CDU Contributing Editor

VIENNA, Austria The market for products used in the diagnosis and treatment of cardiovascular disease in Europe is the second-largest regional market worldwide after the U.S., and has historically been the first to adopt new device technologies. Certain European countries, including a number in Eastern Europe such as Hungary, Poland, the Czech Republic and Romania, rank among the highest in the world in deaths from cardiovascular disease. As shown in Table 1 below, the death rate for coronary heart disease in many countries in Europe ranks above that for the U.S., which in turn ranks at about the median for all countries worldwide. Nevertheless, the rates of utilization of techniques such as percutaneous coronary intervention are typically lower in Europe than in the U.S., due in part to a lower level of total spending on healthcare.

The utilization of the newest technology to be introduced for coronary intervention, drug-eluting coronary stents, is no exception. Although the Cypher sirolimus-eluting coronary stent from the Cordis (Miami Lakes, Florida) unit of Johnson & Johnson (New Brunswick, New Jersey) has been available for clinical use in Europe since April 2002, and the Taxus paclitaxel-eluting stent from Boston Scientific (Natick, Massachusetts) was introduced in February, rates of utilization have only reached about 16% of total coronary stent procedures, according to Patrick Serruys, MD, of the Thoraxcentre (Rotterdam, the Netherlands), who discussed the trends in stent utilization at the 2003 Congress of the European Society of Cardiology (ESC; Nice, France).

In contrast, experts such as Marie Claude-Morice of L'institut Cardiovasculaire Paris-Sud (Paris) presented estimates showing that the Cypher drug-eluting stent will be used in 65% of all coronary stent procedures in the U.S. by the end of this year, even though the FDA did not clear the device for marketing in the U.S. until April. Although the rate of adoption has been slower than expected by some in the U.S., the rate in Europe is obviously well below that expected by many when the technology was first developed.

Peripheral vascular stents also are more widely used in the U.S. than in Europe, although there is considerable interest in applications such as carotid stenting for prevention of stroke. Other topics in vascular intervention discussed at the ESC congress included vulnerable plaque detection, noninvasive imaging of the coronary arteries and the latest developments in approaches using stem cell therapy for heart failure treatment. Emerging approaches for risk assessment in cardiovascular disease, preventative therapy, and advances in monitoring the progression of coronary artery disease also were highlighted at the congress.

Trends in adoption of drug-eluting stents

The primary reason cited for the slow adoption of drug-eluting coronary stents in Europe is cost. The most recent data on costs for the Cordis Cypher stent, for example, collected in the RESEARCH registry, shows that costs for drug-eluting stents range from EUR 2,789 to EUR 5,558 per procedure. On average, patients receive 2.2 drug-eluting stents per procedure in Europe, at a typical cost for the device alone of EUR 1,800 each. The high cost of drug-eluting stents, which is at least three times the cost of about EUR 600 for a bare-metal stent in Europe, has caused some cardiologists to employ drug-eluting stents only in the most difficult cases and to use bare metal stents for the majority of patients. At the other extreme, the cardiology team led by Serruys has established a policy of using drug-eluting stents in all cases. Rates for drug-eluting stent utilization vary considerably in countries throughout Europe. As of April, the utilization rate was 2% to 3% in Spain and 20% in Austria, but was 60% in Switzerland. Overall utilization rates in Europe vary from 3% to 60%, with the average for Europe at 16% as of April, according to data presented by Serruys at the ESC congress.

The cost issue for drug-eluting stents may be resolved rather quickly in Europe as competition drives down selling prices. The Taxus stent has performed well in trials, achieving target lesion revascularization rates of 4.7% at 12-month follow-up in the TAXUS II trial. The device has been used to treat over 2,000 patients worldwide. Recent studies involving more challenging groups of patients have indicated that performance of the Taxus and Cypher stents is at least equivalent in terms of revascularization rates, although the question will be answered definitively by a head-to-head comparison study now under way that is being funded by Cordis. Hospitals can clearly be induced to switch devices based on cost savings, as indicated by the recent decision at the Thoraxcentre in the Netherlands to begin using the Taxus stent instead of the Cypher because of a better financial arrangement.

