CDU Contributing Editor

PARIS – The European market for devices used in vascular diagnosis and intervention is the second-largest worldwide after the U.S., and also is exhibiting rapid growth that in some cases rivals that in the U.S. market. The largest segment of the market, products used in percutaneous coronary intervention (PCI), continues to grow as advances in device technology allow expansion of indications for use to include increasingly complex lesions such as bifurcations an d small-diameter vessels. Drug-eluting stents are driving growth in the dollar-volume market because of higher unit prices compared to bare-metal stents, along with acceptance by national healthcare systems of the demands of patients for new technology and continued expansion in the number and type of patients being treated with the devices.

Drug-eluting coronary stents were first launched in the European market, although acceptance there was slow because of cost issues. Utilization has since grown as prices dropped due to competition, with some centers in Europe now using drug-eluting stents in more than 90% of cases. Over 6 million drug-eluting stents have been implanted in patients worldwide in just the last three years. Cardiologists are now evaluating next-generation drug-eluting stents with features such as biodegradability that promise to further expand the market.

As discussed here by leading experts in interventional cardiology at the EuroPCR 2006 conference sponsored by the Europa Organization (Toulouse, France), a variety of other new developments are expected to result in expansion of the interventional device market in Europe by opening up new applications such as percutaneous heart valve repair, and by enhancing the capabilities of interventionalists to treat a wider range of conditions including peripheral vascular diseases such as critical limb ischemia, carotid atherosclerosis and vascular aneurysms.

Emerging technologies for intravascular imaging are also playing a role in expansion of the market in Europe by allowing device-based therapy to be employed more effectively, and by helping cardiologists identify vulnerable plaque for preventative therapy.

New developments in interventional guidance technology also were described at the EuroPCR conference that will facilitate PCI procedures and potentially enable more complex interventions to be performed, as well as improve efficiency in the cath lab.

Bioabsorbable devices for stenting

A major focus for next-generation stents for coronary applications is bioabsorbable and biodegradable stent materials. The development of bioabsorbable devices is being pursued in large part because of issues with polymers used in existing drug-eluting stents that cause adverse hypersensitivity reactions in some patients, and can produce thrombosis within the stent. Because of advances in diagnostic technology, particularly in areas such as CT angiography, stents are being implanted in a wider range of patients, including patients who are asymptomatic but are considered to be at high risk for an acute coronary event because of a vascular defect detected in an imaging procedure. Since the consequences of stent thrombosis are often severe, resulting in death in a high percentage of cases, physicians are faced with a difficult risk trade-off. Using biodegradable stents or polymers, physicians hope to eliminate the factors leading to thrombosis in drug-eluting stents.

One promising new stent under development by Xtent (Menlo Park, California) uses a bioabsorbable polylactic acid coating to carry the drug Biolimus A9, a sirolimus analog licensed from Biosensors International (Singapore). The stent scaffold is made of cobalt chromium, one of the most bio-inert metallic alloys available for stent fabrication.

The device design features individual inter-digitated sections that can be joined to customize the stent to any desired length. Balloon expansion can be tailored so that high pressures are applied only where needed, in principle minimizing vessel wall damage and thereby limiting restenosis. The stent also can be tapered for applications where varying diameters are desirable.

The Xtent has performed well in the CUSTOM 1 safety trial, and CUSTOM II is now under way to show safety in long lesions, using multiple customized stents. Device deliverability has exceeded expectations, and a zero percent restenosis rate has been reported at eight month follow-up. Late loss in the CUSTOM trial is only 0.29 mm, and neointimal volume is comparable to that observed in the RAVEL trial, which employed the Cypher stent from Cordis (Miami Lakes, Florida).

Another development-stage bioabsorbable drug-eluting stent was described at the EuroPCR conference by John Ormiston, MD, of Auckland City Hospital (Auckland, New Zealand). The BVS stent, under development by Guidant (now part of Boston Scientific; Natick, Massachusetts), is fabricated completely with polylactic acid and consequently fully absorb-able. The polymer is loaded with everolimus to eliminate neointimal hyperplasia in the treated vessel. Some 80% of the drug is released over a 28-day period.

The device is being evaluated in the ABSORB first-in-man study at Auckland City Hospital, with 10 patients evaluated as of May. Additional patients will be enrolled in the study in certain European centers, with planned enrollment of a total of 30 patients. In addition to elimination of the adverse effects of polymers, use of a fully absorbable stent allows vascular surgery to be performed at the stented site at a later date, and allows the vessel to return to normal vasomotion after the PLA scaffold dissolves. About one year is required for complete absorbtion with the existing design.

