CD&D Contributing Editor
BARCELONA, Spain —EuroPCR, a prestigious meeting organized by the European Association of Percutaneous Cardiovascular Interventions (EAPCI), an association of the European Society of Cardiology (Sophia Antipolis, France) and a group focused on interventional devices used for diagnosis and treatment of cardiovascular disease, is the leading interventional meeting in Europe and an important forum for introducing new devices.
At the EuroPCR 2008 gathering held here in mid-May, transcatheter heart valves were a key focus, with growing interest about the technology among cardiologists throughout Europe now that devices are commercially available. The wide range of new devices under development described at EuroPCR indicates that the transcatheter valve market will quickly become highly competitive in Europe, while still representing a significant opportunity for expansion for device suppliers.
Advances in stents, including drug-eluting stents (DES), bioabsorbable devices, stents for bifurcation lesions, and new peripheral vascular stents also were described at the EuroPCR congress.
Bifurcation stents are potentially applicable to 20% of all percutaneous interventional procedures performed worldwide, or about 450,000 procedures annually, with a market opportunity approaching one-third of that for existing drug-eluting coronary stents.
Other areas addressed at the EuroPCR conference included new devices for thrombus removal, as well as new vascular protection devices for reducing procedure-related complications and stroke prevention.
A major theme of this year's EuroPCR conference was promotion of increased collaboration among disciplines, particularly between interventional cardiologists and cardiac and vascular surgeons, in the implementation of new procedures and treatments.
For example, in the implementation of new technologies such as transcatheter repair or replacement of heart valves, interventional cardiologists lack the daily hands-on experience in working with the heart that cardiac surgeons obtain in performing open-heart surgical procedures. Working as a team, cardiologists and surgeons along with nurses and technicians can apply their complementary expertise in heart anatomy and interventional technology to optimize transcatheter valve procedures. All of this represents a divergence from talk of turf battles, perhaps more of an analyst' concern than actual practice.
Surgeons are increasingly adopting interventional techniques themselves, as the continued replacement of open surgery with minimally invasive treatment reduces demand for their services. The trend is likely to continue, driven by patient preference for less invasive therapy and the on-going evolution of interventional technologies that in many cases now produces outcomes for interventional treatment that are equivalent to those achieved with surgery.
Emerging: transcatheter valves
Heart valves that can be implanted via transcatheter techniques have been under development for over a decade, building on vascular stent technologies combined with conventional prosthetic and tissue heart valve components.
The first device has now reached the market in Europe, the Sapien valve launched in the first quarter of 2008 by Edwards Lifesciences (Irvine, California). Transcatheter valves address a significant and growing market opportunity, as shown in Table 1.
At present, indications for use for transcatheter valves are for patients with severe valve disease who are not eligible for surgical treatment due to co-morbidities that place them at high surgical risk. Due to the restrictions for use of surgically implanted valves, treatment is limited to 47% of patients in Europe and 36% of patients in the U.S. who could benefit from valve repair or replacement.
In European registries, transcatheter valves have mainly been implanted in patients over the age of 70. However, as transcatheter valve technology advances and physicians gain experience with the devices, indications could expand to include some of the patients who are now treated with open surgery, and possibly patients with moderate valve disease whose condition does not warrant surgical repair but who could benefit from minimally invasive therapy.
Leading companies with transcatheter valves and valve repair devices in development in addition to Edwards are described in Table 2.
Companies with the most advanced development programs include CoreValve, EValve, and Medtronic. CoreValve received a CE mark for its Percutaneous Aortic Valve Replacement (PAVR) Revalving System over a year ago, and is continuing with an expanded clinical evaluation of the device at a small number of centers.
As of mid-May, more than 1,000 high-risk patients had been treated using the CoreValve PAVR system. Both EValve and Medtronic also have received the CE mark for their transcatheter heart valve repair and replacement devices.
Since Edwards introduced the Sapien transcatheter aortic valve in Europe under a CE mark at the start of this year, more than 200 have been implanted, and sales of the device totaled $8.1 million for 1Q08. Edwards is forecasting sales of more than $20 million for all of 2008. Including devices implanted in clinical trials, more than 1,000 Sapien valves have now been implanted worldwide. Patient outcomes have improved as physicians have gained experience, with survival improving from 78% to 93% and significant improvement in patient symptoms and quality of life.
