CDU Contributing Editor

PARIS Although drug-eluting stents were launched in Europe about a year prior to their introduction in the U.S., the market penetration of the devices in Europe is now significantly less than in the U.S. As discussed at the EuroPCR meeting (formerly the Paris Course on Revascularization), held here in mid-May, the slow trend in adoption is mainly attributable to reimbursement policies in a number of countries that cap the amount paid by the national health system at a level below that which would allow hospitals to use drug-eluting stents on all patients. In spite of such policies, a number of drug-eluting stents have been introduced in Europe and many more are in development. In addition, new types of bare metal stents, such as special types designed to treat bifurcation lesions, are being introduced, expanding the range of applications in interventional cardiology, and driving continued growth in the market, as shown in Table 1.

Other developments described by researchers at EuroPCR include new alternatives to restenosis prevention, devices for removal of thrombus in patients with acute myocardial infarction, and new devices for closing femoral artery access sites following percutaneous diagnostic and interventional procedures. The pace of new device development in the European market remains rapid, creating new opportunities for both established suppliers and new entrants in the market.

Recent trends in DES utilization

As shown in Table 2, the utilization of drug-eluting stents (DES) in Europe, although still low compared to the U.S. at 20% to 25%, has nevertheless increased more than twofold in the past year, rising from 10% in February 2003 to 23% in February 2004, based on data compiled by Boston Scientific (Natick, Massachusetts), the current leader in the worldwide DES market. Overall stent utilization in Europe, including use of bare-metal stents, is quite high, at 85% to 90% of percutaneous coronary interventional (PCI) procedures.

About 850,000 PCI procedures are performed annually in Europe at present. Another feature of the market is a wide variation in the utilization rate for drug-eluting stents between countries, from 11% in Germany and 27% in France to as high as 40% in the U.K. and 60% in Switzerland. Boston Scientific estimates that overall utilization in Europe will soon reach 30%, and will rise to 40% by 2005.

A recent analysis performed by the company suggests that the use of drug-eluting stents could double if physicians become convinced of the efficacy and cost-effectiveness of drug-eluting stents in applications such as in-stent restenosis, acute myocardial infarction, bifurcation lesions, ostial and left main coronary artery lesions, chronic total occlusions, and bypass grafts. However, 64% of physicians need more clinical data on device performance in such applications to convince them to change their practice patterns.

At present, the market for drug-eluting stents in Europe is dominated by two companies: Boston Scientific, with a share of more than 50% in 2003, and Cordis (Miami Lakes, Florida), a Johnson & Johnson (New Brunswick, New Jersey) company, which holds most of the remainder. That share structure is likely to change in the future, however, as additional products enter the market. As shown in Table 3 below, a wide range of devices is available or under development for the market in Europe. In addition to the devices listed in Table 3, other companies developing stents for the European market include Aachen Resonance (Germany), with the VITA Stent, a vitamin A acid-eluting stent expected to receive a CE mark soon; Hexacath (Reuil-Malmaison, France), with the HeliStent Titan 2 titanium nitride oxide anti-restenosis coating on a stent platform with variable strut thickness (exhibiting a 3% TLR at six months in a pilot trial); and Eucatech AG (Bad Kissingen, Germany), with a paclitaxel-eluting, polymer-covered stent and athrombogenic coating derived from red blood cell membranes. Other devices include a poly-L-lactic acid bioabsorbable stent from Igaki Medical Planning (Kyoto, Japan); the Infinnium paclitaxel-eluting polymer-coated stent from Sahajanand Medical Technologies (Surat, India), now in clinical trials; the Taxcor paclitaxel-eluting stent with biopolymer coating from EuroCOR GmbH (Bonn, Germany), now on the market in Europe; and a new drug-eluting stent from MilliMED (Helsingborg, Sweden), with a nitric oxide coating using nanotechnology in the fabrication process.

