CDU Contributing Editor

PARIS – New developments in medical technology are often commercialized in the European market prior to their introduction in the U.S., due to the more rapid regulatory approval process and receptivity of physicians in Europe to new technologies, particularly in the interventional device segment. One emerging market segment that exemplifies that trend is the use of stents for the treatment of carotid artery stenosis to prevent stroke. As discussed by physicians at the Paris Course on Revascularization (EuroPCR), held here in late May, there is growing interest in carotid stents in Europe, as well as in a variety of other new devices for stroke prevention such as devices for closure of patent foramen ovale (PFO). While carotid stents have not yet been approved for use by the FDA in the U.S., utilization in Europe has began to increase as the number of devices available there has expanded, according to physicians presenting at the EuroPCR conference. In addition, advances in technologies for the treatment of other types of peripheral vascular disease, including critical limb ischemia and vascular aneurysms, are driving growth in the use of interventional devices in Europe. New developments in interventional technologies for the treatment of chronic total occlusions in the coronary and peripheral arteries were also described at the PCR meeting, along with the latest developments in percutaneous heart valve technologies.

In spite of the earlier acceptance of new interventional technologies in Europe, and a larger population as compared to the U.S., markets for vascular interventional devices are typically smaller in Europe than in the U.S. once developed. Factors responsible for that apparent discrepancy include somewhat lower rates of cardiovascular disease in certain major European countries (e.g., France, Italy, Spain, and the Scandinavian countries); lower utilization of advanced treatment technologies due to restrictive reimbursement policies within the nationalized healthcare systems in Europe; and lower unit pricing in the device markets, a factor also related to reimbursement policies and the resulting pressure to contain healthcare costs. However, recent trends indicate growth in the percentage of Gross Domestic Product devoted to healthcare spending in Europe, to levels more comparable to but still below that in the U.S. Consequently, the vascular device market in Europe is expected to exhibit attractive growth, at least equivalent to that for the global market, with certain product segments such as carotid stents expanding much more rapidly than the overall market.

Carotid stenting, stroke prevention expand

Underscoring the growing level of activity in the carotid stent market in Europe, a number of companies exhibited new carotid revascularization devices at the EuroPCR meeting, including new types of stents as well as embolic protection devices for use during carotid stenting procedures to minimize the risk of inducing a stroke during the stent procedure. Abbott Vascular Devices (Redwood City, California) exhibited the Xact, a rapid-exchange carotid stent system developed by MedNova Ltd. (Galway, Ireland). The Xact is a nitinol device with a low crossing profile of 5.7 Fr that is available in both straight and tapered-diameter versions. A unique feature of the Xact is its variable cell size, which provides increased radial force at the lesion but reduced force at the ends of the stent that are in contact with healthy vessel segments. The cell design also provides increased vessel wall coverage at the lesion, minimizing plaque extrusion through the stent struts that could increase the risk of downstream embolization.

Angiomed GmbH (Karlsruhe, Germany), a subsidiary of C.R. Bard (Murray Hill, New Jersey), exhibited the Conformexx Carotid Stent, another self-expanding nitinol device with a 6 Fr delivery system (S.A.F.E.) that features unique locator markers to help ensure accurate placement. Other nitinol carotid stents on the market in Europe or under development for the European market include the Precise from Cordis (Miami Lakes, Florida); the AccuLink from Guidant (Indianapolis, Indiana) and the NexStent from EndoTex Interventional Systems (Cupertino, California), a company in the process of being acquired by Boston Scientific (Natick, Massachusetts).

In addition, Jotec GmbH (Hechingen, Germany) exhibited a new carotid stent, introduced in Europe in January, that features a high-density winding of the nitinol struts in the center of the device and lower density at the ends, providing less mechanical stress on healthy tissues as well as high flexibility. The company also believes the tightly-spaced struts in the center portion of the device may act like a covered stent to prevent embolization of particulates during and after implantation. In the undeployed (stretched) configuration, the device assumes a very low profile, helping to protect against debris dislodgement during positioning of the device prior to implantation.

