Cardiovascular Device Update Contributing Editor
BARCELONA — The treatment of cardiovascular disease in Europe is increasingly reliant upon interventional technologies, moving away from the use of open surgical techniques both for coronary and peripheral vascular disease. As shown in Table 1, interventional therapy is still less widely utilized for coronary artery disease in Europe than in the U.S., but the number of interventional procedures in Europe is continuing to grow, with the most recent projections indicating that the number of percutaneous coronary intervention procedures could reach 1.5 million by 2010.
In addition, the field is expanding to include a variety of peripheral vascular procedures including angioplasty and stenting of a widening range of vessels in the lower extremities as well as carotid stenting. There also is increasing interest in the use of transcatheter technologies for repair and replacement of heart valves, and of device-based interventions for treatment of congenital heart defects. The annual EuroPCR conference, held here in late May, provided an update on the latest trends in interventional technologies in Europe, including new technologies under development that promise to further expand the range of applications of endovascular therapy.
Advances were also described at the EuroPCR conference in guidance and imaging technologies that will impact the use of vascular intervention in Europe, including advanced technologies for treatment of chronic total occlusions and delivery of cell-based therapies for congestive heart failure.
Fusion in various ways
Image fusion technology, particularly the integration of computed tomography (CT) scans with angiographic images and integrated intravascular ultrasound (IVUS) and angiography, is rapidly becoming a standard capability in cath labs in Europe, providing interventionalists with improved information on lesion characteristics and distribution during a procedure, as well as on the quality of stent placement which can play a role in determining the rate of long-term complications such as late stent thrombosis.
Fusion is becoming a hot topic in med-tech these, especially when talking about bringing together devices and drugs — not just a matchup of technologies but a matching of the skill sets of physical engineers and bioengineers.
Drug-eluting stent (DES) technology — which has been widely employed in Europe longer than in any other region of the global medical device market — continues to be widely used in coronary procedures in Europe in spite of the highly publicized data showing long-term adverse events in patients with DES implants. Although the results of studies that indicated elevated long-term rates of stent thrombosis compared to bare metal stents (BMS) were first disclosed in Europe less than a year ago, DES utilization rates in Europe dropped only a few percent in the ensuing months, and stood at 51% of coronary stent procedures as of year-end 2006.
At the conference, the results of an electronic poll of attendees indicated that most (about 78%) expect the number of DES procedures to increase over the coming year. This may, in part, reflect the impending introduction of a number of new and improved devices in Europe that are expected to resolve, or at least diminish, the safety issues that have emerged for the current generation of DES. In addition, as discussed by Jean Marco, MD, of Unite de Cardiologie Interventional (Toulouse, France) at the EuroPCR conference, the confidence level of the metanalysis performed by Kastrati et al. and presented last September at the World Congress of Cardiology conference which first raised concern about long-term safety of DES is not as robust as one would like as the basis for a radical change in interventional strategy for coronary artery disease.
Other issues cited by Keith Dawkins, MD, of Southampton University Hospital (Southampton, UK) include the lack of correlation of the results from the Swedish Coronary Angiography and Angioplasty Registry (SCAAR), which showed an excess in mortality for patients DES-treated, compared to results from other studies.
COURAGE casts broad shadeow
Released at EuroPCR was a trial that cast doubt both on the efficacy of DES devices and on angioplasty/stenting in general, whether in DES- or BMS-use. Significantly, the COURAGE trial may have had the most impact on the general public as the result of global headlines and stories stating the trial’s main point — that the data found no difference between medical therapy (drug/behavior modification) and angioplasty/stenting, but providing no nuance concerning the various qualifiers to that primary conclusion. Those qualifiers are multiple.
COURAGE may not be relevant to the European setting, according to Dawkins, since it involved only those patients with stable coronary artery disease, and only 41% of those patients have a diagnostic catheterization performed in Europe. Furthermore, more than 35,500 patients were screened to enroll the approximately 3,000 patients who were included in COURAGE, casting doubt on how representative that study, which showed no benefit for stent therapy vs. medical therapy, is of the types of patients encountered in routine practice.
Patient compliance with medical therapy is another factor that may make it difficult to achieve the outcomes observed in COURAGE. While patients in COURAGE were closely managed to ensure complete compliance with multi-drug therapy regimens, patients in the real world are generally less compliant and compliance drops over time.
