne, Australia), and Ramus Medical Technologies (Santa Barbara, California). Ramus Medical is the furthest along in development, having started clinical trials with the Rapidgraft device in Europe. Ramus is in the initial stages of starting U.S. trials. None of the companies have stated that their graft will outperform autologous vessels, but tissue-engineered devices may at least provide performance equivalent to autologous vessels. However, these products are further away from market launch than are synthetic grafts.

The demand for artificial grafts, whether synthetic or tissue-engineered, may grow as an increasing proportion of procedures are performed using minimally invasive techniques. Between 15% and 20% of all CABG procedures in the U.S. were performed using minimally invasive techniques in 1999. As minimally invasive surgery advances, harvesting of autologous vessels becomes the most invasive part of the procedure, increasing the attractiveness of synthetic grafts. On the other hand, competing catheter-based techniques are obviously having a negative impact on CABG usage, and emerging technologies such as percutaneous in situ coronary venous arterialization, which is under development by TransVascular (Menlo Park, California), or angiogenesis using growth factors or gene therapy, could further reduce demand for conventional CABG. However, surgical bypass has the advantage of a long history of success, which may favor its continued use by the traditionally conservative medical community.

Dialysis access applications

Most companies involved in developing synthetic or tissue-engineered bypass grafts for coronary bypass are also evaluating devices for use in peripheral applications. Table 2 presents an overview of trends in dialysis procedure volumes in the U.S., indicating recent growth in use. A number of synthetic dialysis access grafts are already in widespread use, supplied by companies including W.L. Gore, Boston Scientific (Natick, Massachusetts), Bard Vascular, and Horizon Medical Products (Manchester, Georgia). New products under development using advanced biocompatible materials, such as Thoratec's Thoralon and CardioTech's ChronoFlex, are primarily aimed at improving ease of use and patency.

For example, the Thoratec Vectra graft has the advantage of accessibility within one day of implantation, while other synthetic grafts require many weeks before being used. Vectra is approved for sale in Japan, Canada, and Australia, and clinical trials of the device were initiated in the U.S. in February 2000. As of December 1999, more than 7,000 patients had been successfully implanted with Vectra access grafts. The product will be distributed by Guidant (Indianapolis, Indiana) worldwide except in Japan. The CardioTech VascuLink graft is a self-sealing device, providing a time to hemostasis of three minutes vs. five to 30 minutes with other grafts. Studies have shown that the graft reduces complications due to infections, which could result in major cost savings for patients with end-stage renal disease. An initial study with the VascuLink conducted in Turkey found that nine of 13 grafts remained patent at six months.

Additional revascularization alternative

While synthetic grafts fabricated from new biocompatible materials, or developed using tissue engineering technologies, promise advances in the ability to surgically treat patients with coronary artery and peripheral vascular disease, endovascular grafts also have emerged as a major new technology for revascularization as well as for repair of various vascular lesions including aneurysms and trauma-induced perforations and dissections. The primary application so far is for treatment of abdominal aortic aneurysm (AAA). At least 10 major suppliers of cardiology and interventional radiology devices are developing various types of endovascular grafts, and two – Medtronic (Minneapolis, Minnesota) and Guidant – have obtained FDA approval for devices used in the treatment of AAA. Forecast sales of endovascular grafts in the U.S. market are presented in Table 3.

Applications in revascularization still are under development, with mixed results. Studies described at the annual meeting of the Society of Cardiovascular and Interventional Radiology using the Boston Scientific Wallgraft and the Gore Hemobahn in the treatment of arterial lesions and femoro-popliteal stenosis reported 100% initial success rates, but long-term patency was low (48% at 28 months with the Wallgraft, and 45% six months with the Hemobahn). Re-occlusions occurred primarily outside of the stented region, however. The JoMed coronary stent graft from JoMed AB (Helsingborg, Sweden) has been applied to the treatment of saphenous vein graft disease in CABG patients, as well as in the treatment of perforation, rupture, aneurysm and fistula, and for aneurysms in the iliac arteries. However, for treatment of most stenoses in the coronary and peripheral vessels, conventional angioplasty and stents are the preferred treatment modality, and results are continuing to improve with the development of improved stents tailored for specific applications (e.g., for complex coronary lesions, carotid stenosis, and renal artery stenosis). As a result, endovascular grafts will probably play a niche role in primary revascularization, but will prove valuable in the treatment of patients with damaged vessels, where additional support and physical integrity of the vessel wall is needed.

Peripheral vascular applications

While synthetic grafts also have applications in the treatment of peripheral vascular disease, the main focus of most developers outside of coronary artery bypass remains in the area of dialysis access. In part, this is due to the declining utilization of surgical bypass for peripheral vascular disease, as less invasive transcatheter methods increasingly become the preferred treatment modality. Surgical bypass procedures have been declining over the past few years, while alternative percutaneous angioplasty and stenting procedures have increased over the 1995-1998 period, although dropping slightly in the most recent year for which data is available based on trends in the Medicare population. Stents are being used in an increasing proportion of peripheral revascularization procedures. In 1999, for example, an estimated 70% of the 62,240 iliofemoro-popliteal procedures performed in the U.S. used stents, and the percentage is continuing to increase. Since outcomes are continuing to improve with stenting, and such procedures lead to lower rates of morbidity than bypass surgery, the opportunity for synthetic grafts in peripheral bypass is declining. However, because synthetic grafts also help to lower morbidity by eliminating the need for harvesting of autologous vessels, synthetic devices could help to maintain the use of surgical treatment for patients with more severe peripheral vascular disease.