Another advance that could help to lower the cost of stenting and thereby make drug-eluting stents more affordable in Europe is the transition to direct stenting, which eliminates the use of a predilatation step with a balloon catheter, thus saving the cost of an extra catheter as well as reducing time in the catheterization lab. A study described by Professor Joachim Schofer of the Center for Cardiology and Vascular Intervention (Hamburg, Germany), using the Cypher stent in a more challenging patient cohort than in previous clinical trials, assessed the use of direct stenting in a subset of 92 patients, comprising 26% of the total patients participating in the E-SIRIUS trial.

The study also compared the Cypher to a Cordis bare-metal stent (the BX Velocity). Patients treated with direct stenting had a 2.4% restenosis rate vs. 7.2% for those who had predilatation, and the rate for major adverse cardiovascular events was 4.4% vs. 9.2%. The researchers concluded that direct stenting not only saves the cost of an extra balloon catheter (between EUR 200 and EUR 300), but also may provide more benefit for the patient. In addition, the reduction in cath lab time with direct stenting results in additional cost savings of EUR 500 to EUR 600, making the total savings as much as EUR 900. While the ability to achieve lower restenosis rates with direct stenting could not be proven, since the patients were not randomized for direct stenting, the results are encouraging and support the practice of using direct stenting to reduce costs and help offset the cost of drug-eluting stents. One limitation, however, is that not all patients are candidates for direct stenting, based on the rate of utilization in the E-SIRIUS trial.

Implementation of cost reduction measures will be critical in allowing hospitals in Europe to afford drug-eluting stents. Most countries in Europe have not increased the rate of reimbursement for stenting to cover the added cost of drug-eluting stents, and that situation is not expected to change over the next two to three years by experts at the congress. At present, only Switzerland, Luxembourg and a few other smaller countries provide additional reimbursement. Dr. B. De Bruyne of the Cardiovascular Center (Aalst, Belgium), who has assessed the reimbursement situation for drug-eluting stents in Europe, suggests that on average a usage rate of more than 25% cannot be supported, and that cardiologists should develop criteria for selection of patients for drug-eluting stent implants, including site of the lesion, lesion length, vessel size and presence of diabetes.

The situation will change, of course, as prices drop. In addition, Serruys maintains that drug-eluting stent costs should not be compared with costs for bare-metal stents, but rather with costs for bypass surgery, since the improvement in restenosis rates is now enabling interventional treatment of patients who would previously have been referred for surgery, with a net savings of about EUR 3,000 even at existing prices for drug-eluting stents.

In spite of the breakthrough in reduction of restenosis with the Cypher and Taxus stents, there are still many problems that remain to be addressed in interventional cardiology, as well as new types of drug-eluting stents in development that may provide even greater reduction in restenosis while increasing the level of competition in the market in Europe and thereby helping to resolve the cost issue. As discussed by Antonio Colombo, MD, of Emo Centro Cuore (Milan, Italy) at the ESC congress, challenges still exist in the treatment of chronic total occlusions, left main artery disease, complex lesions, saphenous vein grafts and disease progression in diabetes. However, a number of new device technologies are now showing promise for addressing those more difficult cases. For example, Colombo cited a new version of the Frontrunner catheter from LuMend (Redwood City, California) with a 3 Fr sheath that is having a significant impact on the ability to treat total occlusions. The CrossPoint TransAccess catheter from TransVascular (Santa Rosa, California), acquired recently by Medtronic (Minneapolis, Minnesota), also is proving valuable in allowing treatment of total occlusions that cannot be successfully recanalized with one of the new-generation guidewires now available in Europe. Such lesions account for 20% to 30% of total occlusions. Treatment of complex lesions with drug-eluting stents may prove problematic because tortuous vessel anatomy may prevent good contact of the stent with the vessel wall, thereby impairing drug delivery to the tissue. Colombo has addressed this issue by implanting one Cypher stent within another, doubling the drug dose given for more complex lesions, and achieved 0% restenosis in eight patients.