As discussed by Martyn Thomas, MD, of Kings College Hospital (London) at EuroPCR, analysis of patients receiving implants of the Edwards valve in the U.K. has also demonstrated that the treatment is cost-effective, with a computed cost per quality life year of between £1,760 and £2,200 (about $3,500 to $4,400). That figure is well under the acceptable threshold for adoption of new medical devices, which for some commonly used devices ranges up to $50,000.
New developments in transcatheter valve technology are focusing on improved durability (i.e., implant life), greater ease of use, and reduced or modified device profiles to minimize access site complications, which remain high at 5-7% due to the relatively large device diameter.
The latest version of the Edwards Sapien transcatheter valve, with the RetroFlex II delivery system, features a nosecone at the tip of the delivery catheter to provide less trauma upon femoral artery insertion. Edwards will introduce the RetroFlex III system later this year which will feature a smaller overall device profile. Improvements in durability are being pursued although the flexibility required of the components in an expandable valve limits the durability that can be achieved, and it is likely to prove difficult to achieve a lifetime equivalent to that of a surgical valve in a transcatheter device.
In vitro durability testing of the Sapien valve has demonstrated a lifetime of five years so far, and accelerated fatigue testing indicates the device will last up to 15 years. Device durability is becoming increasingly important for heart valves since patients with prosthetic valves are living longer than in the past, with a lifetime post-implant of 10 years not uncommon.
Avoidance of multiple valve repair or replacement procedures is very important to patients, so increased device lifetime will continue to be a development focus for manufacturers. For surgical valves, the current benchmark for valve lifetime, 90% of patients are free from re-operation at 20 years, so considerable room for improvement for transcatheter valves remains.
New uses for RF energy
Two devices, the MiCardia Dynamic Annuloplasty Ring and the QuantumCor Catheter, that employ a unique approach to mitral valve repair using RF energy are under development. The MiCardia device is a surgically implanted shape memory metal ring that can be activated using low-energy (less than 4 watts) RF energy applied for three minutes to effect an adjustable change in shape of the ring for elimination of mitral regurgitation. The surface temperature of the ring does not exceed 42 C during the procedure, avoiding damage to the surrounding valve tissue.
The company has completed in vitro fatigue testing of 600 million cycles, and has also successfully completed a 20-week trial in animals. Human trials are planned for later this year. MiCardia will subsequently develop a catheter-based version of the device.
The QuantumCor Catheter does not employ an implantable device, but rather uses RF energy to modify the tissue structure of the native mitral valve for correction of regurgitation.
The initial version of the catheter is designed for transapical access, and has a 6F profile. A StarClose vascular closure device from Abbott Vascular Devices (Santa Clara, California) is used to seal the puncture site. An advantage of the QuantumCor Catheter is that no permanent implant remains in the body, and the minimally invasive nature of the procedure may allow treatment of a larger proportion of the 400,000 patients with mitral regurgitation than are currently treated with surgical techniques.
Symetis (Lausanne, Switzerland) is a relatively recent entrant in the transcatheter valve arena. The company was founded in 2001 to develop a tissue-engineered heart valve, but for the past one and one-half years has focused on development of a transcatheter aortic valve comprised of a self-expanding nitinol stent and a porcine valve sutured into the stent frame. The device is designed for transapical access, with a relatively large 30 Fr profile.
Advantages of the Symetis valve include lack of a requirement for rapid pacing of the heart during implantation, a feature achieved via the self-centering capability of the self-expanding stent; and transapical access which avoids crossing of the often calcified native valve and the attendant risk of neurological complications due to embolization of friable material during passage.
Symetis is performing animal studies with the device, and plans to enter human trials in about a year.
JenaValve (Jena, Germany) is another recent entrant in the transcatheter valve competition, having been founded in September 2006 to develop minimally invasive heart valve replacement systems. A key feature of the JenaValve is its ease of placement, which derives from the active fixation feature of the device including positioning feelers that provide real-time feedback to the physician on the position of the stent relative to the native valve. The valve also is completely retrievable prior to release. The JenaValve will be supplied in 22 Fr and 32 Fr sizes.
New developments for stenting
Drug-eluting stents were another major focus of the conference. The segment is fast-moving in Europe, where a number of devices are now on the market, including second-generation stents that, based on recent clinical trial results, offer advantages over the first-generation Cypher and Taxus stents from Cordis (Miami Lakes, Florida) and Boston Scientific (Natick, Massachusetts).