New designs are expected to allow a wider range of lesions to be treated by providing increased mechanical flexibility, improved efficiency and targeting of drug release, and lower delivery profiles. In addition, they may address certain issues with first-generation drug-eluting stents, such as adherence of the delivery balloon to the stent coating, a problem that EuroCOR believes it has resolved with a new non-adherent polymer material. The expected proliferation of suppliers, especially in Europe, is likely to drive prices down, resulting in further increases in utilization. At present, for example, European cardiologists are reluctant to use more than one drug-eluting stent per case due to cost considerations.

New developments described at the EuroPCR meeting included initial results of the first clinical trials with the Conor Medsystems (Menlo Park, California) COSTAR drug-eluting stent. The COSTAR, unlike existing drug-eluting stents on the market in Europe, does not use a permanent polymer coating for drug delivery, but instead has more than 500 laser-drilled holes cut in the struts that serve as drug reservoirs. The drug is loaded into a resorbable polymer that is placed in the holes in the stent. The design allows various doses of drugs, as well as multiple different drugs, to be delivered at a variety of controlled rates. In the PISCES trial, the COSTAR was evaluated in a total of 191 patients at a variety of doses and delivery rates. One configuration gave 0% restenosis at four months, vs. 11.6% restenosis with no drug. A large-scale randomized trial using the device, EUROSTAR, is now being organized in Europe.

Promising results also were reported in a trial of the Magic bioabsorbable stent, a device being developed by Biotronik (Bulach, Switzerland). The Magic is made from a magnesium alloy, providing high mechanical strength initially. The stent is then absorbed over the ensuing weeks following implantation, leaving minimal residues in the body, and avoiding the potential for inflammatory reactions that have been reported with polymers used in drug-eluting stents. Some of the investigators involved in the initial trial of the Magic stent believe that the restoration of normal vasomotor activity of the vessel when the stent biodegrades may help prevent restenosis not only at the treated site but also in the entire vessel.

Biotronik already is moving forward to develop a next-generation absorbable stent that will include drug elution capability in partnership with Conor Medsystems. The two companies announced a partnership at the EuroPCR meeting that will focus on the development of a drug-eluting absorbable metal stent platform, and will use the Biotronik magnesium alloy technology in combination with the non-deforming micro-reservoir technology from Conor Medsystems. The combination of the two technologies promises to allow development of a next-generation drug-eluting stent that will be able to deliver a wide range of drugs with up to six times the capacity of polymer-coated drug-eluting stents, while avoiding issues with inflammatory reactions to polymer coatings and eliminating the potential long-term issues associated with a permanently implanted device.

The most recent results of clinical studies with the Boston Scientific Taxus stent also were presented at the EuroPCR meeting. Previous Taxus trials in patients with simple lesions have demonstrated performance that is at least equivalent to that for the Cypher stent from Cordis. The Taxus VI trial evaluated long (20cm+) lesions in patients with complex coronary artery disease, and also demonstrated performance at least as good as that for the Cypher stent. At nine months, the target vessel revascularization (TVR) rate was 9.1% vs. 19.4% in controls, and the target lesion revascularization (TLR) rate was reduced from 18.9% to 6.8%, a highly statistically significant result. Stent thrombosis was 0.5% in the drug-eluting stent group, less than the 1.3% reported in the control group. The Taxus VI results demonstrate that the stent can be used successfully to treat lesions that would typically have poor long-term outcome if treated with bare-metal stents.

The expanding range of applications for stent therapy enabled by drug-eluting stents also is demonstrated by results of the SICTO trial, which evaluated the Cordis Cypher stent in the treatment of chronic total occlusions. As discussed by Dr. Y. Almagor of the Shaare Zedek Medical Center (Jerusalem, Israel) at the EuroPCR meeting, patients whose chronic total occlusions were treated with the Cypher stent had an 8% TVR rate at six months, and no major adverse events, vs. restenosis rates of 30% to 50% typically observed for chronic total occlusions treated with bare metal stents. Another study, conducted in Milan by Dr. Antonio Colombo using the Taxus stent in chronic total occlusions, also reported good results, with a TVR rate of 4.3% for Taxus vs. 14% for Cypher, indicating that the Taxus stent may be superior to Cypher for treatment of total occlusions.