Dawkins showed data from a 2005 study performed by the Duke Clinical Research Institute (Durham, North Carolina) demonstrating that the percentage of coronary artery disease patients who are compliant with triple-drug therapy (combining aspirin, statins, and beta blockers) is only 21%. Furthermore, the percentage of patients who remain compliant drops from 69% for compliance with single-drug beta-blocker therapy at 30 days after discharge for myocardial infarction to 45% at one year. Such findings cast doubt on the likelihood of achieving the outcomes demonstrated in the COURAGE trial in actual practice.
DES 2.0 poised for sector entry
Clincians appeared to be less impressed by the COURAGE results, perhaps because the DES devices studied in the trial aren’t going to be the major market players by 2008, because they are likely to be elbowed to minor sector share by second-generation devices.
Several of the new DES devices under development were described by investigators at the EuroPCR conference that show promising results in clinical trials.
Sahajanand Medical Technologies (New Delhi, India) is developing the Supralimus Core sirolimus-eluting stent, based on the company’s Coronnium stent platform and employing a multi-layer bioabsorbable polymer coating, as well as similar drug loading and release characteristics to the Cypher stent now marketed by Cordis. A pilot study (the MAXIMUS trial) involving 100 patients treated with the stent showed a low 4% target lesion revascularization rate at 30-month follow-up and a low rate of late stent thrombosis.
One of the most promising new DES devices under development for initial introduction in Europe is the BVS stent from Abbott Vascular (Santa Clara, California). The BVS consists of a bioabsorbable backbone combined with a bioabsorbable polymer layer loaded with Everolimus.
The polymer dissolves more rapidly than the backbone, releasing the drug with a profile similar to that for the Abbott XIENCE V stent and the Cordis Cypher. That provides inhibition of neointimal proliferation to reduce restenosis while the backbone provides mechanical support for the vessel during the first few weeks post-implant. Both the polymer layer and the backbone dissolve over time, leaving no permanent implant in the vessel.
In the initial study of the BVS, the ABSORB trial, a higher-than-expected late loss was observed of 0.44 mm, which is midway between that for Cypher and a bare metal stent. The trial is encouraging in that no target lesion revascularization or stent thrombosis events have been observed at nine months. However, Abbott is re-designing the stent to provide added mechanical support to reduce late loss.
The BVS will expand Abbott’s coronary stent portfolio in Europe, which now includes the Xience V Everolimus-eluting stent launched late last year internationally.
SPIRIT trials look at Xience
Recent results from the SPIRIT trials of the Xience V, discussed by Greg Stone at the EuroPCR, continue to be favorable compared to leading coronary stents in the European market such as Cypher and Taxus. According to Stone, the target lesion revascularization rate in the SPIRIT First trial of the Xience V stent at three year follow-up is 7.7% compared to 25% for a BMS.
In the SPIRIT II and III trials comparing Xience V to Taxus, the target lesion revascularization rate is only 2.4% for Xience vs. 5.1% for TAXUS, and the rates of stent thrombosis at nine months are statistically equivalent (0.45% for Xience vs. 0.25% for TAXUS). A key differentiating feature of the Xience stent is its thin struts, which are the thinnest of any device now on the market in Europe. That feature reduces the exposure of tissue to the stent materials, in principle diminishing inflammatory reactions and facilitating endothelial cell coverage of the stent.
In fact, as discussed by Renu Vermani, MD, of CVPath Institute (Gaithersburg, Maryland), less inflammation has been observed in studies of the Xience stent compared to the Cordis Cypher. With the new BVS stent, Abbott hopes to achieve at least equivalent low rates of TLR while minimizing the incidence of late stent thrombosis, since there is no device remaining in the vessel once the stent backbone dissolves.
Another promising DES product is under development by Biosensors International (Singapore). The company’s Biomatrix stent uses a polymer loaded with Biolimus A9 plus an abluminal surface coating that reduces exposure of the polymer to the bloodstream and that therefore may produce less thrombosis.
