CDU Contributing Editor

PARIS Europe often serves as the launch ground for new interventional device technologies due to the less time-consuming regulatory approval process and the propensity for European physicians to embrace changes in medical practice. Drug-eluting stents first entered the interventional device market in Europe, with the launch of the Cypher stent from the Cordis (Miami Lakes, Florida) unit of Johnson & Johnson (New Brunswick, New Jersey), followed by the Taxus stent from Boston Scientific (Natick, Massachusetts). As discussed by presenters at the annual EuroPCR conference, held here in May, a number of new stent technologies are now in development that will transform the interventional device market in Europe, and eventually the markets in the U.S. and worldwide.

New developments in drug-eluting stents may result in a reshuffling of the market leaders in Europe, and will expand the use of interventional techniques at the further expense of surgical treatment, including both bypass graft surgery and valve surgery, and allow treatment of patients who now lack effective options. Experts such as Antonio Colombo, MD, of the EMO Centro Cuore Columbus and San Raffaele Hospital (Milan, Italy), predict that eventually only the most difficult cases will be left for surgery.

Based on trends in data from European registries of stent procedures, the number of percutaneous interventional procedures in Europe is expected to reach 700,000 in 2005. New developments are also driving expanded use of device-based therapy for peripheral vascular disease, opening up additional market opportunities. Advances in diagnostic technologies were also described at the EuroPCR conference that will guide more effective use of new device therapy and aid in identifying individuals who will benefit from treatment.

Advances in drug-eluting stent technology

As shown in Table 1 below, the European market for drug-eluting stents totaled almost $670 million in 2004, and is projected to expand to almost $1.2 billion by 2009. Unit volume will grow even more rapidly due to continued declines in selling price as more players enter the market. In addition, as increasingly complex lesions are treated with drug-eluting stents, the number of stents used per patient has increased from 1.2 just a few years ago to 2.2 now. The ratio of percutaneous interventional procedures to surgical bypass for treatment of coronary heart disease is now three to one in Europe, according to data from the most recent Euro Heart Survey conducted by the European Society of Cardiology (Sophia Antipolis, France).

Table 2 demonstrates that a number of new drug-eluting stent suppliers are poised to enter the market in Europe with technologies that address shortcomings of existing devices including elimination of potentially inflammation-inducing polymer materials, complete elution of drugs, promotion of endothelial cell growth on the stent and reduced propensity for thrombosis. However, most of the suppliers developing new drug-eluting stents are not significant players in the interventional device market in Europe at present. The drug-eluting stent market in Europe has two primary competitors at present Boston Scientific and Cordis.

Leading cardiologists such as Patrick Serruys, MD, of the Thoraxcenter (Rotterdam, the Netherlands), have predicted that percutaneous intervention will replace surgery for all but a few patients, and the trend in Europe is certainly in that direction. Trials such as ARTS I and II have shown equivalent outcomes for patients with complex coronary artery disease treated with percutaneous intervention and CABG. Furthermore, Serruys estimates that in actual practice, interventional cardiologists are treating a third of all patients with multi-vessel and main stem disease.

In the Netherlands, less than 10,000 CABG procedures are now performed annually, whereas percutaneous interventional procedures continue to increase. The market is expected to expand as improved devices are introduced that allow stenting of more complex lesions, smaller and more tortuous vessels, and high-risk lesions. Treatment of in-stent restenosis, chronic total occlusions, and bifurcation lesions with high success rates is also expected to become routine with drug-eluting stents.