Other major players in the interventional cardiology market, including Medtronic (Minneapolis, Minnesota) and Guidant (Indianapolis, Indiana), announced results of recent trials with their development-stage drug-eluting stents at the EuroPCR meeting. Dr. I. Meredith of Monash Medical Center (Melbourne, Australia) discussed the results of the ENDEAVOR 1 study using the Medtronic Driver cobalt-chromium stent with an ABT-578-eluting phosphorylcholine coating. While the device was deemed safe and effective, based on the results of the study, and binary restenosis as well as target lesion revascularization rates were low at 3.3% and 1%, respectively, at 12 months, late loss was relatively high at 0.58 mm, with the minimal lumen diameter dropping from 2.84 mm post-procedure to 2.27 mm within the stent. In-segment late loss was 0.4 mm. One-month results from the ENDEAVOR II study, discussed by Richard Kuntz, MD, of Brigham & Women's Hospital (Boston, Massachusetts), are encouraging, with TLR and TVR of 0.3% or less, and major adverse event rates of 2.9% to 3.5% depending on the patient group studied. ENDEAVOR 2 is a 1,200-patient study being conducted at more than 70 hospitals in Europe, the Middle East and Asia-Pacific.

Guidant is initiating the FUTURE 3 trial after achieving promising results in FUTURE 1 and 2 with the Champion drug-eluting stent. However, the company also reported that it was evaluating "issues" with the Champion stent platform that may result in changes to the manufacturing process or design changes. If only manufacturing process changes are required, the company expects the timeline for its drug-eluting stent program to remain on track, but if design changes are needed, a delay of up to six months in its investigational device exemption filing could result. The Champion stent uses a bioabsorbable polylactic acid coating that elutes everolimus, a cytostatic drug to prevent restenosis. Polylactic acid is a well-characterized biomaterial that has been in use for more than 20 years in vascular, dental, orthopedic and surgical (suturing) applications. Guidant also is developing the cobalt-chromium Vision stent platform that will employ a durable polymer coating, and will be evaluated in the SPIRIT FIRST trial.

New devices expand applications

Advances in coronary intervention are not limited to new developments in drug-eluting stents, however. One example is new stents for the treatment of bifurcation lesions; such lesions comprise 7% to 10% of all lesions encountered in routine practice. Bifurcation lesions have in the past required the use of improvised techniques such as crushing of two separate stents together at the bifurcation junction. Now, companies including Guidant and Minvasys (Gennevilliers, France) have developed stents specifically designed for placement in bifurcation lesions. The Guidant Frontier, launched in Europe in May, is a branched device that is deployed using two balloon catheters and two guidewires, to provide complete coverage of an entire bifurcation lesion. If needed, an extra stent, such as the Guidant Multi-Link PIXEL, can be placed in the side branch to extend coverage for extensive lesions. The stainless steel stent is priced at EUR 1,000, can be deployed through a 7 Fr guide catheter, and can accommodate a bifurcation angle of up to 75 . The Frontier cannot be used in calcified lesions, however, limiting its applicability to about 40% of all bifurcation lesions.

Minvasys has developed the Nile bifurcation stent system, a single-operator system that allows two rapid exchange catheters to be independently manipulated to perform a dual stent implant at a bifurcation lesion using the kissing balloon technique. Although the Nile system allows both the main and side branch catheters to be controlled separately, the two catheters are held together until they reach the area of the bifurcation. The main branch catheter is used to deploy the Nile stent, and the side branch catheter is then advanced through the stent struts into the ostium of the side branch and inflated, expanding the struts in the region of the bifurcation to provide coverage of the entire vessel wall at the bifurcation. The Minvasys system uses .014" guidewires to maintain a low profile, and simplifies the stent deployment procedure while allowing choice of the stent to be implanted.