Other promising technologies now under development include a new stent from Orbus Medical Technologies (Fort Lauderdale, Florida) that uses an antibody coating to capture endothelial progenitor cells on the stent surface and improve biocompatibility; a cobalt chrome stent from Conor Medsystems (Menlo Park, California) that elutes two drugs in different directions; and a biodegradable everolimus-eluting stent from Biosensors/Guidant (Newport Beach, California). The Orbus and Biosensors devices both address an issue that concerns many cardiologists related to inflammatory reactions that occur in response to the polymeric coatings employed on existing drug-eluting stents, and the potential for long-term adverse events. Another approach being developed by Eucatech AG (Kissingen, Germany) features a polysaccharide coating on a bare metal stent to provide biocompatibility and a second coating of polylactic acid that contains a drug. Studies already have demonstrated a 15% to 18% lower restenosis rate for the polysaccharide-coated stent alone, and further reductions are likely when the drug-eluting coating is added. The company expected to obtain a CE mark for the polysaccharide-coated stent last month and hopes to launch the double-coated drug-eluting stent in early to mid-2004. Sorin Biomedica Cardio (Saluggia, Italy) is developing the Janus stent with a drug-eluting carbofilm coating. The company plans to launch the device in Europe by early 2004. B. Braun Melsungen AG (Berlin, Germany) is developing a new drug-eluting version of its CoroFlex stent that is targeted for launch in 2005.

Peripheral vascular stenting also is an area of considerable development activity in Europe. Carotid stents are attracting most of the attention at present, due to the large potential market for prevention of stroke via carotid stenting. The clinical implementation of carotid stenting was delayed by the need to develop embolic protection devices to prevent strokes induced by the stent procedure, but devices such as the Medtronic PercuSurge, along with a number of filter devices, are now available in Europe that have reduced adverse event rates over three-fold, to under 2%. About 10,000 carotid artery stent procedures have now been performed worldwide, according to Antonios Polydorou (Piraeus, Greece), who discussed the topic at the ESC congress, and procedure volume is steadily increasing. Most carotid stent procedures employ self-expanding stents such as the Carotid WallStent from Boston Scientific and the Precise stent from Cordis. There are still some remaining issues with carotid stents, such as late embolization that occurs from six to 24 hours post-procedure after the protection device has been removed; restenosis in about 3% of cases; and some problems with perforations due to protection devices, at least during the learning phase.

Sorin Biomedica also has developed an entry in the peripheral vascular stent market. The Sorin InPeria stent is a carbofilm-coated device for use in the infrapopliteal arteries mounted on an RX balloon catheter. A pilot randomized controlled study involving 34 patients who had either PTA or stent implantation showed an improvement in patency from 51% to 81% with the stent.

Europe comprises the second-largest regional market worldwide for vascular stents and endovascular grafts, with sales approaching $500 million in 2002 and projected to grow in excess of 15% a year over the 2003-2009 period, as shown in Table 2. Coronary stents account for the majority of sales in the market now and will continue to dominate the market in Europe for the foreseeable future. However, other segments will represent significant opportunities for suppliers, including the emerging market for carotid stents, for which the estimated size of the target patient population in Europe totals about 40% of that for coronary stents, and which represents an additional market opportunity not included in the estimates shown in Table 2.

Diagnostic, monitoring technologies grow

Due in large part to the high cost of drug-eluting stents, particularly in cases in which multiple stents are used, there is growing interest in technologies that will allow cardiologists to more accurately assess coronary heart disease, including lesion characteristics, in order to determine if a drug-eluting stent is needed or if a conventional bare-metal stent, or perhaps angioplasty alone, will suffice. In addition, there is growing recognition of the high risk of a second acute coronary event in the period immediately following a initial event: the risk of a second event is highest immediately after discharge from the hospital following an initial event, and decreases exponentially thereafter. A wide variety of technologies, including both invasive catheter-based devices and high-resolution non-invasive imaging modalities, are now being studied for use in vulnerable plaque characterization as well as for initial diagnosis. Up to 40% of coronary angiography exams are not followed by interventions, indicating a need for noninvasive imaging methods that can allow improved selection of patients for angiography. Technologies for coronary artery lesion assessment now under development are described in Table 3 below.

