CDU Contributing Editor

ANAHEIM, California – The annual meeting of the American College of Cardiology (ACC; Bethesda, MD), held here early last month, was attended by approximately 30,000 cardiologists, researchers, and industry representatives seeking to learn about the latest advances in the typically fast-moving field of cardiovascular care. While no major breakthroughs were announced at the conference, a number of incremental advances were described that are expected to drive the continued expansion of interventional cardiology, and perhaps create some new product segments in the market. Radiation therapy to prevent restenosis after angioplasty or stenting is one area of rapid progress, and it now appears likely that a major new product segment will emerge for these devices in the relatively near future. Considerable progress is also occurring in the use of adjunctive intravenous drug therapy in interventional procedures, particularly in the use of platelet inhibitors such as ReoPro, a drug developed by Centocor (Malvern, Pennsylvania); Integrilin, from Cor Therapeutics (South San Francisco, California); and Aggrastat from Merck Human Health (West Point, Pennsylvania). While the benefits of ReoPro have been demonstrated in many studies, the newer drugs promise to provide similar improvement in outcome at less than one-third the cost.

The use of coronary stents and PTCA is continuing to expand, although market growth has slowed because of heavy price competition. While the percentage of patients stented may not increase substantially from the current rate of about 70%, improved devices and adjunctive therapies should expand the range of patients who can be treated with interventional techniques. In particular, patients with chronic total occlusions, those with diseased saphenous vein grafts, and patients with bifurcation lesions may soon be treated via catheter techniques, using a combination of new devices along with systems for distal embolization protection to allow such lesions to be treated safely. Treatment of the inoperable patient is an area attracting increased attention, particularly as the number of such patients continues to grow because of population aging coupled with advances in vascular treatment that have allowed more patients to survive an initial cardiac event. At present, only about 3% to 4% of patients fall into the inoperable category on initial presentation, i.e., are not eligible for either CABG or PTCA. But the percentage rises to between 25% to 37% if one includes patients who have had prior treatment. Overall in the U.S., about 125,000 patients per year fall into the inoperable category, according to Jeffrey Popma, MD, of Brigham & Women's Hospital (Boston, Massachusetts), who discussed the topic at ACC.

Advances in imaging technology are also playing a role in driving growth in the cardiology marketplace. Cardiac MRI is one promising technique, allowing noninvasive measurement of myocardial perfusion and perhaps providing clinicians with a means to assess the degree of viability of myocardial tissues following an infarction. The technique can also allow determination of infarct size, allowing more accurate prognosis and helping to improve guidance of interventions. Invasive catheter-based imaging methods are also progressing, including techniques using miniaturized MRI coils at the tip of a catheter, as well as infrared and thermal mapping methods to guide catheter-based interventions and detect vulnerable plaque.

In the longer term, some revolutionary new developments may have a major impact in reducing the invasiveness of surgical treatments for cardiovascular disease. Robotic guidance of surgical bypass and heart valve repair and replacement may eventually allow more complex operations to be performed through small incisions, avoiding the morbidity of full open-chest surgery. A new technique under development by TransVascular (Menlo Park, California) called percutaneous in situ coronary venous arterialization (PICVA) has recently been performed for the first time in humans in clinical trials being conducted in Germany. The method could allow catheter-based treatment of a considerable number of patients who have limited options such as angiogenesis or transmyocardial revascularization, and could also allow revascularization of patients whose lesions are too severe or complex to be treated with existing catheters or stents. PICVA also may be a viable alternative to bypass in the future. Since PICVA employs the veins surrounding the heart as bypass conduits, the method could also allow bypass therapy to be offered to patients who no longer have suitable saphenous veins or internal mammary or other arteries that can be harvested.