For example, Gregg Stone, MD, of Columbia University Medical Center (New York) discussed two-year results from the SPIRIT III trial comparing the Xience V drug-eluting stent from Abbott Vascular to the Taxus in 1,002 patients. A statistically significant 31% reduction in target vessel failure was observed for Xience vs. Taxus at two years (10.7% vs. 15.4%), and major adverse cardiac events were 7.3% compared to 12.8% for Taxus, also a statistically significant reduction. Importantly, stent thrombosis rates were also lower for the Xience V, indicating a superior safety profile.
Another promising stent is the S-Stent from Biosensors International (Singapore). The S-Stent employs Biolimus A9, a rapamycin analog with potency and mode of action similar to that of Sirolimus, the drug used in the Cordis Cypher stent. The S-Stent, however, uses a biodegradable D,L-polylactic acid coating, in principle avoiding the inflammatory reactions that occur with first-generation polymer coatings, and also is designed to elute drug only from the abluminal surface of the stent, resulting in lower blood levels of drug vs. Cypher.
As discussed by Stephan Windecker, MD, of the Swiss Cardiovascular Center (Bern) at EuroPCR, the latest version of the S-Stent does not use a primer coating underneath the biodegradable coating, thus eliminating a potential source of inflammatory reactions. The more targeted delivery of drug may explain the significantly lower rate of late acquired stent malapposition observed with the S-Stent compared to Cypher and Taxus, a factor thought to increase the risk of stent thrombosis, particularly late thrombosis. In fact, in clinical studies with the Biolimus A9-eluting stent conducted so far, there have been no late or very late stent thrombosis events, according to Windecker, although so far the number of treated patients is small.
Another next-generation drug-eluting stent, the Custom NX DES stent from Xtent (Menlo Park, California), offers an innovative approach for more effective stenting of complex cases, particularly in patients having multiple separate lesions as well as long lesions.
The device consists of multiple DES devices loaded onto a single delivery catheter, enabling the stent length to be customized to both the length and diameter of a lesion. A biodegradable polylactic acid coating is applied over a Parylene C undercoat, and the PLA coating is loaded with Biolimus A9, licensed from Biosensors. Multiple separate lesions can be treated with a single stent delivery catheter, as can long lesions of up to 60 mm.
A key feature of the device, as described by Bernard De Bruyne MD, PhD, of Cardiovascular Center, OLV Hospital (Aalst, Belgium), is the elimination of overlap between adjacent stents, as can occur when stenting long lesions with individual stents. Thrombus is often observed at the site of such overlaps, according to De Bruyne, increasing the risk of stent thrombosis.
The Xtent device avoids that problem since the segments are pre-positioned to eliminate overlap. In animal studies conducted with the Xtent NX DES to date, no inflammatory reactions have been observed, and good conformation of the stent to the vessel contour is achieved even for long convoluted lesions.
Three clinical trials have now been conducted with the Xtent device (CUSTOM I, II and III), all showing consistent results. In CUSTOM III, as described by Eberhard Grube, MD, of Helios Heart Center (Siegburg, Germany), no late thrombosis has been observed in patients with lesions of 20 mm in length treated with dual anti-platelet therapy for three months, and the TLR rate at six months was 5.6%. Neointimal volume at six months is equivalent to that seen with the Cypher stent.
A potential issue for the NX DES, as discussed by Grube, relates to regulatory approval, since there are no other comparable stents on the market for long lesions. The FDA has already determined that comparison to multiple DES use in long lesions, such as multiple Cypher stents, is not valid, necessitating a different regulatory approval strategy for Xtent in order to commercialize its device.
Alternate stent coatings
MIV Therapeutics (Vancouver/Atlanta) is developing a new DES based on a hydroxyapatite surface coating that can be loaded with drug-containing lipid particles which sequester in nanopores formed in the coating. The lipid encapsulation improves drug uptake in the surrounding tissue, and prevents premature washout. As a result, drug dosage can be minimized, and biocompatibility is improved since there is no polymer coat.
A clinical trial of the Vestasync stent initiated in late May 2007 has shown that deliverability is similar to that for a bare metal stent, due to the lack of a polymeric coating, and no major adverse coronary events or target lesion revascularization has been observed at nine month follow-up. Late loss at nine months is only 0.2 mm, comparable to the Cypher stent.
Medtronic Vascular, one of the leading DES suppliers in Europe, is continuing to improve its Endeavor stent family with the development of a new surface coating, the BioLinx polymer coating, employed on the Endeavor Resolute DES. Endeavor Resolute received CE marking in October 2007 and is now available in more than 100 countries outside the U.S.