The carotid stent market is unique in that companion devices for embolic protection are used in virtually all carotid stenting procedures because of concerns about release of particulate material during the procedure that could migrate directly to the small-diameter vessels in the brain and cause a stroke. A survey of attendees at the carotid stent symposium at the EuroPCR meeting found that 97.6% of the respondents believe the use of embolic protection devices is mandatory in carotid stenting procedures. At least 15 different distal filter devices are on the market or under development with applications in carotid stenting, including the AngioGuard XP from Cordis, the FilterWire EX from Boston Scientific and the 2.4 Fr Rubicon Filter from Rubicon Medical (Salt Lake City, Utah), as well as a number of distal or proximal balloon occlusion devices. As discussed by A. Cremonesi of Villa Maria Cecilia Hospital (Cotignola, Italy) at the EuroPCR meeting, complication rates have dropped from 10% to 2% as a result of the use of embolic protection devices and dedicated stents for use in carotid procedures.

Balloon occlusion devices include the M.O.M.A. from Invatec (Roncadelle, Italy), a next-generation version of the TriActiv FX balloon-protected flush extraction system from Kensey Nash (Exton, Pennsylvania), the Parodi Anti-Emboli System from ArteriA Medical Science (San Francisco, California), the PercuSurge GuardWire Plus from Medtronic PercuSurge (Minneapolis, Minnesota), and the EUR 1,200 Proxis Embolic Protection System from Velocimed (Minneapolis, Minnesota). Kerberos Proximal Solutions (Mountain View, California) is developing the Kept, now in clinical trials in the U.S. and Canada, which combines proximal occlusion with an aspiration system that dispenses a flushing solution through a central catheter and evacuation via a guide catheter.

Although results of an in-session survey of EuroPCR attendees indicated that distal filters are the preferred embolic protection technology for complex carotid lesions, Cremonesi said he has found balloon occlusion devices to be preferable in the treatment of ulcerated lesions or in the presence of thrombus. Some physicians in Europe, in fact, now perform the majority (65% to 75%) of their carotid stent procedures using balloon occlusion devices such as the M.O.M.A.

Based on a survey conducted in the carotid stenting session at the EuroPCR meeting and comments of leading physicians performing the procedure, carotid stenting is becoming a highly-utilized treatment modality in some centers in Europe, and the procedure is being adopted by a growing number of interventionalists. As shown in Table 1 below, a sampling of physicians attending the session on carotid stenting showed that more than half had some experience with the procedure, and almost one in five were performing a relatively high volume. More than 16,000 carotid artery stent procedures have been reported in registries worldwide. FDA approval of carotid stents in the U.S. is expected to result in a significant increase in procedure utilization, and could occur in the near future following a positive FDA panel recommendation for the Cordis Precise stent in April.

Other device-based therapies for stroke prevention were also described at the EuroPCR conference including a new implantable device for long-term protection against particle embolization, an ultrasound enhanced thrombolysis system, and devices for PFO closure. MindGuard Ltd. (Caesarea, Israel) exhibited its D-fence device, a self-expandable cobalt/chromium fine-wire mesh tube that is implanted in the carotid bifurcation from the distal external carotid artery to the proximal common carotid artery. The mesh covers the orifice of the internal carotid artery and diverts particles having a diameter of about 300 microns and larger to non-hazardous locations. It is being evaluated for use in patients at high risk for stroke, such as patients with atrial fibrillation, carotid stenosis, history of stroke, hypertension, coronary artery disease, a history of systemic embolism and certain other conditions. Studies have been initiated using the D-fence in Germany and Italy. Patients receiving the D-fence device undergo anti-platelet therapy for one year following implant, and aspirin therapy for life. The risk of occlusion of the device appears minimal, according to the company, because laminar blood flow is maintained following implant, and growth of neointimal tissue on the device is minimal and stabilizes at three months.

A new device with potential applications in the treatment of acute thromboembolic stroke was exhibited at EuroPCR by Ekos (Bothell, Washington). The Ekos MicroLysus Infusion Catheter combines ultrasound with thrombolytic drug therapy to reduce the time required to lyse a clot by a factor of two-fold to three-fold, and also allows lysis to be performed using two to three times less drug. Low-level (0.45 watts) ultrasound energy at 1-2 MHz is employed, allowing drug to more readily permeate the clot. The system also includes temperature monitoring of the catheter to detect when blood flow is restored. The 3 Fr device profile allows the device to be used in the cerebral vessels, and any thrombolytic drug can be used.

A number of companies now are marketing devices used in PFO closure in Europe, and sales are beginning to expand according to suppliers. Sales of the Helex from W.L. Gore (Flagstaff, Arizona), for example, are beginning to grow rapidly in Germany, where physicians now prescribe the device for PFO patients following an initial stroke, whereas in the U.S. physicians typically wait until a patient has suffered a second stroke before prescribing a closure device. About 1,700 Helex devices have been implanted worldwide so far.

