CDU Contributing Editor

ATLANTA – This year’s annual scientific sessions of the American College of Cardiology (ACC; Bethesda, Maryland), held here in early March, included a newly launched meeting-within-a meeting focusing on interventional cardiology, a change that is indicative of the growing importance of device-based therapies in cardiovascular disease. Drug-eluting stents (DES) continue to play a key role in market expansion, and now dominate the field of percutaneous intervention (PCI) in the U.S. and, increasingly, in Europe. However, new technologies for PCI continue to emerge, targeted at expanding the applications of transcatheter therapy, and further diminishing the role of surgery in the treatment of coronary artery disease, heart valve disorders and congenital heart defects. New ancillary technologies to improve less-invasive therapy of cardiovascular disease also were described at the ACC conference, which promise to improve the efficacy of percutaneous intervention.

Another area attracting considerable R&D focus is advanced diagnostic and imaging technologies. Both noninvasive and intravascular imaging techniques are under development, and in some cases are beginning to have a significant impact on the way in which cardiovascular disorders are diagnosed and managed.

While the growth rate for PCI procedures appears to be diminishing according to experts presenting at the ACC conference, particularly in the U.S., the market nevertheless is expected to provide attractive opportunities for device companies for at least the remainder of the decade.

Next-generation DES advance

The two drug-eluting stents now available in the U.S., the Cypher from the Cordis (Miami Lakes, Florida) unit of Johnson & Johnson (J&J; New Brunswick, New Jersey) and the Taxus from Boston Scientific (Natick, Massachusetts), have now been evaluated in a number of head-to-head comparison trials, while also competing in the market. A meta-analysis of eight trials comparing Cypher and Taxus presented by Stephan Windecker, MD, of University Hospital (Bern, Switzerland), at a pre-ACC symposium on drug-eluting stents sponsored by the Cardiovascular Research Foundation (New York) showed that the Cypher consistently has the lowest late loss in lumen diameter, averaging 0.09 mm vs. 0.31 mm for Taxus in one of the largest trials, the REALITY study. In another major head-to-head study, SIRTAX, the late loss was 0.12 mm for Cypher vs. 0.25 mm for Taxus. For all eight trials analyzed by Win-decker, the combined risk reduction for Cypher compared to Taxus for re-intervention was 39%. Despite the lower re-stenosis rate, there was no difference between the two devices in major adverse cardiovascular events or mortality. In addition, target vessel revascularization also was not different.

Another meta-analysis of 15 head-to-head randomized controlled trials involving a total of 5,854 patients discussed by Giuseppe Biondi-Zoccai, MD, of Policlinico San Donato (Italy), also showed lower rates of restenosis for Cypher vs. Taxus, as well as lower rates of target lesion revascularization, which often is considered a more clinically meaningful parameter since revascularization is the factor that affects the patient.

As noted by many presenters at the ACC conference, even target vessel revascularization as measured in clinical trials is not necessarily a good indicator of real-world performance of drug-eluting stents, since the revascularization rate may be different in controlled trials in which patients undergo follow-up angiography than in routine clinical practice. Results from registries that accumulate data from real-world clinical practice may be more indicative of the true performance of drug-eluting stents, even though there are no controls in such registries.

As shown in Table 1, which presents data from the Strategic Transcatheter Evaluation of Stent Therapies (STENT) registry through February, data from one of the largest registries of drug-eluting stent procedures also shows a trend favoring the Cypher stent overall and in most patient subsets, with the exception of insulin-treated diabetic patients. The differences in TVR and thrombosis rates are small, and would only begin to reach statistical significance in randomized controlled trials involving many thousands of patients.