Unique drug-eluting stent and related technologies described at the EuroPCR conference include the Paccocath drug-delivery catheter from Meomedical GmbH (Augsburg, Germany). The Paccocath is not a stent, but instead is a PTCA catheter with a balloon that can be coated with paclitaxel, the same drug used in the Taxus drug-eluting stent. Upon inflation, the drug is released over a 60 second interval, infusing the vessel wall with drug while also eliminating stenosis. A particularly promising application for the device is treatment of in-stent restenosis, since elastic recoil is less of an issue and the drug may act to prevent a recurrent stenosis. The ISR I trial, discussed by Bruno Scheller, MD, of the University of Saarland (Homburg, Germany), at the EuroPCR conference, is the first clinical study using the Paccocath. At six-month follow-up of 25 patients treated with the device who had diffuse in-stent restenosis, the restenosis rate dropped from 40.9% in a control group to 8.7% in the group treated with the Paccocath. The target lesion revascularization rate dropped from 24% to 0%. The performance of the device was somewhat better than has been observed when using drug-eluting stents such as Taxus and Cypher to treat in-stent restenosis. Importantly, animal studies using the Paccocath have not revealed any evidence of inflammation at the treatment site, an effect that has been observed with drug-eluting stents and is believed to be related to interaction of the stent's polymer coating with the vascular tissue.

Another unique technology for use in drug-eluting stents was described by Christophe Bureau, PhD, of Alchimer SA (Massy, France). Alchimer has developed a nanoscale technology for engineering of metal surfaces that uses electrografting to build a surface polymer layer rather than coating. There is effectively no limit to the type of polymer that can be used. Advantages of the Alchimer technology include complete release of drugs loaded into the surface layer, lack of delamination, and the ability to load multiple compounds into the layer, such as hydroxyapatite to promote endothelial cell colonization of the metal surface.

A variety of other approaches are in development aimed at improving the performance of drug-eluting stents. Conor Medsystems (Menlo Park, California) is developing a stent with hundreds of small holes in the surface that can be loaded with a drug and then covered with a polylactic glycolic acid coating. The coating is fully metabolized following implant, leaving no residual polymer or drug. As discussed at the conference by CEO Frank Litvack, MD, initial data using the device in the EuroSTAR trial is promising, with very low (0.26 mm) late loss and no late thrombosis observed at six months in 845 patients. There have been no late thrombosis events in patients who have stopped taking plavix, supporting the concept that complete elimination of a polymer resolves the thrombosis issue with drug-eluting stents.

Another advantage of the Conor stent design is the ability to use essentially any drug without the need to modify a polymer coating. Although paclitaxel has been used in the EuroSTAR trial, the company is evaluating multiple drugs, including pimecrolimus, an anti-inflammatory agent; midostaurin, which inhibits protein kinases and extracellular matrix synthesis associated with vascular endothelial dysfunction; and imatinib, an anti-proliferative agent. All three drugs have been licensed from Novartis (Basel, Switzerland). In one configuration, an anti-inflammatory drug has been combined with an anti-mitotic agent in the Conor stent, with each drug having independent release kinetics. In animal studies, the company has observed the lowest restenosis rate ever reported. Another application involves addition of a drug to promote tissue perfusion in a stent for use in myocardial infarction patients. Such a device could potentially provide both improved salvage of myocardial tissue in heart attack patients as well as improved long-term patency of the culprit vessel following treatment.

A unique approach using gene-eluting stents was discussed by Douglas Losordo, MD, of Tufts University School of Medicine (Boston), at EuroPCR. A stent using coated stent technology developed by Biodyvisio has been designed to elute the vascular endothelial growth factor II (VEGF-II) gene, in an attempt to promote angiogenesis and thereby enhance healing of the endothelium after stenting. In initial clinical studies, a higher level of circulating endothelial progenitor cells has been measured, and the stent appears to inhibit both restenosis and thrombosis.

Abbott Vascular (Redwood City, California), which introduced a dexamethasone-eluting stent in Europe early in 2003, is now developing the Trimaxx stent, which features very thin (0.003") struts covered with a thin layer of tantalum for improved visibility, and a coating that elutes ABT-578, an anti-proliferative drug with similarities to sirolimus. Studies in animals have indicated that the Trimaxx elicits less neointimal hyperplasia than Cypher, but the differences are not statistically significant.