Other companies developing absorbable stents include Biotronik (Berlin) and Cordis. Biotronik and Conor Medsystems (Menlo Park, California) are partnering in a development program called DREAMS (DRug-Eluting Absorbable Metal Stent) aimed at eliminating the problems with fully absorbable metal stents such as the Biotronik AMS, which include early recoil (when the scaffold dissolves) and neointimal formation due to lack of a drug to inhibit smooth muscle cell proliferation in response to balloon/stent injury of the vessel.

The DREAMS design employs a new scaffold configuration using the Conor microreservoir fabrication technology and a modified alloy to provide longer-term radial support for eight weeks post-implant.In addition, the microreservoirs contain a biodegradable polymer loaded with pimecrolimus, an anti-inflammatory drug that also acts to prevent neointimal tissue formation. The development program is in the pre-clinical stage. The companies are also assessing the possibility of incorporating additional drugs in the absorbable polymers, including anti-thrombosis agents and vascular endothelial growth factor.

Other stents with biodegradable components are being investigated as potential solutions to the drawbacks of existing drug-eluting stents. Cordis is developing a next-generation bioabsorbable drug-eluting stent that may be particularly useful in peripheral vascular applications. The company’s first-generation drug-eluting stent platform has not proven suitable for use in vessels such as the superficial femoral artery, for example, because of strut fractures. The new bioabsorbable device could address that problem since the struts will dissolve before wearing to the point of fracture. In addition, the new design allows higher doses of drug to be delivered since the drug can be distributed throughout the polymer structure.

As discussed by Peter Fitzgerald, MD, of Stanford University Medical Center (Palo Alto, California), who is participating in the initial evaluation of the new stent, it also has been found that higher doses enable the drug to distribute at significant concentrations to regions of the vessel outside the stented area, perhaps in excess of 60 mm to 80 mm. That feature could allow a wider region of the vessel to be treated without using a longer stent, perhaps preventing a subsequent stenosis adjacent to the one being stented. The device could also have applications in the coronary arteries for treating vulnerable plaque, since use of a non-permanent implant would be desirable in such applications.

While bioabsorbable stents may have significant advantages over today’s drug-eluting stents, there are other potential solutions to the problems of polymer biocompatibility, lack of endothelial cell coverage, and strut fracture. For example, Biosensors has developed the Calix stent, which is now CE-marked, and features a synthetic glycocalyx coating on the stent surface to improve biocompatibility and endothelial coverage.

The new Guidant Xience stent employs a fluorinated acrylic polymer coating, which uses materials having a long history of high biocompatibility, and releases 100% of the drug over a 90-day period. Studies with the device, which is targeted for release in Europe in the second half of this year, have shown no thrombosis, 0.1 mm late loss, and a 3.8% target lesion revascularization rate at six months. The Xience, which now is part of the Abbott Vascular (Redwood City, California) product portfolio now that Abbott’s acquisition of Guidant’s vascular business is complete, will be priced somewhat higher than Taxus, and probably will be priced competitively with Cypher, since both the drug and the polymer will represent advances over Boston Scientific’s Taxus.

Other approaches to improving drug-eluting stent biocompatibility include the endothelial cell-binding coating used in the Genous R Stent from OrbusNeich (Hong Kong); a cyclic RGD peptide stent coating, also designed to attract endothelial cells, under development by Guidant; and a Tretinoin coating to bind endothelial cells plus an anti-mitotic drug used in a stent being developed by Aachen Resonance (Aachen, Germany).

Percutaneous heart valve therapy advances

Unlike drug-eluting coronary stents, the first generation of percutaneously implantable heart valve devices has not yet reached the market in Europe. There is strong interest in using the devices once they become available, however, as indicated by an electronic survey conducted at a EuroPCR session on percutaneous valve technology that showed 81% of the attendees would perform aortic valve implants, 72% would perform pulmonary valve implants, and 78% would perform mitral valve implants if percutaneous devices become available.

At least 28 companies are pursuing 35 development programs for percutaneous valve repair or replacement devices. Both synthetic and combination synthetic/biological materials are being employed, and a wide range of design concepts are under development. Table 1 on the following page describes devices discussed at the conference. Development programs that have progressed the furthest include the Edwards LifeSciences/PVT (Irvine, California) percutaneous aortic valve replacement development program and the CoreValve (Paris) program to develop its ReValving System.