While many studies indicate that the Taxus stent may have a somewhat higher rate of TLR than Cy-pher across all patient subsets, results from the TAXUS V ISR trial, reported by Gregg Stone, MD, of Columbia University Medical Center (New York), at the ACC conference show that Taxus is highly effective in treating in-stent restenosis. Stone reported that nine-month TVR in 396 patients with in-stent restenosis treated with the Taxus stent at 37 sites in the U.S. was 10.5%, significantly lower than the 17.5% rate reported for patients treated with vascular brachy-therapy, currently the only FDA-approved treatment for in-stent restenosis in bare-metal stents. The TLR and MACE rates also were lower for Taxus compared to brachytherapy.

Market share data indicates that interventional cardiologists may be responding to data from numerous trials and registries showing some superiority in clinical performance for Cypher. As shown in Table 2, data from Cordis on U.S. market share in the DES segment shows that Cypher has gained share rapidly since mid-2004, following a significant loss in share in early 2004 after the initial U.S. release of the Taxus stent. Market share in the top 50 U.S. hospitals almost doubled for Cypher between 2Q04 and 4Q05.

The share gains for Cordis also may be attributable to its marketing partnership for the Cypher stent with Guidant (Indianapolis), which was implemented in 1Q04. That factor is likely to be negated once Guidant is acquired by Boston Scientific, a transaction that was expected to close by the end of March. Sales of Taxus also were negatively impacted by a mid-2004 recall in the U.S. related to balloon deflation issues with the Taxus delivery system, but that issue has since been resolved. Continued market share transitions are likely as both Cordis and Boston Scientific introduce next-generation drug-eluting stents and as new players enter the market.

New drug-eluting stents under development discussed at the ACC meeting include the Endeavor from Medtronic (Minneapolis); the BioMatrix stent from Biosensors International (Singapore); the Dura-flex stent from Avantec Vascular (Sunnyvale, California), a unit of Goodman Co. Ltd. (Japan); the CoStar from Conor Medsystems (Menlo Park, California); a stent combining heparin and sirolimus elution from Sahajanand Medical Technologies (Surat, India); the Genous stent from OrbusNeich (Hong Kong/Fort Lauderdale, Florida); the Zomaxx from Abbott Vascular (Redwood City, California); a new 17-beta estradiol-eluting stent from X-Cell Medical (Princeton, New Jersey); and a new drug-eluting stent from CardioMind (Sunnyvale, California).

Results of trials with the Endeavor stent, which uses the drug ABT-578, licensed from Abbott (Ab-bott Park, Illinois), were discussed by David Kandzari, MD, of Duke University Medical Center (Durham, North Carolina). Endeavor uses a stent platform that has exhibited improved deliverability compared to the Cypher stent (98.1% procedural success vs. 91.2% for Cypher in the Endeavor III trial). However, the Endeavor trials have consistently shown higher late loss and higher rates of target vessel revascularization (TVR) compared to Cypher, although the TVR differences are not statistically significant. Rates of adverse events with the two devices are equivalent. Another trial, Endeavor IV, is comparing the Endeavor stent to the Taxus. Nine-month results for a total of 1,300 patients as cited by Kandzari are a 7.6% rate of major adverse cardiovascular events (MACE) and a 4.9% target lesion revascularization rate, with consistent results observed across all patient subgroups.

Results of clinical trials with the BioMatrix stent were discussed at the conference by Alexandre Abizaid, MD, of Institute Dante Pazzanese (Sao Paulo, Brazil). The BioMatrix uses the S-Stent platform with a corrugated ring design for added flexibility, a biodegradable polylactic acid polymer that is designed to only release drug to the lumen wall, and the drug Biolimus A9, which is similar in its mechanism of action to sirolimus, the drug used in Cypher. In a retrospective analysis performed by Abizaid comparing results with the BioMatrix vs Cypher at six months post-implant, a lower neointimal volume was observed for the BioMatrix, a TVR rate of 1.2% was reported, and no stent thrombosis was observed.