Efficacy of beta radiation shown

A major advance in the field of radiation treatment for restenosis was announced by investigators who have evaluated the Beta-Cath technology under development by Novoste (Norcross, Georgia). In the START (Stereotactic Assisted Radiation Therapy) trial, which evaluated the use of beta radiation with the Novoste system in 476 patients at 50 sites, restenosis was reduced from 41% in control stented segments to 14% in the irradiated segments. Restenosis in the entire segment analyzed, including regions outside the stented segment, was reduced from 45.2% to 28.8%. The target vessel revascularization rate was reduced from 24.1% to 16%, and major adverse cardiac events were reduced from 25.9% to 18.0%. In contrast to some earlier studies with gamma irradiation, thrombosis in the irradiated region was not a major issue, in part because of the use of aggressive anticoagulation therapy. There were no cases of stent thrombosis in the radiation-treated group of patients who had new coronary stents placed throughout the follow-up period out to 270 days. A key characteristic of the patient population studied, according to Brigham & Women's Popma, was that it is considered to be representative of a typical population of patients who are treated routinely in everyday practice.

The results are essentially equivalent to those obtained in trials using gamma radiation for restenosis prevention, such as the GAMMA-1 and GAMMA-2 trials, as shown in Table 1. While results from different trials are never strictly comparable due to inevitable differences in the group of patients studied, the consensus among experts discussing intracoronary brachytherapy at the ACC gathering is that gamma and beta radiation treatment are essentially equivalent from a standpoint of efficacy and patient safety. The data indicate that, at a minimum, there is now a second viable radiation technology to help minimize restenosis after interventional procedures such as angioplasty and stenting. In addition, the reduced radiation shielding requirements for beta systems along with the shorter required treatment times (2 to 6 minutes vs. 15 to 45 minutes) may prove to be an advantage for many cath labs in adopting radiation technology. Facility remodeling is not required, and the physician can remain with the patient throughout the five-minute irradiation procedure. The Beta-Cath system is now available for sale in selected countries in Europe, as well as in parts of Asia, Australia, and New Zealand.

The field of radiation treatment appears poised for rapid expansion once products are approved by the FDA and introduced to the market. The potential market has been projected at between $500 million and $1 billion according to companies involved in the development of radiation treatment devices. A variety of systems are under development, as shown in Table 2 on page 4, employing numerous different technologies for delivering the radiation dose. In addition, other modalities including heat treatment with heated stents, the use of the Cutting Balloon, sonotherapy, anti-restenosis drugs delivered via coated stents, cryotherapy, and red light treatment are under evaluation. The goal in developing new anti-restenosis technologies is to further improve upon the patient outcomes now achieved with stents and PTCA, particularly in more difficult-to-treat patients with long or diffuse lesions. Effective anti-restenosis techniques may allow some patients to be treated with angioplasty alone who now require stents, and may also provide a significant reduction in in-stent restenosis, one of the more vexing problems with today's stent therapies. Furthermore, the technology may provide an incentive for cardiologists to treat certain patients using interventional techniques who now must undergo surgery because prospects for restenosis are too high.

Expanding use of interventional treatment

Expanding the range of patients who can be treated with interventional methods remains a key driver of the cardiology market. The treatment of chronic total occlusions is drawing considerable interest, as new technologies begin to enter clinical evaluation. For example, IntraLuminal Therapeutics (Carlsbad, California) is developing a forward-looking guidance and control technology for intravascular use that may allow safer and more effective opening of total occlusions. The IntraLuminal Safe-Steer TO Crossing System uses near-infrared light and optical coherence reflectometry to detect when the tip of the wire being used to cross a total occlusion begins to approach the vessel wall. According to the company, the primary problem faced by interventionists using guidewires, lasers, and experimental techniques such as ultrasound and RF to open total occlusions is the lack of precise guidance of the therapeutic device. The IntraLuminal technology differentiates between plaque, thrombus, blood, and arterial tissue using optical reflectance signals. When the signals indicate that the wall is being approached, the wire tip can be deflected either in a conventional manner or using a special steering feature to guide it back into the center of the vessel. As a result, the operator can use more aggressive technique with less concern about perforation of the artery. In the future, IntraLuminal plans to couple its guidance technology with other energy sources including RF, ultrasound, and other mechanical means. The guidance system has already been used successfully to guide laser recanalization of a total occlusion. A dedicated processor connects to the catheter to provide data readout.