The BioLinx coating combines hydrophilic and hydrophobic elements, enhancing compatibility with the body which is 70% water, and shows significantly lower up-regulation of prothrombin genes and inflammatory genes in vascular tissue compared to the polymer coatings employed in the Cypher and Taxus stents. In fact, the inflammation score determined from histopathology analysis is the same for the BioLinx coated stent as for the Medtronic Driver bare-metal stent. The score is also significantly lower than for the original Endeavor stent.
Lack of inflammatory reactions has been verified out to one year with Resolute. At nine month follow-up, late loss for Endeavor Resolute is 0.22 mm, and binary restenosis is 1%, while the MACE rate is 6.9%. Medtronic initiated a pivotal, 2,300 patient international trial, the RESOLUTE III All-Comers Trial, in late April/early May that will compare Resolute to the Abbott Xience V.
Endeavor Resolute clearly appears superior to the original Endeavor stent based on initial results of the RESOLUTE trial. However, cardiologists discussing the trial results at EuroPCR agreed that the Resolute stent should be reserved for high-risk patients for now, with the original Endeavor stent remaining the device of choice for first-line therapy until more data from randomized controlled trials and device registries is available for Resolute.
Medtronic captured 20% of the coronary stent market in the U.S. as of Q4 2007 following the U.S. launch of Endeavor, and the company's worldwide coronary stent revenue for 2007 of $710 million was up 27% vs. 2006 (see Business developments, p. x).
Stents for bifurcation lesions represent an emerging segment of the coronary stent market, addressing 18%-20% of all patients undergoing PCI procedures, or about 450,000 patients worldwide.
A number of bifurcation stents are under development, as shown in Table 3, and three devices now have a CE mark, making them commercially available in Europe. Prior to the introduction of bifurcation stents, cardiologists treated bifurcation lesions using conventional coronary stents, including DES devices, and many continue to use that approach rather than switching to newer dedicated bifurcation devices.
However, use of separate stents is a demanding technique, requiring precise placement of the stents and optimal expansion to achieve conformation to the highly variable contours of bifurcations encountered in clinical practice. Dedicated bifurcation stents promise a less complex, more reproducible procedure and, potentially, more uniform coverage of the bifurcation than can be practically achieved with separate stents.
One of the first bifurcation stents to be developed, the Axxess stent from Devax, is a self-expanding, nitinol DES with a PLA coating loaded with Biolimus A9 that covers the carina of a bifurcation with a single device, and allows two additional stents to be placed distally in the main and side branches if needed.
Clinical trial results with the Axxess stent, as reported in the DIVERGE trial, show a restenosis rate of 4% to 8%. As of December 2007, more than 500 patients had been treated worldwide with the Axxess stent, including more than 400 with the drug-eluting version.
Stentys a newcomer
Stentys (Paris) is one of the more recent entrants in the bifurcation stent segment, and is developing a stent with detachable connectors integrated into the struts. After placement of the stent in the main branch of a bifurcation, a balloon catheter is inserted through the struts into the side branch and inflated. The balloon causes the struts to disconnect, allowing them to be expanded to the vessel wall, leaving no metal in the ostium. The design allows tolerance in positioning of the stent, and provides complete ostium coverage while exerting a high radial force to avoid elastic recoil.
Another important feature of the Stentys system is its use of only one guidewire for placement of the primary stent as well as a second sidebranch stent if needed. ther bifurcation stent designs that require use of two guidewires for delivery create a risk of wire wrap, or entanglement of the wires.
A further advantage of the Stentys device is its lack of distortion of the vessel anatomy, which may lead to improved outcomes although so far there is no data to demonstrate that benefit. In the first-in-man trial of the Stentys device, there have been no target lesion revascularization or major adverse coronary events in treated patients since the study began in September 2007.
The Minvasys (Genevilliers, France) Nile CroCo is one of the most widely used dedicated bifurcation stents in Europe. More than 3,000 have been implanted to date. The privately held company, which has annual sales of more than EUR 6 million and was founded in 2003, has patented its bifurcation stent design and will next introduce a drug-eluting version, the Nile Pax. Three clinical trials of the Pax are under way or in the planning stage, including the BiPAX trial that will begin in summer 2008.