Another advance in drug-eluting stents is the use of dual drug elution, combining two drugs with different properties to address the multiple factors that are involved in tissue response to stent implantation. Shortly after conference ended, Conor Med-systems reported an agreement with Novartis Pharma (Basel, Switzerland) to license pimecrolimus for use in drug-eluting stents on a worldwide exclusive basis. Conor plans to evaluate a stent employing its micro reservoir technology that will elute both pacilitaxel and pimecrolimus, resulting in a device/drug combination that will have both anti-proliferative as well as anti-inflammatory properties.

The Genous stent from OrbusNeich uses a unique antibody coating designed to capture endothelial cells on the stent surface, which is believed to halt proliferation of smooth muscle cells and minimize restenosis without the need for a drug. The rapid formation of an endothelial cell layer may minimize tissue inflammation and reduce the rate of long-term events such as stent thrombosis. Michael Kutryk, MD, of Erasmus University Medical Center (Rotterdam, the Netherlands) described results from the HEALING II registry of patients receiving the Genous stent. Although the observed TLR rate was somewhat high, comparable to that seen with the Endeavor stent, it was noted that revascularization events only occurred in patients who had low levels of endothelial progenitor cells (EPCs) in their blood, making stent performance a function of EPC titer.

CardioMind is developing a new drug-eluting stent using a drug from the limus family that promises to have improved deliverability compared to existing devices. The stent is mounted on a .014” guide-wire, providing an extremely low profile, and is compatible with any balloon for deployment. XStent (Redwood City, California) also is developing a new device that will offer advances in deliverability. The XStent technology will allow multiple stents of various lengths to be implanted in one procedure using the same catheter. A .014” guidewire expands to form a stent at the desired location or locations within an artery. First-in-man studies with the stent have demonstrated that up to three lesions can be treated in two different vessels with a single system.

Expanded range of indications for stents

Market introduction of the new drug-eluting stents now under development, along with next-generation devices from existing suppliers including Cordis and Boston Scientific, is expected to drive continued growth of drug-eluting stent utilization in the U.S. and worldwide, due to an expansion in the range of indications for stent treatment. As shown in Table 3, drug-eluting stents were used in 90% of percutaneous interventional procedures performed in the U.S. as of 3Q05, up from 19% in 2Q03 when the devices first were launched in the U.S. market.

The increased utilization of drug-eluting stents also is driving continued erosion in the use of bypass surgery in favor of less-invasive therapy. Studies comparing patient outcomes for stent therapy vs. bypass surgery were discussed by a number of cardiologists at the ACC meeting. Spencer King, MD, of Piedmont Hospital (Atlanta), described recent outcome studies comparing drug-eluting stents and bypass surgery that show no difference in survival or MACE for patients treated with stents vs surgery, with the exception of patients with multi-vessel disease.

A recent advance for stents, enabled by the introduction of drug-eluting stent technology, is improved outcomes in diabetic patients. While the preponderance of available data still gives a slight edge to CABG surgery, outcomes with drug-eluting stents in diabetics are coming much closer to those for surgery, and if the trend continues stent therapy may prove equivalent in the not too distant future for the diabetic population. Outcomes in certain other high-risk patient populations also may prove to be equivalent for the two modalities, particularly as on-going clinical trials reveal how stents should best be used.

For example, results from the Angina With Ex-tremely Serious Operative Mortality Evaluation (AWESOME) trial, which involved patients treated within the Veterans Affairs healthcare system, showed that survival for stent patients was equivalent to that for surgical patients in a high-risk group. Other data, derived from a patient registry in New York State and cited by King at the conference, indicates that limiting the use of stents in patients with multi-vessel disease is not the best strategy, and results in a significant (14%) increase in mortality at three years if patients are incompletely revascularized.

A number of trials are now in progress, including FREEDOM, SYNTAX and CARDia (in the UK and Ireland) to evaluate the use of DES vs. CABG in patients with multi-vessel disease, and should provide more definitive information on treatment strategies in complex coronary artery disease. The trend, however, is for a continued expansion in the use of percutaneous intervention at the expense of surgery. King said that the improved outcomes now being observed with stents likely are due both to the transition to drug-eluting devices as well as to the use of improved anti-coagulant therapy and refined interventional techniques.