As discussed by Alain Cribier, MD, of Charles Nicolle Hospital (Rouen, France) at the EuroPCR conference, more than 100 implants of the Edwards valve have been performed to date, with no valve dysfunction observed in a subgroup of 15 to 20 patients followed up so far. The implant procedure for the Edwards valve has been modified from the original antegrade approach to a retrograde approach, since it was found that extensive training is required to implant the device properly using an antegrade approach. A Flex catheter has been developed by Edwards that is specifically designed for use in the retrograde procedure and facilitates crossing of the native valve.

As in many percutaneous valve development programs, investigators in the Edwards trial are using larger-diameter valves, typically 26 mm versions, and achieving improved results. While initial implants of the Edwards valve were performed only in patients with very severe valve disease who had no other treatment options, patients with less severe disease are now being included in the trial as the technology has been refined.

As demonstrated in a live case presented at the EuroPCR conference, the CoreValve percutaneous aortic valve replacement procedure is employing multiple technologies for guidance and patient support along with the multi-segment valve replacement device. As of late April, 56 implants of the CoreValve devices had been performed worldwide.

At present, investigators implanting the CoreValve device are using a femoral-femoral bypass support system as a backup in case of a procedural problem during the beating-heart implant, but it may be possible to eliminate that requirement if clinical trials indicate that it is unnecessary. CoreValve is performing studies aimed at obtaining CE certification, and will subsequently begin studies to gain FDA clearance. The AorTx percutaneous valve also looks promising, according to experts presenting at the EuroPCR conference, because of its use of a protective wrap to prevent damage to the device during the implant procedure.

Accurate guidance remains a key aspect of a successful percutaneous valve implant procedure. One promising device, now being used in the venous system to provide real-time images of the heart during the implant procedure, is the AcuNav ultrasound catheter from Siemens Medical Systems (Erlangen, Germany). Cardio-Optics (Wilmington, Massachusetts) is developing a cardiac endoscopy device that also may prove useful in guidance of valve implantation. The device uses infrared optical technology initially developed for military applications to provide real-time images through blood. Other enabling technologies include the Tandem Heart LVAS manufactured by Cardiac Assist (Pittsburgh), which is used to provide temporary cardiopulmonary support during percutaneous heart valve implant procedures.

Once percutaneous aortic and pulmonary valves are launched commercially in Europe, suppliers expect the unit price to be in the EUR 15,000 range, vs. costs for existing surgically implanted valves of around EUR 5,000. Total procedure cost, however, will probably be significantly less for percutaneous valves compared to the $65,000 to $85,000 for a surgical procedures. Suppliers have estimated the total market for percutaneous heart repair and replacement devices could exceed $1 billion worldwide.

Explosion of peripheral intervention

Another growth segment within the interventional device market in Europe is devices for use in peripheral vascular therapy. As shown in Table 2, the total number of peripheral vascular therapy procedures performed in Europe is projected to increase by 25% between 2004 and 2009, to over 340,000. Almost all of that increase will be due to growth in endovascular intervention, with surgical procedures increasing only 4% while endovascular procedures increase by 37%.

Table 3 presents trends in volume in Europe for specific peripheral vascular procedures between 2001 and 2004, demonstrating that annual volumes for major types of endovascular procedures such as abdominal aortic aneurysm (AAA) repair, aorto-iliac revascularization and carotid stenting have increased substantially, while surgical procedure volumes have declined.

As discussed by David Allie, MD, of the Cardiovascular Institute of the South, (Houma, Louisiana), factors driving growth in peripheral vascular intervention include continued improvements in device technology leading to better procedural outcomes that in some cases rival those of surgery, lower overall costs for endovascular intervention as compared to surgery, and patient preference for and increased awareness of endovascular treatment.

One important area in which endovascular intervention may become the preferred treatment option is therapy for critical limb ischemia (CLI). In the U.S., management of critical limb ischemia accounts for between $10 billion and $20 billion in health care spending annually, according to Allie. Initial treatment, which often involves limb amputation, costs about $50,000 per patient, and follow-up care in a nursing home can cost $100,000 per year.