In the STEALTH I trial, discussed at the conference by Alexandre Abizaid, MD, of Instituto Dante Pazzanese de Cardiologia (Sao Paulo, Brazil), results of two year follow-up show no late stent thrombosis, although the rate of major adverse coronary events was not statistically different from that for a BMS device at 6.5% for the Biomatrix vs. 8.1% for the Biosensors’ S-Stent. Studies are now underway using the Biomatrix stent in more complex lesions where it may have significant advantages compared to a bare metal stent. Biosensors expects to receive a CE mark shortly to allow the Biomatrix stent to be launched in the market in Europe.
Another emerging competitor in the European coronary stent market, Medtronic (Minneapolis), markets the Endeavor DES. The Endeavor has the thinnest polymer of any DES on the market in Europe, and perhaps as a result has exhibited lower rates of stent thrombosis compared to stents such as the Cypher and TAXUS, although so far there is no data from large randomized studies directly comparing the devices. Rates for TLR appear slightly higher at 7.3% at three years.
As discussed by Andreas Zeiher, MD, of J.W. Goethe University (Frankfurt, Germany) at the conference, three- and four-year follow-up in the Endeavor trials shows rates of stent thrombosis of 0.5%, lower than achieved in randomized trials with either Cypher or Taxus, although it is not valid to compare results from different trials. Medtronic has just initiated an 8,800-patient trial, PROTECT, that will provide a head-to-head comparison with the Cypher stent.
Although newer DES devices appear to have some advantages compared to the first-generation devices, there are also some measures that can help to reduce adverse events with all stents. As discussed by Antonio Colombo, MD, of EMO Centro Cuore Columbus (Milan, Italy) at EuroPCR, DES should not be used when a detailed medical history cannot be obtained, since the ability of a patient to comply with long-term antiplatelet therapy cannot be assessed.
In addition, most patients are still not evaluated for resistance to anti-platelet drugs, which occurs in at least 10% of all patients, because a good test for resistance is not yet available, according to Colombo. In the RE-CLOSE study, for example, non-responders had a two-fold higher rate of events. Another factor cited by Colombo is optimization of stent placement using IVUS guidance. Colombo has found that early stent thrombosis can definitely be reduced if IVUS is employed to ensure optimal placement.
New technologies under development for coronary stents were described in a special session at the conference highlighting recent advances in revascularization technology. Refat Jabara, MD, of St. Joseph’s Research Institute (Atlanta) described a new polymer platform developed by Bioabsorbable Therapeutics (Menlo Park, California) to address issues with inflammation caused by currently available polymer coatings for stents.
The new polymer includes salicylic acid as its base component, which is the active ingredient in aspirin, and therefore acts as an anti-inflammatory agent. The polymer is biodegradable, and dissolves over a period of about one month. The company has performed an animal study using its polymer as a stent coating loaded with sirolimus, and found that the drug release characteristics are very similar to those of the Cypher stent. Binary restenosis in the animal study was similar to that for the Cypher stent (6% at one month follow-up compared to 5% for Cypher).
BTI is developing a fully absorbable stent employing its polymer platform that consists of a three-layer structure with a top coating, a drug-eluting layer, and an undercoat layer deposited on a bioabsorbable polymer stent. Radial strength of the stent is 1.1 compared to 1.85-1.9 for Cypher. The company is now performing a large-scale animal study with the new device, and plans to begin first-in-man studies in Israel in 2008.
2.0 coatings also coming
Another new stent coating technology was presented at the EuroPCR sessions by AlchiMedics (Massy, France). AlchiMedics is developing electrografting coating technology, in which electrical current is employed to covalently bond a polymer to the surface of a bare metal stent. Coatings ranging from 1 to 300 microns in thickness can be fabricated which are biodegradable and produce minimal inflammation in animal studies.
In addition, greater than 90% of the stent surface is covered with endothelial tissue. A coating consisting of butyl-methacrylate plus a PC2 layer has been developed that eliminates the need for the Parylene C primer layer used in most stents now on the market, and which can be loaded with antiproliferative drugs.
A key advantage of the AlchiMedics technology is that the thickness of the drug-eluting polymer can be precisely controlled, allowing the total drug dose to be optimized. According to Renu Vermani, MD, who discussed the AlchiMedics electrografting technology, a possible limitation of existing DES is that the total drug dose is excessive.