A third device for the treatment of bifurcation lesions has been developed by Devax (Irvine, California). The company's self-expanding nitinol Axxess stent has a patented conical shape that preserves side branch patency, eliminates stent "jailing" and controls plaque shift. The stent provides mechanical support by conforming to the natural shape of the bifurcation, a feature that also promotes smooth blood flow, and thereby helps to avoid turbulence in the bloodstream that is believed to lead to restenosis. A pull-back deployment system is used. Although Devax has received a CE mark for the Axxess system, the product will not be released to the market in Europe until September.

Another area of continued development highlighted at the EuroPCR meeting is methods to prevent restenosis that do not rely on stents for anti-restenosis drug delivery. One device under development by Meomedical GmbH (Augsburg, Germany), the Paccocath, employs a PTCA balloon with drug-eluting coating, which can be used in combination with the company's Meo-Flex bare-metal stent for primary treatment, or alone in applications such as treatment of in-stent restenosis. Rather than delivering a drug to the vessel wall from the stent, the drug is delivered from the balloon during the implant procedure. The device is currently in animal studies, and the company plans to file for a CE mark for its use to treat in-stent restenosis in December or January.

Another approach to restenosis prevention employs orally delivered agents rather than using device-based delivery. Recent results from the IMPRESS-2 trial were described at the meeting by F. Ribichini of Ospedale Maggiore della Carite (Novara, Italy), using prednisone, an orally administered anti-inflammatory agent, administered following stenting in an effort to inhibit the proliferative response that leads to restenosis. A central tenet of the study is that use of a systemic treatment rather than a focal one, as is employed with drug-eluting stents, will not only inhibit tissue proliferation at the site of injury, i.e., the site of stent implantation, but also in other at-risk segments of the coronary vasculature that are not addressed by stenting. As described by Ribichini, an initial study using the drug resulted in a restenosis rate of 7% vs. 33% in controls, plus a reduction in major adverse events. At 1.5 year follow-up, the major adverse cardiac event rate was 4.7% vs. 34.6% in controls, and the TVR was 7% vs. 27% in controls. While the TVR rate is somewhat higher than for the most recent studies with drug-eluting stents, Ribichini believes oral prednisone may prove to be an alternative to drug-eluting stents in some patients.

Another company, Biorest (Israel), is taking a similar approach to restenosis prevention using its coronary stent platform in combination with systemic therapy with a bisphosphonate drug. Bisphosphonates are powerful inactivators of macrophages, which are the principle agents of restenosis. Animal studies have shown that neointimal hyperplasia is reduced by the drug, and a 30-patient trial is now being organized in Brazil that will use intravenous injection of bisphosphonates to study the reduction of restenosis in patients receiving stents. Biorest was founded by Koby Richter, MD, who earlier founded Medinol (Tel Aviv, Israel), which at one time was partnering with Boston Scientific to develop coronary stents before that collaboration collapsed in a flurry of lawsuits filed against one another.

Removal of thrombus in patients with acute coronary syndromes is another area that continues to attract the interest of device developers in the European market. Kerberos Proximal Solutions (Mountain View, California) exhibited the Rinspiration System, which is being studied for use in the treatment of saphenous vein grafts. The system simultaneously rinses and aspirates to remove debris from a target site. The Rinspiration is not yet released in Europe, although it has received the CE mark as well as 510(k) clearance for peripheral vascular use in the U.S.

Possis Medical (Minneapolis, Minnesota), the leading supplier of mechanical thrombectomy systems, reported at the EuroPCR meeting that it received the CE mark, as well as 510(k) clearance in the U.S., for the rapid-exchange version of its AngioJet system, the XMI-RX, for coronary use. Possis is conducting the AiMI trial using its AngioJet technology to evaluate the potential benefits of thrombus removal in patients with myocardial infarction (MI), and expects to announce the results of that trial in September. Although studies using other devices to remove thrombus in MI patients, such as the EMERALD trial that employed the GuardWire system from Medtronic, have failed to show benefit, Possis remains hopeful that the AiMI results will be positive, leading to a major expansion in the use of the AngioJet system. For its fiscal third quarter ended April 30, Possis reported a 32% in increase in revenues vs. the comparable period.