Velocimed also is planning to introduce a device for PFO closure in Europe, the Premere PFO Closure System, which uses two independent flexible nitinol anchors that can be placed independently to allow the device to be adapted to the atrial anatomy. Following placement, the anchors are gradually cinched together to close the PFO.

Advances in peripheral vascular therapy

The use of transcatheter technologies for the treatment of disease in the extremities is also expanding in the European market. One topic highlighted at the EuroPCR meeting was management of critical limb ischemia (CLI) using interventional methods. About 10% of patients with peripheral vascular disease develop CLI annually, or about 185,000 patients per year in the European Community. CLI is diagnosed based on visible tissue necrosis in a limb, or if a patient experiences rest pain in a limb lasting more than two weeks. Patients with CLI have the same risk of death as patients with coronary heart disease, cerebrovascular disease, colorectal cancer or breast cancer, and the first-year mortality rate following a diagnosis of CLI is 20% to 25%.

At present, treatment outcomes are less than optimal: the first-year mortality rate for patients undergoing conservative drug therapy is 40%, and 50% of patients treated with conservative therapy undergo amputation within the first year. Only 31% of patients who undergo amputation for CLI become independently mobile. Within the past decade, encouraging results have been obtained with angioplasty in selected CLI patients, mainly those with short lesions and no occlusions. Stents have also been used with some benefit in reducing the rate of early failures, although long-term patency is not improved vs. angioplasty. Outcomes with angioplasty and stenting are now as good with respect to limb salvage as with peripheral bypass surgery, with salvage rates of about 90% observed.

An important factor in achieving improved outcomes has been the development of advanced stents with optimal features for use in peripheral vascular applications. As discussed by F. Vermassen of the Ghent University Hospital (Ghent, Belgium), newer devices such as the Cordis S.M.A.R.T. stent are significantly better that the Wallstent in maintaining patency in patients diagnosed with CLI, and next-generation devices may provide further improvements. Among the new devices that show promise for use in peripheral vascular stenting are the Luminexx 3 stent from Bard Peripheral Vascular and the Maris self-expanding peripheral stent from Invatec. As a result of the advances in stent technology, and the resulting expansion in the range of applications for peripheral stents, the peripheral vascular stent market in Europe is expected to exhibit substantial growth over the next few years, as shown in Table 2.

Another modality that may have advantages for CLI treatment in the future, according to presenters at the EuroPCR conference, is laser ablation. Spectranetics (Colorado Springs, Colorado), the leading supplier of laser devices for vascular therapy, is conducting a multi-center study, the Laser Angioplasty for Critical Limb Ischemia (LACI) registry, to assess the safety and efficacy of excimer laser-assisted angioplasty for the treatment of CLI in patients who are poor surgical candidates. To date, results from the registry indicate a 90%+ limb salvage rate at six months in CLI patients with chronic total occlusions, obviously a challenging patient population. A European study, LACI Belgium, produced similar results.

Perhaps the most important advances in peripheral vascular disease therapy, however, are being realized with endovascular grafts. A number of the devices are on the market in Europe, and next-generation devices now under development promise to provide further improvements in performance as well as expansion in the range of applications. As discussed by J. Bleyn of the Antwerp Blood Vessel Center (Antwerp, Belgium), endovascular grafts have provided a significant improvement in outcome for patients with peripheral vascular disease treated with interventional techniques. In patients with occlusions in the superficial femoral artery, which includes about 50% of those presenting with lower limb claudication, covered stents now allow treatment outcomes to be achieved that are equivalent to those for surgical bypass, at least for bypass employing synthetic vascular grafts. With the latest-generation endovascular grafts available for treatment of peripheral vessels, including the Viabahn and Hemobahn from W.L. Gore, the Fluency from Bard Peripheral Vascular (Tempe, Arizona), a unit of C.R. Bard, and the A-Spire from Vascular Architects (San Jose, California), Bleyne quotes patency rates of 50% at five years. A key advance was the development of devices that avoid blood contact with the metal framework of the stent-graft by placing the polymer covering on the inside of the device. In Antwerp, about 25% of patients undergoing peripheral revascularization procedures now have endovascular grafts implanted, with clinical outcomes equivalent to surgical bypass, but with significantly reduced treatment cost because of the avoidance of general anesthesia and long hospital stays.