Balloon catheter in development
An alternative approach to drug delivery for use in coronary stent applications under development by GlobaMed (Switzerland) was described at EuroPCR by Christian Herdeg, MD of Eberhard-Karls-Universitaet (Tuebingen, Germany). GlobaMed is developing the GENIE catheter, a balloon catheter designed to infuse an anti-proliferative drug such as paclitaxel into the wall of a stented vessel.
Potential advantages include more homogeneous distribution of drug than can be achieved via a DES, coverage of tissues at the stent edges and in adjacent regions of the blood vessel, elimination of inflammatory or thrombogenic polymers, ability to treat several vessel segments with a single catheter, and lower cost compared to DES.
The device is configured as a double occlusion balloon catheter, with drug infused between the two balloons. Total contact time for the drug infusion procedure is about two minutes, and studies show that 5% to 10% of the total infusion drug is delivered to the vessel wall.
Drugs such as paclitaxel are highly lipophilic, and thus tend to sequester in the tissue and exert a lasting anti-proliferative effect after the catheter has been removed. Initial studies in animals have demonstrated complete inhibition of proliferation at 14 days. The company completed enrollment in a pilot trial of the device in February 2007 (the LOCAL TAX trial), and expects to present results in August.
A paclitaxel-eluting balloon catheter using microporous balloon technology, the Dior, is already available in Europe from Eurocor (Bonn, Germany). The Dior uses a single balloon which is inflated at the lesion site for 60 seconds to achieve full release of the drug into the vessel wall. The technology was originally evaluated in the Paccocath paclitaxel-eluting balloon catheter for treatment of in-stent restenosis.
Another area highlighted at the conference was new technologies for treatment of chronic total occlusions (CTOs), which remain the most common factor responsible for patient referral to bypass surgery rather than interventional therapy. More than 30% of coronary artery disease is attributable to CTOs, yet only 25% of CTOs are treated using percutaneous coronary intervention. More than 80% of failed PCI procedures can be attributed to CTOs.
CTOs are also an important issue in peripheral vascular disease, and are the cause of roughly 150,000 amputations of the leg in the U.S. annually. One new device for CTO therapy, the CiTOP guidewire, was exhibited by Ovalum (Rehovot, Israel). The CiTOP is a 0.014 inch nitinol/stainless steel guidewire with a controllable, expandable tip. The wire is advanced in 1 mm increments through a CTO, and can be expanded to allow penetration of microchannels that are found to occur in more than 85% of all CTOs.
The microchannels typically measure between 100 and 200 microns in diameter, and are believed to develop as a natural response to the local ischemia occurring at the site of a total occlusion. The CiTOP wire allows controlled penetration of a CTO via microchannels, and provides a more precise approach for crossing an occlusion than alternatives such as radiofrequency ablation. The CiTOP is supplied with a companion microcatheter that provides mechanical support during the crossing procedure. After the CTO is crossed, the wire can be used like any other guidewire to deploy balloon catheters and stents.
A second technology for crossing of CTOs is being developed by Stereotaxis (St. Louis). The Stereotaxis Magnetic Navigation System is being used in conjunction with fused multi-slice CT and magnetic resonance imaging to guide a radiofrequency ablation wire through a total occlusion. The system provides 3D control of the RF guidewire, allowing the interventionalist to position the wire’s tip in the desired location in an occlusion and then ablate a pathway through it.
The company expects to receive a CE mark for use of the Navigant user interface and magnetic navigation system for CTO procedures later in 2007, and will also seek FDA clearance. The Stereotaxis system is being marketed in Europe by Siemens Medical Solutions (Munich, Germany).
Interventions for peripheral disease
The utilization of vascular intervention in peripheral vascular disease is also expanding in Europe, largely through replacement of open surgery. As shown in Table 2, total peripheral vascular procedure volume in Western Europe, including both endovascular and surgical procedures, is increasing at about 1.2% a year, but endovascular procedures are expanding at 14.6% per year while surgical procedures are declining at 9.7%, based on 2004-2005 data. Femoro-popliteal and aorto-iliac procedures account for most endovascular procedures performed in Western Europe, although carotid stent procedures are increasing the most rapidly.