The newest entrant in the bifurcation stent segment is Medtronic, which is developing a device based on its Driver BMS platform. The Medtronic bifurcation stent is now undergoing first-in-man trials, with 12 patients treated as of May 2008. The trial will enroll a total of 60 patients, and results are expected by the end of 2008. The device has a 7F profile, and plans call for development of a drug-eluting version. Medtronic has developed a tool to eliminate wire wrap for its bifurcation stent, and may sell that device separately for use with other bifurcation stents.
The latest developments in vascular protection devices for reducing the rate of adverse events in high-risk procedures such as PCI in diseased saphenous vein grafts and in patients with acute coronary syndromes were discussed in numerous sessions at the EuroPCR conference.
InspireMD (Tel Aviv, Israel) reported the most recent results from the MGuard Coronary Stent First-in-Man study, which demonstrated a target lesion revascularization rate of 6.6%, a MACE rate of 6.6%, late loss of 0.38 mm, and binary restenosis of 6.6% at six-month follow-up. The study has enrolled 60 high-risk patients with complex lesions.
The key feature of the MGuard stent used in the trial is its use of an ultra-thin, micron level fiber mesh covering over a metal stent framework. The mesh captures debris that would otherwise be released into the bloodstream during an implant procedure, or subsequent to the procedure, that could cause distal embolization. The MGuard stent, which already has a CE mark, is particularly promising for use in saphenous vein grafts, arteries containing thrombus, and in patients with acute coronary syndromes where significant amounts of thrombus may be present.
The results in complex applications such as saphenous vein graft treatment are similar to those achieved with drug-eluting stents, but without the need for extended dual anti-platelet therapy. The mesh also has the potential for use as a drug-eluting element that could provide highly uniform drug delivery directly to the vessel wall.
InspireMD has invested $6 million so far in the development of the MGuard stent, and is now seeking an additional $10 million to $20 million to fund a pivotal 1,000-patient trial.
Another device with applications in acute coronary syndromes and saphenous vein graft treatment was described at EuroPCR by Haim Danenberg, MD, of the Heart Institute at Hadassah Hebrew University Medical Center (Jerusalem, Israel). The Over and Under is a pericardium-covered stent under development by ITGI Medical (Or Akiva, Israel). A thin layer of heterologous tissue is employed as a stent covering to block debris embolization and capture thrombus. Because of the thin and flexible nature of the pericardium layer, the device is highly deliverable compared to other covered stents such as the Jpstent from Abbott Vascular that are used for saphenous vein graft treatment. Results from the SLEEVE II trial using the ITGI-covered stent are encouraging, with no target lesion revascularizations and a MACE rate of about 10%.
The Over and Under has been launched in Europe and South America, and an agreement has been signed with MedStar Research Institute (Hyattsville, Maryland) to obtain HDE approval for the device in the U.S.
New vascular protection strategies
A new device with applications in vascular protection in saphenous vein graft treatment was exhibited at the EuroPCR conference by Lumen Biomedical (Plymouth, Minnesota). The Lumen FiberNet EP System is an intravascular, fiber-based filter that can be deployed to capture emboli as small as 40 microns during an interventional procedure. The FiberNet system has been evaluated in more than 200 patients worldwide, and is being studied for use in saphenous vein graft procedures in the RETRIEVE trial.
The product is not yet approved for sale in the U.S. The FiberNet system also has applications in neurointerventional procedures such as carotid artery stenting, as well as in renal intervention. The system includes the Xtract Catheter for suction of entrapped debris and for filter retrieval.
Another technology with applications in improving outcomes for patients with acute coronary syndromes was described by TherOx (Irvine, California). The TherOx SuperSaturated Oxygen Therapy has been in development for 13 years, and a pivotal randomized trial, AMIHOT II, was recently completed involving 304 patients. The TherOx DownStream AO System dissolves pressurized oxygen in saline at 200 times normal physiological levels, mixes the solution with the patient's blood, and then delivers the hyperoxemic blood containing 10 times the physiological level of oxygen to the heart via an infusion catheter. The goal of the therapy is to limit ischemic tissue damage in patients with myocardial infarction, providing adequate tissue oxygenation to the heart until normal blood flow can be restored via an interventional procedure.
In the initial trial of the TherOx technology, AMIHOT, patients were treated at times of up to 24 hours after an infarct, and outcomes were not significantly improved compared to controls. In the pivotal AMIHOT II trial, the interval over which treatment was allowed was shortened to six hours post-infarct, and the patients treated were those with anterior MI.