According to IntraLuminal, 80% of interventional cardiologists and radiologists do not currently perform recanalization procedures on total occlusions because of the lack of ability to visualize the device's tip, and because existing diagnostic methods do not provide sufficient information to allow proper device selection. The company believes that the use of its guidance system can allow a large number of open surgical revascularization procedures to be replaced with interventional therapy, lowering patient cost and shortening hospital stay. U.S. launch of the Safe-Steer is planned for 4Q00, assuming marketing approval is obtained in the third quarter.

Another new technology for use in total occlusion therapy is the Sonicross device, under development by Guidant's (Indianapolis, Indiana) Advanced Cardiovascular Systems unit. The Sonicross uses 20 kHz ultrasound energy to create microbubbles inside the plaque occluding an artery. In initial studies described at the ACC conference by Louis Cannon, MD, of Brigham & Women's Hospital, an overall success rate of 42% was achieved in the treatment of total occlusions. While the investigators noted some problems with steerability and trackability of the Sonicross catheter that resulted in a failure to treat a number of occlusions, the benefit when the procedure is successful is that patients can be taken off multiple medications.

A second major category of patients that are difficult to treat with existing interventional devices is patients with diseased saphenous vein bypass grafts. Such patients comprise a steadily growing group, since about half of all surgically implanted vein grafts occlude within 10 years, and the number of coronary artery bypass graft procedures is continuing to increase. New devices continue to be developed for treatment of diseased grafts, including covered stents from companies including Jomed AB (Helsingborg, Sweden), fibrin-coated stents, and other stents with biocompatible coatings such as the BiodivYsio phosphorylcholine-coated stent from Biocompatibles International (Surrey, United Kingdom). The role of covered stents in the treatment of saphenous vein graft disease remains to be shown, and there are possible issues with debris that may be pushed free into the circulation upon stent expansion, as well as concerns about thrombosis. Protection devices are likely to play a major role in improving the safety of interventional treatment of saphenous vein grafts, as demonstrated in the SAFE study using the PercuSurge (Sunnyvale, California) GuardWire system. In this study of 103 patients, the rate of major adverse cardiac events was reduced from 17.8% to 4.9% using the PercuSurge device, and a procedural success rate of 95% was achieved. Other protection devices that may find applications in the treatment of saphenous vein graft disease are under development by AngioGuard (Plymouth, Minnesota), now a unit of Cordis/Johnson & Johnson; MedNova (West Sussex, United Kingdom); and Microvena (White Bear Lake, Minnesota).

However, a more important issue for treatment of diseased saphenous vein grafts is the demonstration that percutaneous techniques are beneficial in such patients. So far, no device has proven truly effective, and in fact, the most recent studies have indicated that percutaneous intervention alone will not provide a satisfactory outcome for most patients. For example, a study by Jean Marco, MD, of Pasteur Clinic (Toulouse, France), that employed the Boston Scientific (Natick, Massachusetts) Wallstent to treat diseased saphenous vein grafts found that about 60% of treated patients suffered a major adverse cardiac event (including death, myocardial infarction, or target vessel revascularization) at three years post-procedure.