As discussed by Frank Vermassen, MD, of Ghent University Hospital (Belgium) at the EuroPCR sessions, DES devices have so far had limited applications in peripheral vascular therapy, partly because of the high level of inflammatory response of such vessels, as well as because of fractures occurring in the struts of some stents used in initial trials in the superficial femoral artery.
Stents are of little value in treating small lesions in peripheral vessels, since angioplasty (peripheral transluminal angioplasty or PTA) is generally effective in those cases. Stents are also not used extensively in long peripheral vascular lesions due to high rates of restenosis in long stents used in peripheral vessels.
However, a number of new devices have entered the market in Europe that provide improved performance, and that are helping to drive the trend toward greater use of interventional therapy in the peripheral vessels. Stenting is even being employed in the tibial vessels below the knee for limb salvage in patients with critical limb ischemia, where small-diameter stents including DES are being evaluated.
Bioabsorbable stents may also play a role, such as the Igaki-Tamai stent being developed for treatment of superficial femoral artery stenosis by Kyoto Medical Planning (Japan). The Igaki-Tamai stent has been re-designed to provide enhanced radial strength, and is being evaluated in a clinical trial with over 100 patients now enrolled.
The company expects to receive a CE mark in the fall of 2007, enabling launch of the device in Europe. IDev Technologies (Houston) is another emerging player in the peripheral vascular stent market in Europe, and expects to obtain a CE mark for its Supera stent in early June. The Supera is a self-expanding nitinol stent with a woven design.
Unlike the Boston Scientific Wallstent — which is widely used in peripheral vascular applications — the Supera can be re-captured after it is first deployed if positioning is not optimal, and re-deployed in the correct location. The Supera also features 10-fold higher radial strength compared to other stents available for superficial femoral artery applications.
Abbott Vascular reported the initiation of a clinical trial to evaluate a new self-expandable DES for treatment of superficial femoral artery stenosis at the EuroPCR conference. While DES devices have been evaluated in the SFA previously by Cordis in the SIROCCO trial, issues with stent fractures have so far proven challenging.
The Abbott stent, which uses the Everolimus drug employed in the Xience V coronary stent, has been specifically designed to withstand the stresses encountered in vessels in the leg. The first patient was enrolled in the SFA Treatment with Drug-Eluting Stents (STRIDES) trial on May 23.
Growth in Europe projected
There is considerable potential for growth in the peripheral vascular interventional device market in Europe.
According to experts presenting at the EuroPCR conference, such as Giancarlo Biamino, MD, of Heart Center (Leipzig, Germany), from 35% to 40% of the approximately 180,000 leg amputations performed in Europe annually could be avoided through the use of endovascular techniques.
Demand is increasing in part due to the continue increase in prevalence of diabetes in Europe, as well as in many other countries, which often leads to peripheral vascular disease.
Results from the BASIL study have shown that endovascular therapy is at least equivalent to surgery for treatment of critical limb ischemia, and less invasive therapy is clearly the preferred option from the patient perspective.
As indicated by the data in Table 2, carotid stenting is an expanding segment of the peripheral interventional device market in Europe. While procedure volume remains relatively low, there is substantial growth in the market. For Europe as a whole (including countries outside of Western Europe), suppliers estimate total carotid stent procedures at about 25,000 annually, compared to about 100,000 carotid endarterectomy procedures.
The market for carotid stents in Europe is dominated by Germany and Italy as a result of reimbursement policies which have few limitations in those countries, whereas in countries such as France and Belgium the limitations on reimbursement have so far limited the use of carotid stents.
Leading devices in the market include the Carotid Wallstent and the NexStent from Boston Scientific, the XACT and AccuLink stents from Abbott Vascular, the Cordis Precise Rx stent, the Protégé stent from ev3 (Plymouth, Minnesota), and the Exponent RX stent from Medtronic. Boston Scientific claims a 50% share of the carotid stent market in Europe for the Wallstent.
Invatec (Roncadelle, Italy) also markets a carotid stent in Europe, the Cristalle iDEALE, along with the MOMA cerebral protection system. According to Trevor Cleveland of Sheffield Vascular Institute (Sheffield, UK), who discussed carotid stent selection at the conference, closed cell designs, as represented by the Wallstent, NexStent, and Xact stent, have generally produced superior outcomes in symptomatic patients compared to open cell stents such as the AccuLink, Precise and Protégé.