Even though there are no outcomes data that demonstrate the effectiveness of limb amputation for CLI, about two-thirds of patients have an amputation as their initial therapy, resulting in between 220,000 and 240,000 limb amputations annually in the U.S. Allie cited data showing that amputation for CLI actually results in a complication rate that is 20-fold higher than that for endovascular treatment. In contrast, endovascular therapy for CLI costs as little as EUR 600 per year.

A number of new endovascular devices have been introduced in Europe recently for use in peripheral vascular therapy, and more are in development. The two leaders in the drug-eluting stent market, Cordis and Boston Scientific, both have introduced new peripheral vascular balloon catheters (the Savvy catheter from Cordis and the Ultrasoft SV from Boston Scientific) that can be used in CLI treatment and other types of peripheral vascular procedures.

New stents with applications in peripheral vascular therapy include the ML Vision from Guidant and the Lekton coated stent from Biotronik. Cordis also is beginning a randomized trial with its Cypher coronary stent for use in CLI patients, and initial results indicate a 94% limb salvage rate and very low rates of restenosis. The Lekton Magic Explorer, a bioabsorbable stent from Biotronik, also has shown promise for peripheral vascular therapy, with a 73% primary patency rate at six months in CLI patients.

Even better results have been demonstrated with the Xpert peripheral stent marketed by Abbott Vascular, a unit of Abbott Laboratories (Abbott Park, Illinois), as well as with Abbott’s Xceed stent, which has proven to be particularly effective for treatment of lesions in the superficial femoral artery. Studies with the Xpert stent have shown a 100% limb salvage rate and 90% primary patency at six months.

Another device that is gaining growing acceptance for peripheral vascular applications is the CLiRpath laser system from Spectranetics (Colorado Springs, Colorado). The Spectranetics system is particularly effective in treating long peripheral lesions, according to M. Bosiers of Imelda Hospital (Bonheiden, Belgium), and limb salvage rates of 95% have been reported when using the CLiRpath to treat CLI. Spectranetics reported a 97% increase in revenue from laser atherectomy products for 1Q06 compared to the like period in 2005, indicating both the rapidly growing use of endovascular techniques in peripheral vascular therapy and the expanding adoption of the Spectranetics technology in the treatment of conditions such as CLI.

In a presentation on CLI treatment at the EuroPCR conference, Dr. Sambeek said that up to 80% of all limb amputations may be preventable through use of the latest endovascular techniques. If only 25% of patients who are slated for amputation are salvaged through the use of endovascular therapy, the expected savings in healthcare cost in Europe are projected at EUR 3 billion.

In addition to the treatment of CLI, many interventional device suppliers also are targeting revascularization of the superficial femoral artery (SFA) as a major emerging opportunity in the European market.

For example, IDev Technologies (Houston) exhibited a new self-expandable nitinol stent for peripheral vascular applications, which will soon be available in Europe. The device has the highest radial strength of any device now on the market, but also exhibits the mechanical flexibility needed for applications in the SFA. According to IDev, Cordis now has a 50% share of the market for SFA stents in Europe, but IDev believes its new stent will allow it to capture increased market share once a delivery system for the stent is launched.

ev3 (Plymouth, Minnesota) also is targeting the SFA market, and is selling its Protégé EverFlex stent for SFA applications. Another new peripheral stent exhibited at the EuroPCR conference by Invatec (Roncadelle, Italy), the Cristallo iDEALE, is a self-expanding nitinol stent for use in carotid stenting. According to Invatec, about 15,000 carotid stent procedures are performed annually in Europe, and procedure volume is growing at more than 20% a year. In contrast, fewer than 100,000 carotid endarterectomy procedures are performed annually, and the number is stable or declining. More than 50% of carotid stent procedures are performed by interventional cardiologists. Since 70% to 75% of patients with a treatable carotid stenosis are asymptomatic, suppliers believe there is considerable room for market expansion in Europe.

Importance of vulnerable plaque detection

Another application highlighted at the EuroPCR conference was detection of vulnerable plaque, with the goal of identifying vascular lesions that are at high risk of rupture, leading to acute blockage of a coronary or peripheral artery. Technologies under development for detection and characterization of vulnerable plaque include optical coherence tomography (OCT), Virtual Histology using intravascular ultrasound imaging (IVUS), multi-slice CT, biomarkers, NIR spectroscopy, MR imaging including intravascular MRI, and radionuclide imaging to detect plaque metabolic activity.