New devices for access site closure

A number of new access site closure devices were exhibited at the EuroPCR meeting, adding to a wide array of products already available in the market in Europe for use in both diagnostic and interventional coronary and peripheral vascular procedures. Abbott Vascular Devices (Redwood City, California), a unit of Abbott Laboratories (Abbott Park, Illinois), introduced the STARCLOSE, a new device that uses a star-shaped nitinol clip deployed subcutaneously at the wound site and providing 360 tissue apposition to promote immediate hemostasis and rapid healing. The nitinol clip remains in place in the tissue permanently following the closure procedure. The closing process involves a four-step procedure using the STARCLOSE clip applier, and allows the clip to be applied through the primary introducer sheath used in a diagnostic or interventional procedure, eliminating the need for sheath exchange. A CE mark for the STARCLOSE was received in February.

Access Closure (Mountain View, California) exhibited the Matrix VSG, which has received the CE mark in Europe. The device uses a polyethylene glycol gel, a material that has been used extensively in surgery and in pharmaceutical products, as a sealing medium. The procedure involves deployment of a polyethylene balloon inside the vessel at the access site, followed by injection of the gel to seal the puncture tract from the vessel to the skin surface. Hemostasis is achieved by applying pressure to the site for one minute. The entire procedure requires about two minutes to complete, and the gel is reabsorbed in 14 to 28 days, leaving no residues in the body. Patients can ambulate in one to two hours after site closure.

Cardiva Medical (also Mountain View) exhibited the VasoStasis system for vascular closure. The product is not yet launched in Europe, as the company plans to introduce the device first in the U.S., followed by European launch in September. Cardiva is about to submit its 510(k) application to obtain FDA marketing clearance in the U.S. The Vasostasis system offers a 90% efficiency of closure, and consequently may require the use of extended manual compression in 10% of cases. However, studies with the device have shown no occurrences of major complications. The device is deployed through an existing sheath, and uses a membrane to achieve hemostasis. The membrane must be held in place for about 15 minutes, and then is removed, followed by application of conventional manual pressure to the wound site for two to three minutes. No foreign residues are left in the body. The device significantly reduces manual compression times and will be priced at $130, an attractive level vs. currently marketed devices.

Another new closure device, the Auto-Close, was exhibited at the EuroPCR meeting by Rex Medical (Conshohocken, Pennsylvania). The company expects to receive a CE mark for the product by the end of this year, and will subsequently introduce the product in the U.S. pending 510(k) clearance. Only two steps are required to deploy the Auto-Close: an insertion step in which a sealing pad is deployed inside the vessel lumen, and a withdrawal step in which the pad is pulled against the vessel wall and held in place by a nitinol clip that deploys in the tissue surrounding the vessel as the applier is removed. No foreign substance remains inside the vessel permanently, and immediate hemostasis is achieved.

Access site closure devices have achieved a significant level of acceptance in the U.S. and certain markets in Europe, but their use is discouraged in France and countries such as Japan, according to suppliers, because of the added cost involved. Companies supplying access site closure devices include Datascope (Montvale, New Jersey), with the VasoSeal product line; St. Jude Medical (St. Paul, Minnesota), with the Angio-Seal; Vascular Solutions (Minneapolis, Minnesota), with the Duett; Sutura (Fountain Valley, California) with the Super Stitch; Marine Polymer Technologies (Danvers, Massachusetts) with the Syvek Patch; and Scion (Miami, Florida) with the Clo-Sur Pad.

Sales growth has slowed somewhat due to price competition as more suppliers have entered the market and due to expansion of the global market into regions that characteristically have lower average selling price. However, sales of vascular closure devices by the market leader in Europe, St. Jude Medical, have continued to expand, increasing 54% in 2002 and almost 40% in 2003 on a worldwide basis. St. Jude announced shipment of the 4 millionth Angio-Seal device in May, indicating that the use of vascular closure devices is continuing to expand worldwide.