Sorin Biomedica Cardio (Saluggia, Italy) is developing the Janus drug-eluting stent that uses the company's non-polymeric drug-elution technology and tacrolimus, or FK506, a compound from Astellas (Tokyo). The drug is contained in sculpted reservoirs on the stent's surface, eliminating the need for a polymer coating. In addition, the stent platform is Sorin's Tecnic carbostent, which features a unique carbon film coating over the stainless steel stent to improve biocompatibility. That approach offers numerous advantages, including the ability to perform direct stenting due to the lack of a polymer coating, directional release of drug into the vessel tissue, and low thrombogenesis based on the properties of the carbon coating. The Janus stent was cleared for marketing in Europe in October 2004, and now has an estimated 5% share of the market, Sorin said, with implants in more than 10,000 patients worldwide. In the JUPITER II trial involving a total of 332 patients with moderately complex lesions, an 11.8% restenosis rate has been observed at six-month follow-up, and no thrombosis events have been observed.

Technologies broaden patient pool

Drug-eluting stents, as well as other advanced technologies for vascular intervention, are driving an expansion of the market by allowing a wider range of patients to be treated. For example, patients with chronic total occlusions (CTOs) were until recently not candidates for percutaneous intervention, because of the inability to safely penetrate the occluded region with a guidewire in most cases and generally poor results with bare metal stents if the lesion was crossed and stented. Now, as discussed by Colombo at EuroPCR, a number of new dedicated guidewires and guidance devices have been introduced that have enabled most CTOs to be successfully treated, with good outcomes.

Dedicated guidewires favored by Colombo for use in crossing CTOs include the Choice PT, Dasher and Fast Dasher from Boston Scientific, the Mirage from Microtherapeutics/ev3 (Plymouth, Minnesota), the Shinobi from Cordis and the Cross-It and Whisper wires from Guidant (Indianapolis). In the most difficult CTOs, devices such as the Frontrunner catheter from LuMend (Redwood City, California) or the Safe-Cross from Intraluminal Therapeutics (Carlsbad, California) can help in crossing the lesion. A new wire for crossing CTOs was introduced recently by Brivant Medical Engineering (Galway, Ireland). Brivant's CTO wire, priced at EUR 70, requires less force to penetrate an occlusion than wires such as the Cross-It, and remains straighter as it traverses the lesion. The market opportunity for devices used in the treatment of chronic total occlusions is estimated at $1 billion by suppliers. According to Intraluminal Therapeutics, 2.3 million of the 7.6 million patients who undergo coronary and peripheral diagnostic procedures annually have one or more CTOs.

Patients with diffuse coronary artery disease represent an even more difficult population for treatment than those with CTOs. As discussed by A. Jain, MD, at the conference, 12% to 22% of patients undergoing revascularization in countries in Europe, such as the UK, have poor outcomes due to diffuse coronary artery disease. A number of technologies are being evaluated for use in treating such patients, including stem cell therapy as well as mechanical revascularization techniques. Jain described a new device that will soon be evaluated in animal studies, the Percutaneous Arterio-Venous Endo Stent (PAVES). The device is similar to one developed by Transvascular (Menlo Park, California), a company acquired by Medtronic (Minneapolis) in 2003, which employs the coronary venous system (the Thebesian venous system in the case of the PAVES device) as an alternative means of supplying blood to poorly perfused regions of the heart. According to Jain, the PICVA revascularization system developed by Transvascular exhibited a low success rate because of the inability to accurately image the coronary veins: only two of 11 patients treated with the device could be revascularized successfully and not have significant adverse events. The new PAVES system includes a send/receive ultrasound catheter as an integral component that provides 0.5 mm placement accuracy when delivering the stent that bridges the arterial and venous system. In addition, a nitinol crossing needle is used, providing a highly flexible means for defining the pathway along which the stent is placed. In addition to coronary revascularization, the PAVES system also has potential applications in treating femoral artery occlusions, as well as in the delivery of stem cell therapy.

Another new tool with applications in interventional treatment of CTOs, small and tortuous vessels encountered in patients with diffuse disease and other complex patients such as those with bifurcation lesions, is the Niobe Artis system marketed by Stereotaxis (St. Louis), in partnership with Siemens Medical Solutions (Erlangen, Germany). The Niobe Artis is a magnetic guidance system that employs two low-strength magnets to automatically move a guidewire along a pre-programmed path. The system can upload image data from an angiography or multi-slice computed tomography (CT) system and perform a 3-D reconstruction to allow a pathway or roadmap to be defined, and can then be programmed to move a guidewire along the selected path.