Another approach that has received considerable attention for the treatment of patients who are not amenable to existing therapies is angiogenesis. A number of clinical trials are in progress evaluating the use of both protein factors as well as gene therapy to promote growth of new blood vessels. However, most recent studies with new angiogenesis therapies have not demonstrated a significant benefit, either using protein factors or gene therapy to promote blood vessel growth. Results of the FIRST trial, for example, that studied the effectiveness of recombinant fibroblast growth factor (rFGF) treatment in 337 patients failed to show a statistically significant increase in exercise time. Results of the study were described at ACC by Dr. Michael Simons of Beth Israel Deaconess Medical Center (Boston, Massachusetts) and Dr. N. Chronos of the Atlanta Cardiovascular Research Institute (Atlanta, Georgia). While there was a measurable benefit in patients with severe angina, there was no overall benefit, in part because there was not a large available margin for improvement in patients with low-grade angina, and there was also a significant placebo effect. The investigators believe that further study is warranted, particularly to investigate optimal routes of delivery of the drug.

An alternative approach to angiogenesis, using gene therapy rather than delivery of protein agents, is also being evaluated clinically. Dr. Jeffrey Isner of Beth Israel Hospital (Boston, Massachusetts) reported on a study in which the gene coding for vascular endothelial growth factor (VEGF 2) was directly injected into heart tissue. In the study, which involved 30 patients, 70% had a more than twofold improvement in angina class at 12 weeks. Exercise time increased by two minutes, and the number of angina episodes per week dropped from 31 to six. One death occurred in the treatment group, at 20 hours post-therapy. The trial was sponsored by Vascular Genetics (Durham, North Carolina), a company formed in collaboration with Human Genome Sciences (Rockville, Maryland). Results of another study of angiogenesis gene therapy, using an adenovirus vector to deliver a gene coding for fibroblast growth factor-4, were recently disclosed by Collateral Therapeutics (San Diego, California). The company is partnering with Schering AG of Germany and its U.S. subsidiary, Berlex Laboratories, in the development of its GENERX FGF-4 therapy. Although the results of the studies with GENERX pertain to only 67 patients, and only one group of 13 patients showed significant improvement, the company is moving forward with plans for a large-scale trial. In addition, there were no safety issues or adverse events directly associated with the therapy. Studies using gene therapy to treat cardiovascular disease face significant hurdles because of the scrutiny now being placed on all gene therapy studies in the wake of a widely publicized procedure-related death. The studies being conducted by Isner and Vascular Genetics are on hold while additional data, not related to safety or reporting issues, is prepared for submission to the FDA.

An important aspect of angiogenesis drug therapy, according to most investigators in the field, is the method used for drug delivery. Isner's group has used direct injection via a minithoracotomy, while the Collateral Therapeutics studies employed a standard coronary catheter. However, considerably more sophisticated methods are under evaluation, including the use of the Cordis (Miami Lakes, Florida) NOGA catheter guidance technology to aid in accurately positioning the delivery catheter at the desired treatment site for transcatheter delivery of angiogenesis agents. As discussed by Ran Kornowsky, MD, of the Washington Hospital Center (Washington), a 95% success rate has been achieved in studies of gene delivery with the NOGA catheter, a rate equivalent to that achieved with surgery. There is a great deal of variability in gene expression in spite of consistent gene delivery, but, in some cases, sustained expression has been observed for up to three weeks. While the results of trials so far do not show a significant effect, companies are continuing to invest in studying the technique because of the significant promise that the method holds for performing a wide variety of drug treatments.

New growth segments emerge

In addition to angiogenesis treatment, a number of other new approaches are under study that could evolve into major new segments of the cardiovascular device market. Advanced technologies being studied include instruments for performing PICVA using the coronary veins as bypass conduits. As discussed by Stephen Oesterle, MD, of Massachusetts General Hospital (Boston, Massachusetts), the first PICVA procedure was performed on a human patient in Germany about four months ago, after studies in pigs had shown improved survival using the technique to treat animals with acute occlusion of the LAD. Oesterle's group is using prototype devices developed by TransVascular. An advantage of the PICVA technique is that, as opposed to saphenous veins and various arterial conduits that are often afflicted by the same atherosclerotic lesions as the coronary arteries to be bypassed, the coronary veins are rarely diseased. Patients who can potentially benefit from the procedure include those who are candidates for various types of laser-based transmyocardial laser revascularization procedures; re-do CABG patients; patients with chronic total occlusions; and patients who are candidates for gene therapy. According to Oesterle, the PICVA procedure is not technically challenging. The interventionist only needs to cannulate the coronary sinus from the groin, a procedure performed routinely to insert electrocardiography catheters. However, considerable research remains to be performed before the PICVA procedure can be perfected. In particular, clinicians must learn more about the venous anatomy of the heart, a task that is complicated by the fact that the pig is not a good model in this case. TransVascular has been funded by Three Arch Partners, New Venture Capital Corp., and New Enterprise Associates.