Another growing application for endovascular grafts is repair of aneurysms, including those in the abdominal and thoracic aorta; perforations; and diseased saphenous vein grafts in patients with a prior coronary artery bypass. Jotec GmbH exhibited its E-Vita stent-graft at the EuroPCR meeting, a nitinol/ polyester device designed for implantation in the thoracic aorta in patients with thoracic aorta aneurysms. CardioVasc (Menlo Park, California) is now marketing a new device in Europe, the CardioVasc Advantage, for the treatment of diseased saphenous vein grafts, perforations and vascular aneurysms, which consists of a balloon-expandable stainless steel stent covered with ePTFE, and features a unique biomimetic coating on the ePTFE that promotes binding of endothelial cells. The coating employs P-15, a 15-amino acid peptide containing the binding site of collagen, which halves the time required for coverage of the ePTFE with endothelial cells. The technology was licensed by venture-funded CardioVasc from the University of California, San Francisco. Twenty centers are now using the device, and the company is planning to expand sales through distributors. An application for a humanitarian device exemption also has been filed to allow marketing of the Advantage stent graft in the U.S.

W.L. Gore is marketing the TAG stent graft for treatment of thoracic aorta aneurysms in Europe. Priced at about EUR 10,000, the Gore device consists of a nitinol frame covered with a single layer of ePTFE, and has been designed to resolve issues with fractures of the nitinol stent that occurred with the first-generation thoracic stent graft from Gore. Other suppliers and developers of endovascular grafts for use in the thoracic aorta in Europe include Cook (Bloomington, Indiana), with the Zenith TX1, a device that employs stainless steel stents covered with polyester and is priced at about EUR 10,000; and the Relay Thoracic Stent Graft from Bolton Medical (Sunrise, Florida), a nitinol device covered with .012" thick surgical polyester featuring a double ring of struts at the ends for high sealing force. The Bolton stent graft is not yet approved for marketing in Europe, since clinical trials were not planned to start until last month. Boston Scientific is marketing the Symbiot covered stent system in Europe for the treatment of diseased saphenous vein grafts, and Bard Peripheral Vascular is developing the Fluency vascular stent graft. Cardiologists and other vascular interventionalists consider stent grafts to be promising for the treatment of thoracic aneurysms as well as for other applications, including saphenous vein graft treatment and treatment of vessels in the legs, but believe that evidence of improvement in primary outcome measures is needed, as well as data showing long-term durability, before widespread adoption is warranted. Eventually, the market for endovascular grafts is expected to be distributed by application in accord with disease incidence, as shown in Table 3.

Treatment of CTOs Gathers Momentum

Another application of interventional therapy highlighted at the EuroPCR conference was treatment of chronic total occlusions (CTOs). Occlusions in the coronary arteries are the primary application targeted by suppliers of CTO therapy devices, but important applications also exist in the treatment of occlusions in the superficial femoral arteries. As shown in Table 4 below, devices for CTO therapy represent a significant market opportunity, and one that is continuing to grow along with the number of patients diagnosed with coronary artery and peripheral vascular disease in Europe. Typically, about 30% of CTOs can be recanalized using conventional techniques such as stiff guidewires to penetrate the occlusion, according to presenters at the EuroPCR conference. Laser wires have been evaluated for crossing of CTOs, but success rates and patient outcomes are not significantly better than with mechanical wires. As indicated by the data in Table 3, patient outcome, including survival, is typically improved if a CTO is opened, and symptoms also improve.

A new device for CTO recanalization, discussed by Donald Baim of Brigham & Women's Hospital (Boston, Massachusetts), is under development by FlowCardia (Sunnyvale, California). The FlowCardia Crosser uses ultrasound energy to vibrate the catheter's tip at 20 kHz, providing a mechanical force that pulverizes the occluding material in an artery. The device also provides a flow of saline to clear the ablated material. In early studies conducted with the Crosser, a 70% success rate has been achieved in recanalization of CTOs, with no dissections observed. The company plans to complete its initial trials and file for a CE mark soon and expects to have European clearance by the end of 2004. A trial has also been initiated in the U.S. Typically, about two to three minutes is required to recanalize a CTO using the Crosser. The 1.1mm device is compatible with a .014" guidewire, providing access to most lesions.