As new devices such as next-generation drug-eluting coronary stents become available, particularly bioabsorbable devices that eliminate the need for extended (and perhaps lifelong) anti-coagulant therapy and avoid the presence of a permanent metal implant, interest is growing in the possibility of using stents to not only treat symptomatic stenosis but also in a preventative role to halt the progression of a lesion destined to otherwise cause an acute coronary event.

Multiple technologies may eventually have a role in vulnerable plaque detection, perhaps in a complementary fashion. As shown in Table 4, OCT has by far the highest spatial resolution, allowing assessment of plaque at a high level of detail, but with the disadvantage of requiring a flushing step in order to obtain a clear view of the vessel wall. IVUS, and particularly the Virtual Histology technology developed by Volcano (Rancho Cordova, California), has lower resolution, but has the advantage of not requiring a flushing step and also can be used to characterize plaque, at least to a degree, by analyzing the ultrasound reflectivity of the material.

Conventional angiography is probably one of the least effective techniques for analysis of vulnerable plaque, since recent studies have shown that plaque vulnerability is not associated with the degree of stenosis, and the spatial resolution of fluoroscopy is inferior to that of IVUS.

IVUS is perhaps one of the most promising technologies for vulnerable plaque detection, particularly since further refinements such as palpography are in development that could significantly enhance the ability to determine plaque characteristics and composition. Volcano may introduce palpography for its IVUS system as early as 2007.

Development-stage devices described at the EuroPCR conference for use in vulnerable plaque detection include an NIR spectroscopy catheter from InfraReDx (Burlington, Massachusetts), an intravascular MRI catheter from Topspin Medical (Lod, Israel), a nanotechnology-based MR imaging agent from Kereos (St. Louis) and the LightLab OCT system.

The InfraReDx NIR spectroscopy system uses a 3.2 Fr catheter and can perform a scan in 5 milliseconds to chemically characterize vessel tissue. The first human case was performed using the system in January, and a total of 22 cases have now been completed in the initial clinical evaluation of the device. An autopsy study is now under way to assess the correlation between the NIR spectral data and histology analysis. The technology could be particularly valuable if combined with imaging techniques such as IVUS.

The intravascular MR probe, described at the EuroPCR conference by Robert Wilensky, MD, of the Hospital of the University of Pennsylvania (Philadelphia), is currently deployed through an 8 Fr guide catheter, but the size will be reduced to 6 Fr to 7 Fr within a few months. MR imaging has the capability to differentiate lipid-rich from fibrous plaque, allowing detection of a key defining characteristic of vulnerable plaque. Studies described by Wilensky have shown that plaque characterization using intravascular MRI correlates well with IVUS, and a seven-center Phase II study is now under way to correlate intravascular MRI with angiography, biomarkers, IVUS and clinical factors. So far, 61 patients have been enrolled.

A second-generation version of the Topspin catheter is under development that will provide automatic imaging of the entire vessel circumference. Kereos is developing a nanoparticle MR imaging agent based on gadolinium-labeled perfluorocarbon nanoparticles in partnership with Philips Medical Systems (Best, the Netherlands).

One version of the agent is designed to bind specifically to fibrin, and thus may allow detection of microruptures in plaque corresponding to hot spots where rupture is imminent. Another version targets alpha v beta 3 integrin, which is a marker of angiogenesis, and may allow detection of regions of growing plaque. Studies with that agent have shown that development of collateral vessels can be detected as early as 10 days after vessel injury versus 40 days for conventional angiography. The Kereos technology may also have therapeutic applications. Studies using the alpha v beta 3 integrin-targeted particles loaded with fumagillan, an anti-angiogenesis drug, have shown that plaque growth can be inhibited.

Optical coherence tomography is showing promise for the detection of Thin Cap Fibrous Atheroma (TCFA), and is expected to be particularly valuable for detailed characterization of inflammation and calcification in the vessel wall. LightLab Imaging/Goodman, the developer of OCT technology for intravascular applications, has introduced the M2, a next-generation OCT system that employs a .006” diameter optical fiber to produce real-time, cross-sectional intravascular images of tissues that were previously obtainable only be excising a specimen.

A drawback of the system at present is the requirement for prolonged flushing of the artery to clear blood from the field of view. The flush procedure not only complicates use of the device, but also produces ischemia if used for extended intervals. LightLab is developing a rapid read system that will allow a pullback image to be acquired in five seconds, thus minimizing ischemia. The LightLab system is priced at EUR 40,000, and the disposable OCT catheter sells for about EUR 1,000, making it competitive with IVUS.

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