Another product category that has recently emerged as a major new segment in the cardiology and radiology device market is vascular closure devices. New vascular closure devices continue to be developed, increasing the level of competition in the market for those products that is estimated at about $900 million worldwide in 1999, growing to $1.3 billion in 2000. As discussed at ACC by David Talley, MD, of the University of Arkansas Medical Center (Little Rock, Arkansas), it is estimated that about 7 million vascular closure devices will be used worldwide this year. The three major suppliers of closure devices – Perclose (Palo Alto, California), a subsidiary of Abbott Laboratories (Abbott Park, Illinois); Datascope (Montvale, New Jersey); and Kensey Nash (Exton, Pennsylvania) – all had estimated revenues of about $250 million worldwide in 1999 for closure products, according to Talley. So far, no one device has emerged as being clearly superior, since some complications have been reported with all of the commercially available devices, and time to stasis is similar. There is, however, a considerable difference in device cost, at least based on prices paid at Talley's institution, with the Angioseal from Kensey Nash being lowest at $180, Vasoseal from Datascope next highest at $195, and the Perclose device considerably higher at $325. However, when technical fees and other procedure-related costs are taken into account, the device cost becomes less of an issue. New closure devices are under development by Vascular Solutions (Minneapolis, Minnesota) and BioInterventional (Pleasanton, California), including the Vascular Solutions DUETT and the BioInterventional DISC-CLOSE-SURE. The DUETT may have some advantages in terms of improved deployment success rate, while the BioInterventional device avoids leaving foreign material behind in the body, but still requires some manual compression. In Europe, the BioInterventional device sells for about $100.

So far, studies with various vascular closure devices have shown reduced times to stasis and decreased time to ambulation as compared to conventional manual compression. However, there is as yet no data to prove that time to discharge from the hospital is reduced. Most patients tend to prefer the devices, mainly because of the more rapid time to ambulation and increased comfort, although quality- of-life questionnaires indicate that the perceived benefits disappear at 30 days post-procedure. Users have noted some issues with increased infections using the VasoSeal, and issues with vascular obstruction with AngioSeal. Furthermore, collagen-based closure devices may be less efficacious in patients receiving platelet inhibitors such as ReoPro, vs. other devices such as the DUETT that use thrombin to aid in promoting stasis. A significant advantage of all devices noted by users is that complications tend to occur immediately, and can thus be dealt with efficiently, whereas complications with manual compression usually occur at four hours or later post-procedure, when the patient has left the cath lab.

One new area of intense development activity involves drug-eluting stents, and stents with biocompatible coatings. An example of a coated stent that is already available outside the U.S. is the BiodivYsio coated stent. In addition, Cordis is developing a heparin-coated stent that has appeared promising in trials. Newer devices under development include paclitaxel-coated stents from Boston Scientific and Cook (Bloomington, Indiana), designed to reduce in-stent restenosis using the anti-proliferative effect of drugs. Paclitaxel has been shown to reduce smooth muscle cell proliferation and to reduce neointimal thickening. Some initial studies with paclitaxel derivatives that have an anti-microtubule effect have demonstrated a reduction in restenosis from 34% to zero, according to Campbell Rogers, MD, of Brigham & Women's Hospital, who discussed drug-eluting stents at the ACC gathering. Rogers believes that drug-eluting anti-restenosis stents will be available for use in the relatively near future. However, questions remain as to which patients will benefit from such devices. In diseased vessels post-treatment, the effectiveness of drug delivery is likely to be highly variable depending on the type of vessel being treated and the extent of vessel wall damage resulting from the stent procedure. Nevertheless, such devices can potentially allow a greater number of patients to be treated with interventional techniques.