Another study of stenting in multi-vessel disease was described at an ACC press conference by Shun Kohsaka, MD of the Texas Heart Institute (Houston). Kohsaka and fellow investigators analyzed data from 6,479 patients with multi-vessel disease or a single lesion in the left anterior descending artery who underwent either CABG or bare-metal stent implantation between 1995 and 2003, and found similar mortality rates in both groups. A limitation of the study was its retrospective design, which raises the possibility that patients were selected for stenting or surgery based on the physician’s assessment of their suitability for one type of procedure vs the other. Nevertheless, the data demonstrate that stents are effective in patients with complex disease, justifying their expanded use. Drug-eluting stents combined with improved techniques and drug therapy may produce additional benefits, further driving the balance in favor of stent therapy.

Opportunities in percutaneous intervention

A number of technological improvements are in development for the field of percutaneous intervention. For example, challenges remain in treating bifurcation lesions, chronic total occlusions, heavily calcified lesions, and in-stent restenosis. A number of companies are developing new devices for treating bifurcation lesions, including the Axxess Plus stent from Devax (Plymouth, Minnesota), the SLIT from Advanced Stent Technologies (Pleasanton, California), the PETAL stent from Boston Scientific, the Frontier stent from Guidant, the Nile CroCo and Nile delta stents from Minvasys (Gennevilliers, France), the SideKick from Y-Med (San Diego/Haifa, Israel), and the Twin Rail device from Invatec (Roncadelle, Italy).

As discussed by Abizaid at an ACC symposium on emerging stent technologies, 15% to 25% of PCI procedures involve treatment of bifurcations, and suppliers have estimated the potential worldwide market for stents designed to treat bifurcation lesions at $500 million. First-generation devices have encountered some problems in clinical trials, according to Abazaid, including drug-eluting versions. Some interventionalists have used conventional drug-eluting stents in bifurcations, using kissing balloon and crushing techniques to alter the stent struts to approximate a bifurcated structure, with variable results.

Abizaid described recent experience with the Ax-xess Plus stent, which employs a cone shape at the bifurcation with struts extending into the primary vessel and side branch. The latest version is a drug-eluting design loaded with Biolimus A9. Additional drug-eluting or bare-metal stents can be placed further down in the primary and branch vessels as needed. Abizaid has used two additional stents in 40% of the treated patients. Results with the Axxess device are promising, with a binary restenosis rate of 3.5% observed in the primary vessel and 7.9% in the side branch, vs. rates of 18% to 24% using conventional stents. A 7.5% MACE rate was reported for the Axxess vs. 15% for patients whose bifurcation lesions were treated using the crushing technique.

A new device under development for the U.S. market for use in complex lesions was exhibited at the ACC conference by AngioScore (Fremont, California). The company’s AngioSculpt Scoring Balloon Catheter has been available in Europe for more than a year, and is used for vessel preparation and plaque modification prior to deployment of drug-eluting stents. As discussed by Gary Gershony, MD, of John Muir Medical Center (Walnut Creek, California), who is involved in a multi-center clinical study using the device, currently available devices in the U.S. for plaque modification include the Cutting Balloon and the Rotablator catheters from Boston Scientific. Outside the U.S., FoxHollow Technologies (Redwood City, California) markets the SilverHawk catheter. However, in most stent procedures physicians simply use balloon angioplasty to disrupt the plaque before implanting a stent. Direct stenting also can be employed, which eliminates the use of a separate balloon catheter for pre-dilatation, but that technique is less applicable in complex lesions.