The system has applications for the 10% to 20% of interventional cases that involve complex lesions or anatomy, where it offers the capability to salvage procedures when conventional guidewire techniques have failed, with the added benefit of reduced procedure time. In difficult cases, procedure time has been reduced from 120 minutes to five minutes using the Niobe Artis system.

The company has sold 52 systems so far, including 25 that are installed in the U.S. Three systems are installed in Europe, and Stereotaxis plans to install another 20 systems in 2005. In addition to applications in treating complex disease, the system is being evaluated for use in percutaneous valve implant procedures and delivery of stem cell therapy. The next version of the Niobe Artis system will incorporate the ability to view the guidewire under live fluoroscopy in real time and allow automated image-based guidance.

New devices for treatment of bifurcated lesions were described at the EuroPCR conference that will enable further expansion of the interventional cardiology device market. Minvasys (Gennevilliers, France) exhibited the Nile CroCo and Nile delta stents and the Nile source predilatation system that uses a delivery system with two ultra-low-profile balloon cath-eters, a chromium cobalt stent for the main branch of the bifurcation, and a second chromium cobalt stent designed for side branch placement. Together, the individual components form a system that provides complete coverage of the lesion and adjoining vessel wall, and uses the kissing balloon technique for predilatation and stent expansion. Minvasys estimates the worldwide market for bifurcation stenting systems at $500 million.

Another new device for treating bifurcation lesions, the SideKick stent delivery system from Y-Med (San Diego), was described at the EuroPCR conference by Yaron Almagor, MD, of Shaare Zedek Medical Center (Jerusalem). The SideKick is useful for treating both bifurcation and ostial lesions, which are present in up to 33% of patients with multi-vessel disease. The Y-Med device addresses limitations with the use of standard stents and specialized techniques, such as the crush technique, to treat bifurcations. It consists of a 5 Fr catheter, a steerable fixed guidewire, and a positioning wire used to protect the sidebranch. The system is designed for provisional side branch stenting.

Advances in diagnostic technologies for vascular disease also were highlighted at the conference. Volcano Therapeutics (Rancho Cordova, Caliofornia) reported the commercial launch of its VH IVUS system, which provides real-time virtual histology analysis of plaques in the coronary arteries. The system analyzes the wavelength and intensity of reflected ultrasound signals to characterize plaques, with the goal of identifying vulnerable lesions that are at high risk of rupture. Results are displayed in color-coded form, classifying plaque regions as fibrous, fibro-fatty, necrotic core, and dense calcium. Comparison with conventional histology on coronary arteries obtained at autopsy shows an accuracy of 90% to 97%, depending on the lesion type.

The primary use of the system is to assess non-culprit regions of the coronary arteries, i.e., those regions that are not identified as being directly involved in causing a myocardial infarction or a symptomatic flow limiting stenosis, to determine if additional therapy such as angioplasty or stent implantation is needed. The Volcano VH IVUS system analyzes plaque elasticity at present, but the company plans to add palpography analysis in the future to further improve the system's ability to discriminate different types of plaque. Volcano expects revenues of around $18 million in 2005, of which $16 million will be attributable to IVUS products.

Opportunity in stroke prevention, treatment

New developments in technologies for the prevention and treatment of stroke also were highlighted at the conference, reflecting the growing interest in improved management of stroke patients in Europe as new enabling technologies enter the market. A new device for stroke treatment employing selective hypothermia was described by ThermopeutiX (San Diego). According to Ron Solar, PhD, president of the company, there were 20.5 million strokes worldwide in 2001, of which 90% were ischemic. The only treatment for stroke at present is intravenous delivery of tissue plasminogen activator (tPA) from Genentech (South San Francisco, California) to lyse the blood clot causing the stroke. However, due to a lack of widely available resources for implementing such therapy, issues with timely diagnosis of stroke, and concerns about hemorrhages due to tPA, only about 2% of all stroke patients are treated at present.