Another segment of the cardiovascular device market that continues to witness new product innovation is devices for thrombus removal. Results of initial U.S. clinical studies with the X-Sizer device from EndiCOR Medical (San Clemente, California) were presented at ACC by Thomas Ischinger, MD, of Klinikum Bogenhausen (Munich, Germany). The X-Sizer is a new device used for removal of thrombus from coronary arteries and saphenous vein grafts using vacuum-assisted aspiration and a rotating helical cutter. The device can be deployed through an 8 Fr guide over .014" wires. In the 14-center trial with the X-Sizer, 72% of treated patients had thrombus and 35% had in-stent restenosis. An overall success rate of 64% was observed for the X-Sizer device. The overall procedural success rate was 93%. The percent stenosis was reduced from 88.1% to 11% when the device was used in conjunction with balloon angioplasty and stenting. The device was considered to be simpler to use than the TEC extraction catheter, a similar device from InterVentional Technologies (San Diego, California). EndiCOR is planning to move forward with expanded clinical studies, and to develop smaller devices with diameters ranging down to 1.5 mm.

Another new device, the Helixcision catheter from Prolifix Medical (Sunnyvale, California), was described at ACC that may prove useful in the treatment of in-stent restenosis. The Helixcisor Catheter is a 1.5 mm device with a cutter that rotates at 17,500 rpm, with internal aspiration of tissue contents. The device includes a shielded housing over the tip to avoid disruption of stents. The 6 Fr-compatible device is guided to the lesion over the Heli-Trac Guidewire, a nitinol wire with a helical shape. In animal studies, the area stenosis was reduced from 67% to 37%, and all pigs had TIMI 3 flow post-procedure. No tissue re-growth occurred at one-month follow-up. Human clinical studies are planned for later this spring. The device can be used in any type of stent, but at present there is no data regarding its use for applications other than treatment of in-stent restenosis, e.g., for treatment of native arteries.

New catheter-based techniques for improved diagnosis of coronary artery disease are also under development. While intravascular ultrasound has established a niche in the market, there remains a need for technologies that can help to provide more detailed information on plaque composition to help guide treatment methods. In particular, there may be considerable value in technologies that can allow the identification of plaque that is vulnerable to rupture. One new device described at ACC by Morteza Naghavi, MD, of the University of Texas, is a thermosensor catheter fabricated from nitinol to allow mapping of temperature profiles on the inner surface of a blood vessel. The sensing element is configured as a basket formed from four hollow nitinol wires, each containing two thermistor sensors. The wires expand once released from the 3 Fr catheter's lumen and make contact with the vessel wall. The device can map temperature with a 0.5 mm spatial resolution, and is intended to be low in cost. Previous studies by Naghavi's group have shown that inflamed unstable plaques give off more heat than stable plaque or normal tissues, allowing plaques to be identified that are vulnerable to rupture.

In animal studies, the catheter detected temperature heterogeneity in vessels with lesions, and no complications were observed due to the use of the device. The catheter is designed to allow blood flow during the measurement procedure, avoiding potential discomfort for the patient, but necessitating corrections to the temperature readings for changes in blood flow. A new version is under development that will combine the temperature mapping catheter with IVUS imaging, allowing the use of IVUS imaging to help identify suspect areas, followed by temperature mapping to determine if the plaque is vulnerable to rupture. While such devices may not find routine applications in the cath lab, they may prove valuable for the study of plaque characteristics to provide new information that will allow patients who are prone to MI to be identified as part of a diagnostic catheterization procedure.

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