However, open cell designs have advantages in stenting of tortuous vessels, where the more rigid characteristics of closed cell stents can make optimal deployment difficult.
Another important component for carotid stenting procedures is embolic protection devices, either using filters or balloon occlusion devices. Leading devices include the Filterwire EX from Boston Scientific, the Interceptor Plus filter and the Guardwire occlusion and aspiration system from Medtronic, the TWIN ONE balloon occlusion system from Minvasys (Gennevilliers, France), the Spider FX from ev3, the Parodi balloon occlusion system from W.L. Gore (Flagstaff, Arizona), the Emboshield from Abbott Vascular, and the Angioguard RX from Cordis.
While use of embolic protection is recommended in all carotid stent procedures, the results of an electronic poll at a EuroPCR session on carotid stenting indicate that only about 70% of interventionalists actually employ the devices regularly.
Advances in Percutaneous Valve Repair
Repair and replacement of defective heart valves was a major topic addressed at EuroPCR, including development-stage transcatheter devices for repair of mitral, aortic, and pulmonic valve disorders. Devices for aortic valve treatment address the largest market opportunity in Europe, comprised of three million individuals with aortic stenosis.
About 20%, or 600,000, can benefit from therapy, but at present only 60,000 valve replacement procedures are performed annually, since up to 30% of patients who can benefit from treatment are not referred by physicians. In addition, a significant proportion of patients who are elderly or unsuitable for open heart surgery are not treated. Percutaneous valve repair technologies can potentially expand the market by allowing treatment of a wider range of patients, including those at high surgical risk as well as those who wish to avoid open surgery.
At least 35 companies are developing percutaneous valve repair and/or replacement devices, including major suppliers of surgically implanted valves such as Edwards Lifesciences (Irvine, California), as well as early-stage companies focused on heart valve technology such as CoreValve (Irvine, California). CoreValve received the CE mark for its ReValving System on May 16, making that device the first percutaneous valve replacement system to receive European regulatory approval.
The company will not immediately market the ReValving System, but will continue with clinical evaluations at selected centers to ensure that interventional cardiologists are well trained, that patients are appropriately selected, and that adequate clinical follow-up is achieved.
Edwards is likely to be the second company to attain regulatory approval, based on the total number of clinical procedures performed to date as shown in Table 3. Edwards is the leader in the conventional tissue heart valve market worldwide. The company is also developing the Monarc system for transcatheter mitral valve repair, and has completed a total of 59 procedures using the device in Germany, France, Sweden and Canada.
As described by Alec Vahanian, MD, of Bichat Hospital (Paris) at the EuroPCR sessions, 86.5% of the treated patients were event-free at 90 days, and 92% of patients responded with a reduction in mitral regurgitation at 180 day follow-up. Based on some positive results of the trial, a larger study involving 120 patients at 19 sites, EVOLUTION II, is planned, followed by a randomized controlled pivotal trial.
Implants get ‘smart’
MiCardia (Irvine, California) is developing smart implants for treatment of heart valve disorders that employ radio frequency (RF) energy to re-shape the implant. The MiCardia device provides dynamic control of mitral valve repair, and consists of a nitinol annuloplasty ring with three activation zones. Low power RF is applied either intra-operatively or via a transeptal catheter to selectively activate each zone and effect a change in shape of the implanted ring.
MiCardia is also developing a version of the device that would allow a reversible shape change, and is working on a focused induction device that would provide noninvasive activation.
Percutaneous valve repair and replacement devices represent a significant market opportunity in Europe and worldwide.
According to data from the Millennium Research Group (Toronto) presented at the conference by Valentin Fuster, MD, the total worldwide heart valve market is projected to increase from somewhat more than $500 million in 2005 to more than $720 million by 2010, with growth accelerating beginning in 2008 as percutaneous and transcatheter valves start to impact the market by expanding the patient population.
The percutaneous heart valve market is forecast at $78.4 million in 2008, increasing to $149.2 million by 2010. Sales are expected to exceed $1.15 billion by 2015, with an estimated average selling price for aortic valve repair devices of somewhat less than $10,000 and an average selling price of somewhat less than $8,500 for mitral valve repair devices.