The ThermopeutiX ICEd T system is not intended to eliminate the need for restoring blood flow, but rather is a neuroprotective device that preserves brain tissue that is deprived of blood by reducing metabolic demand and slowing release of toxic substances. The use of hypothermia to prevent tissue damage in stroke patients is not new, but most attempts to use hypothermia in the past have used whole-body cooling, which induces shivering that counteracts the effect of the cooling system. In addition, cooling of the entire body can cause problems with the heart and result in infections, and it has proven difficult to achieve sufficient cooling in a short enough time to achieve an optimal effect. Consequently, results of hypothermia trials have generally been negative.

The ThermopeutiX technology, in contrast, employs the CoolTrac carotid perfusion catheter and extracorporeal pump that allows brain temperature to be reduced to 18 C in about 20 minutes. Studies in baboons have shown a reduction in infarct volume from 40% to less than 1%. The goal is to get patients to the cath lab and implement the hypothermia treatment as soon as possible, extending the therapeutic window and allowing additional time for a detailed diagnosis. It may also be possible, according to Solar, to infuse drugs through the CoolTrac catheter, simplifying the overall treatment process.

Two approaches to stroke prevention are now available in Europe that use interventional devices. Devices for closure of patent foramen ovale (PFO), such as the STARFlex device from NMT Medical (Boston), are available in Europe which may help to prevent thromboembolic stroke. While PFO closure using an interventional device has not yet been shown to be an effective technique for stroke prevention, a number of studies are underway to demonstrate efficacy. So far only a small percentage of individuals believed to have large PFOs have been treated. For example, about 16,000 patients have had their PFO closed with the NMT device worldwide since its introduction.

Other closure devices available in Europe include the Amplatzer from AGA Medical (Golden Valley, Minnesota), the CardioSEAL from NMT Medical, the Intrasept from Cardia (Burnsville, Minnesota) with 6,000 implants worldwide, the Premere from Velocimed (Maple Grove, Minnesota) and the Excluder from W.L. Gore (Flagstaff, Arzona). A similar device, the Watchman from Atritech (Plymouth, Minnesota), is undergoing studies for use in preventing thromboembolic stroke in patients with atrial fibrillation. The Watchman is a left atrial appendage filter system that acts to capture thrombi generated in the appendage during a fibrillation event.

PFO closure may also prove to be a treatment for migraine headaches, since a number of patients with a history of significant migraine headaches have found that symptoms disappear when they undergo PFO closure. Treatment of migraine headache could greatly expand the market, since 27.3% of the population has a PFO. Not all of those are sufficiently large to warrant closure: only about 7% are classified as large PFOs. At the EuroPCR conference, results from the recruitment phase of the MIST (Migraine Intervention with STARFlex Technology) were presented that indicate a considerably larger proportion of migraine patients may be candidates for treatment with the STARFlex device than initially estimated. In a study of patients at two centers, a six-fold higher rate of large PFOs was documented in patients with severe migraine headaches than for individuals in the general population. According to Peter Wilmhurst, MD, of Royal Shrewsbury Hospital in the UK, the association between PFOs and migraine headaches is now well established, and trials such as MIST will now allow a determination of the effectiveness of device-based PFO closure for elimination of migraine headache. Randomization of patients in the MIST trial was targeted for completion by the end of June, and initial results are to be available by the end of this year or early in 2006.

The other technology for stroke prevention, carotid stents, addresses prevention of occlusive strokes resulting from narrowing of the carotid arteries. The technology is increasingly being used as a less invasive, and potentially safer, alternative to surgical endarterectomy for restoring normal blood flow. Leading suppliers of carotid stents in Europe include Cordis, Guidant and Boston Scientific. However, a number of additional suppliers are developing new carotid stents, including ev3. The first human implant of ev3's Prot g Rx carotid stent, which is used in conjunction with the Spider Rx embolic protection device, was reported just prior to the EuroPCR conference.