Types of lesions for which initial dilatation with conventional balloon angioplasty can prove problematic include fibrocalcific lesions, bifurcation stenoses, small vessels, and in-stent restenosis. The AngioScult consists of a semi-compliant balloon with a nitinol wire wrapped around the exterior in a spiral pattern. The wire holds the balloon in place during expansion, avoiding slippage that can result in geographic miss, and allowing full expansion of the vessel at relatively low pressures. The device has a 2.7 Fr profile, and is deployed over a .014” guidewire. Deliverability is considerably improved vs. the Cutting Balloon, according to the company. It also can be used to improve results of non-stent procedures by providing a more uniform and precise expansion of the vessel.

The AngioSculpt has applications in both coronary and peripheral vascular interventional procedures – 510(k) clearance has been received in the U.S. for use of the device in the infrapopliteal arteries. A premarket approval application has been filed for use in the coronary arteries.

New technologies for CTOs, carotid stents

A new technique for treating chronic total occlusions (CTOs), which represent the most common lesion type causing a patient to be referred for bypass surgery, was described by Osamu Katoh, MD, of Toyohashi Heart Center (Toyohashi, Japan). Existing devices for CTO treatment in either the coronary or peripheral vessels include the Magnum guidewire from Boston Scientific, the FrontRunner XP CTO catheter from LuMend (Redwood City, California), the Crosser high-frequency mechanical recanalization system from FlowCardia (Sunnyvale, California), the CLiRpath laser catheter from Spectranetics (Colorado Springs, Colorado), and the SafeCross RF system from IntraLuminal Therapeutics (Carlsbad, California). Abbott Vascular (Redwood City, California) introduced a new CTO guide-wire, the Tornus, manufactured by Asahi Intecc (Aichi, Japan), at the ACC exhibition.

Katoh quoted success rates for recanalization of CTOs using existing devices at 60% to 90% in experienced cath labs. He described a new technique called CART, for Controlled Antegrade and Retrograde subintimal Tracking, that involves insertion of guidewires from both sides of the occlusion, followed by balloon expansion of the vessel at the retrograde end. The balloon is used to expand the subintimal space providing a larger target for alignment of the antegrade wire with the retrograde wire. A corkscrew technique is used to deploy the retrograde wire that allows access to 70% to 80% of CTOs in the left anterior descending and right coronary arteries.

The advantage of the CART method is that penetration to the distal lumen is guaranteed as long as the CTO can be accessed with the retrograde balloon. Katoh said he believes devices designed specifically for use in CART are needed in order to achieve the highest success rates, and that the technique can potentially be applicable to 30% to 40% of all CTOs.

Albert Raizner, MD, of the Methodist Hospital Research Institute (Houston), described the latest experience with magnetically guided wires for CTO therapy using the Niobe Artis system and Navigant 2006 user interface from Stereotaxis (St. Louis). The Stereotaxis system allows 3D images from computed tomography scans to be integrated with the magnetic guidance technology of the Niobe system. Images of the inside of the vessel can be created upon which an image of the guidewire derived from the angiogram can be superimposed, allowing the interventionalist to view the progress of the wire as the CTO is penetrated. In the future, the system will have the capability to remotely control guidewire position by magnetic force as well as balloon/stent advancement.

Advances in interventional technologies for use in the peripheral vessels also were described at the conference. Carotid artery stents are now available in the U.S. from three suppliers, including Abbott Vascular (the Xact stent), Guidant (the RX Acculink) and Endotex Interventional Systems (Cupertino, California), which developed the NexStent carotid stent in partnership with Boston Scientific.