Other devices available in Europe for CTO therapy include the Frontrunner catheter from LuMend (Redwood City, California), the Avion catheter from Invatec, the CTO Wire from Brivant Medical Engineering (Galway, Ireland), and the SafeCross catheter from Intraluminal Therapeutics (Carlsbad, California). The SafeCross combines Optical Coherence Refectometry, to guide the catheter through an occlusion, with radio frequency ablation to ablate the occlusive material and safely recanalize a CTO. As discussed by Baim, a recanalization rate of 56% has been achieved in the GREAT trial using the SafeCross catheter after failure to cross the lesion with a conventional guidewire. A 2.6% rate of vessel perforations was observed in the study. According to Baim, similar success rates have been achieved with the LuMend Frontrunner, although complication rates are somewhat higher at 8%. Higher success rates have been observed using the Frontrunner in the peripheral vessels. An issue with the Frontrunner catheter is that it sometimes fails to penetrate through a CTO and instead tracks around the occlusion.

As discussed by Baim at the EuroPCR meeting, new devices such as the Crosser are allowing continued progress to be made in increasing the success rate for CTO treatment, and in reducing the rate of procedure-related complications from current levels of as high as 20% with guidewire recanalization. Drug-eluting stents will also play a role in CTO therapy, by improving long-term outcomes following revascularization. For example, physicians in Milan have achieved target vessel revascularization rates as low as 4.3% following CTO treatment using the Taxus stent from Boston Scientific. Baim said he believes it will eventually be possible, using advanced recanalization technologies, to increase success rates for CTO procedures to 90%, while reducing the rate of complications. Achieving that goal will help drive further conversion of surgical bypass to interventional therapy in the European market, from a ratio of about three to one (for coronary PCI to CABG) in 2003 to more than five to one by 2010. Similar trends are expected to prevail in the global market, with total worldwide PCI procedures approaching 3.1 million by 2010 while CABG procedures decline to somewhat less than 500,000 per year.

A final area of focus at the EuroPCR conference was emerging technologies for heart valve repair and replacement employing percutaneous transcatheter techniques. As discussed by Alain Cribier, MD, of Charles Nicolle Hospital (Rouen, France), one of the pioneers in heart valve therapy, about 300,000 patients present with aortic valve stenosis annually worldwide and are now treated either with balloon valvuloplasty or surgical repair or replacement of the heart valve. Cribier reported on his experience with implantation of a new percutaneously implantable valve from Percutaneous Valve Technologies (Fort Lee, New Jersey), now a unit of Edwards Lifesciences (Irvine, California). The PVT device consists of a balloon-expandable stainless steel stent combined with a tricuspid tissue valve and is implanted in a 90-minute transcatheter procedure. The device uses the native valve as a support, thus eliminating the need to excise the existing valve. In eight-month follow-up of the first 20 patients treated with the device, Cribier has observed no valvular dysfunction or coronary occlusions, along with a dramatic improvement in hemodynamic function, in patients not amenable to surgery. About 38% of patients with severe valve disease are not candidates for surgical treatment. Cribier projects that the device is about one to two years away from market introduction, not including the time required for regulatory approval.

Another new device, from Cardiac Dimensions (Kirkland, Washington), is under development for the percutaneous treatment of mitral valve regurgitation associated with congestive heart failure. More than five million individuals suffer from congestive heart failure in the U.S. alone. The device will allow an annuloplasty to be performed without open surgery using a nitinol wire that reshapes the mitral annulus. The device is still in animal trials, with the first human studies projected to begin in about nine months.

CoreValve (Paris) exhibited its development-stage revalving device, a self-expanding nitinol stent that is used with any existing pericardial valve available for surgical implantation to allow percutaneous treatment. CoreValve was formed in 2001, and has completed 80 implants of its device in animals, as well as some implants in human cadavers. The company just received approval to begin human clinical studies at sites in France and Germany, and plans to begin a 10 to 20 patient trial shortly. Implantation of the 24 Fr device requires a cut-down procedure, but can be performed in the cath lab on a beating heart without general anesthesia. The company's goal is to refine the procedure so that valve replacement will require only a one-day hospital stay. CoreValve is collaborating with a number of valve manufacturers in the development of its device (see following story for more on CoreValve).

Corazon (Menlo Park, California) is developing yet another approach to the treatment of valvular disease, which targets patients with calcified valves. While the Corazon valve repair kit will initially be designed for open surgical use, the company is also developing a version that will allow percutaneous treatment. The Corazon device is used to isolate the aortic valve and expose it to a low pH decalcifying solution along with gentle mechanical agitation. After demineralization is complete, the solution is aspirated and the device is removed, leaving the renovated native valve intact. Corazon has obtained an investigational device exemption to begin human studies with the open surgical technique, and plans to start clinical trials with its percutaneous device in January 2005 in the U.S. and Europe.

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