Peripheral intervention market expands

The market for devices used in the treatment of peripheral vascular disease, including stents, balloon catheters, and endovascular grafts, is also growing due to a technology-driven expansion in the range of applications. Endovascular grafts for the treatment of abdominal aortic aneurysm (AAA), and more recently for thoracic aortic aneurysm (TAA), are increasingly becoming the preferred treatment modality in Europe. As discussed by P.G. Cao, MD, of Unita' Operativa di Chirurgia Vascolare (Perugia, Italy), referral centers that perform AAA treatment in Europe now use endovascular grafts in about 60% of all procedures, with the remainder performed via surgery. Overall, Cao estimated that 40% to 50% of all AAA repair is performed with endovascular grafts.

For higher-risk patients, endovascular grafts are preferred because of excessive mortality when such patients are treated surgically. Nevertheless, the development of the market has been slowed by performance issues with the current generation of devices. Endoleaks continue to be a problem with the devices, resulting in a requirement for ongoing monitoring of patients who receive implants. Cao believes advances are required to reduce the size of the devices, to improve stability of the neck in order to avoid graft migration, to improve graft material durability, and to implement technology that avoids blockage of side branches.

A number of new stents for use in the peripheral arteries were described at the EuroPCR conference, including some drug-eluting devices designed to lower restenosis rates in challenging peripheral vascular applications. As shown in Table 3, the market for peripheral stents in Europe is estimated at $97 million in 2004, growing to almost $187 million by 2009. While increased adoption of carotid stents will be a significant driver of growth in the market, other types of stents also are expected to generate strong market expansion. For example, a number of companies are developing drug-eluting stents for use in the smaller vessels in the legs. Initial studies using a Cordis sirolimus-eluting stent in the superficial femoral artery, the SIROCCO I and II trials, showed a significant issue with fracture of the stent struts. While it appeared based on early data that there were no significant adverse consequences of such fractures, more recent data using a sirolimus-eluting SMART stent from Cordis discussed by Derek Scheinert, MD, of the University of Leipzig (Leipzig, Germany) contradicts earlier findings, and shows a clear relationship between the extent of fractures and long-term patency. In the case of severe fractures, almost all stents become occluded. While restenosis rates are reduced significantly with drug-eluting stents as compared to bare metal stents used in the superficial femoral arteries, investigators at the EuroPCR conference agreed that stent fractures are an issue that must be addressed before drug-eluting stents can be used in clinical practice in the SFA.

Another topic in peripheral vascular intervention discussed extensively at the conference is treatment of critical limb ischemia (CLI), including treatment of vessel occlusions below the knee, which represents an extremely challenging application for stents. About 500,000 patients per year present with CLI in the U.S., and between 73% and 95% of those patients with CLI who are treated conservatively, i.e., with drugs or physical therapy, undergo amputation. Patients who can be treated surgically have much lower amputation rates of 24% to 28%, but require re-operation in about 50% of cases and are slow to recover due to delayed wound healing, since a high percentage are diabetic.

Interventional techniques such as PTA and stenting have been evaluated for CLI, as has laser atherectomy using devices such as the CLiRpath from Spectranetics (Colorado Springs, Colorado). Conventional bare metal stents, designed for use in the coronary arteries, have been evaluated, but issues arise with crushability and poor conformability to the vessels in the lower leg. A new device has recently been developed by Abbott Vascular, the Xpert stent, which shows promise for applications in critical limb ischemia. The nitinol stent is available in a 4 Fr delivery system, with diameters ranging from 2 mm to 5 mm. As discussed by J. Triller, MD, of Inselspital at the University of Berne in Switzerland at the conference, the stent system exhibits good pushability, an important feature when attempting to access vessels in the lower leg, and a low degree of foreshortening (<6%). The use of nitinol provides a significant improvement in patency compared to stents fabricated from other materials, with 81% primary patency observed at six months in the popliteal arteries.

Other companies developing stents for use in small-diameter and other peripheral vessels include Biotronik (Berlin), with its absorbable metal stent; Igaki Medical Planning (Kyoto City, Japan), with a biodegradable, Tranilast-eluting stent for SFA applications, Invatec (Roncadelle, Italy), with the new Hippocampus renal stent; and Pan Medical (Gloucester, UK), with the Peribalt cobalt chromium peripheral vascular stent.

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