The use of carotid stents is largely driven, at least in the U.S., by Medicare reimbursement policy, which restricts use to symptomatic patients, whereas the surgical alternative, carotid endarterectomy, is reimbursed for both asymptomatic and symptomatic patients. So far, carotid stenting has not had a major impact on the number of carotid endarterectomy procedures performed, which is variably quoted at between 140,000 and 175,000 in the U.S. According to William Gray, MD, of Columbia University Medical Center, who discussed carotid stenting at an ACC symposium, cost and length of hospital stay both favor stenting. Gray quoted the cost of a carotid stent procedure at $3,400, with a 1.4-day length of stay, vs. $5,000 for carotid endarterectomy and a 3-day hospital stay, for a net cost difference of $3,342, including hospitalization costs. Data from 3,000 carotid stent procedures cited by Gray shows that performance in terms of outcomes compares favorably to surgery.

However, Gary Roubin, MD, of Lenox Hill Hospital (New York), said patients need to be carefully selected for carotid stent procedures based on their risk profile in order to achieve outcomes equivalent to surgery. In addition, the use of embolic protection devices has proven to be mandatory if the 3% rate of stroke and death that is routinely achieved with surgery is to be duplicated for stent procedures. At present, according to data presented by Sriram Iyer, MD, of Columbia University Medical Center, 85% to 90% of carotid stent procedures use filter devices for embolic protection, and 10% to 15% use occlusion balloons, even though there is no difference in outcomes observed for patients treated with the two different device types. Choice of the em-bolic protection device used in a procedure depends strongly on patient anatomy.

Carotid stents, however, are primarily used as a preventive measure in patients who are identified as having carotid stenosis before suffering a stroke. Technologies to treat acute stroke are at least as important for reducing the rate of death and disability. A device for the treatment of acute stroke, the Merci Retrieval Catheter from Concentric Medical (Mountain View), now has been available in the U.S. for about a year. As discussed by Johnny Pryor, MD, of Massachusetts General Hospital (Boston) at the conference, new approaches to treatment of acute stroke are urgently needed, since only about 3% of all stroke patients in the U.S. (or about 25,000 out of a total of 700,000) receive intravenous thrombolytic therapy, the primary treatment approved by the FDA, versus almost 600,000 who suffer an ischemic stroke.

The Concentric Merci Retrieval Catheter is useful in removing vascular obstructions in ischemic stroke, but according to Pryor only provides successful re-vascularization in 48% of patients, partly because the device is quite stiff and as a result is difficult to use for many lesions. If intravenous thrombolytic therapy using tissue plasminogen activator (tPA) is used in conjunction with the Merci catheter, revascularization rates increase to about 60%.Nevertheless, mechanical recanalization devices such as the Merci catheter are used in less than 1% of stroke patients based on recent registry data, indicating that improved devices are needed, and would address a large potential market if shown to provide significant improvements in outcomes.

Advances in intravascular imaging

As devices continue to improve in deliverability and efficacy for intravascular therapy, the need for improvements in diagnosis and therapy guidance has also increased. A session at the ACC Innovation in Intervention (i2) Summit addressed advances in interventional imaging, updating the status of technologies for detection of vulnerable plaque. While significant advances have occurred in noninvasive imaging methods for vulnerable plaque detection, there is still strong interest in intravascular imaging techniques, including a variety of ultrasound imaging modalities as well as newer approaches such as optical coherence tomography, intravascular MRI and infrared spectroscopic techniques for tissue analysis.

One of the newest approaches is under development by CardioSpectra (San Antonio), and involves molecular imaging with optical coherence tomography. The goal is to detect macrophages that typically are associated with vulnerable plaque via the use of Feridex iron oxide particles. The particles are first infused, and then an oscillating magnetic field is applied which results in generation of an OCT signal that indicates the presence of vulnerable plaque.

Another approach being investigated by Yoshihiro Takeda of the Toyohashi Heart Center uses molecular imaging techniques to detect activated microphages. Macrophage activation has been shown to be related to expression of matrix metalloproteinases (MMPs), which can be detected via imaging of MION-47 particles used as targeted labels in MR imaging. Takeda also has developed activatable near-infrared fluorescent probes, dubbed NIRF probes, which can detect MMP activation in vivo with high sensitivity using fluorescent molecular tomography.