A number of companies, including Volcano Therapeutics (Rancho Cordoba, California) and Thermocore Medical Systems (Ghent, Belgium), have developed thermography catheters for vulnerable plaque characterization, based on evidence that regions of elevated temperature along the inner wall of a coronary artery are correlated with the density of macrophages, and by inference with the presence of inflamed plaque. So far, the results of studies using thermography have been mixed, with some researchers demonstrating a high degree of correlation between regions of elevated temperature and vessel stenosis, while others have not observed a consistent correlation between elevated temperature and regions that would typically be candidates for treatment as indicated by angiography. One factor that may limit the ability of thermography to identify vulnerable plaque is that inflammation in the coronary arteries tends to be widespread and is often not limited to only the site of a lesion.

Optical coherence tomography (OCT) is another technology that is being evaluated for assessment of vulnerable plaque. A system for performing intravascular OCT has been developed by LightLab Imaging (Westford, Massachusetts). The OCT catheter is a 3.2 Fr device that operates at a wavelength of 1,300 nanometers and provides real-time, high-resolution optical images of the vessel wall. Studies using OCT to analyze vulnerable plaque in diabetic vs. non-diabetic patients were reported at the ESC congress by a group including Ik-Kyung Jang and B. Mac Neill at Massachusetts General Hospital (Boston, Massachusetts). In addition, F. Van Der Meer of Amsterdam, the Netherlands, described studies with OCT for plaque characterization. While the studies indicate that OCT can be used to differentiate intima, lipid-rich plaque, and thrombus, issues remain with imaging through blood, and it does not yet appear that OCT is ready for routine clinical use.

Intravascular ultrasound (IVUS) also is being studied for applications in plaque characterization, including a system that uses an advanced radiofrequency analysis of IVUS data to provide additional information on plaque composition. An investigational version of the technology has been developed by Volcano Therapeutics, called virtual histology IVUS, which can differentiate fibrous and fibro-lipidic plaque, calcified plaque and lipid core. Volcano recently acquired IVUS technology when it purchased certain assets from Jomed AB (Helsingborg, Sweden), following a bankruptcy filing by that firm. While Virtual Histology IVUS provides an improved ability to characterize plaque, using eight spectral parameters of the reflected ultrasound signal, the features of culprit plaques are very heterogeneous, and some vulnerable plaques that cause myocardial infarction do not exhibit characteristics such as high lipid content that were believed to be associated with vulnerable plaque. As discussed by A. Maseri of University Vita-Salute San Raffaele (Milan, Italy) at the ESC congress, many plaques exhibit multiple fissures and inflammation at autopsy, characteristics that might be considered indicative of a propensity to rupture, but are not associated with a stenosis or occurrence of an acute coronary event.

While progress continues to be made in the development of invasive imaging technologies with improved plaque characterization capabilities, rapid progress is also occurring in noninvasive imaging for assessment of coronary artery lesions. Noninvasive imaging has the obvious advantage of allowing evaluation of asymptomatic individuals, or for use as a more convenient, less expensive and lower risk method for follow-up of patients after an intervention. Modalities for performing noninvasive coronary artery imaging include computed tomography (CT) and positron emission tomography (PET)/CT, cardiac magnetic resonance imaging (MRI), echocardiography, and nuclear imaging. Namdar and a group at the University Hospital Zurich (Zurich, Switzerland) have evaluated the Discovery PET/CT system from GE Medical Systems (Waukesha, Wisconsin) for contrast-enhanced imaging of coronary lesions. CT is able to provide accurate lesion morphology, while PET provides lesion relevance. The radiation dose is about the same as for an angiogram. Namdar demonstrated the ability to image ischemic regions of the myocardium during stress. However, improved software for vessel analysis is needed, and underutilization of the CT system when it is part of an integrated CT/PET system is also an issue.

MR imaging also is showing promise for non-invasive imaging of plaque, and exhibits lower artifacts as compared to echocardiography. Using the CV/i MR system from GE Medical, researchers have achieved a sensitivity of 89% and a specificity of 77% for all vessels combined for detection of coronary lesions. By combining CT and MR, researchers using the Philips Medical Systems (Eindhoven, the Netherlands) Intera CV MR system along with the MX8000 CT have demonstrated a negative predictive value that they believe will allow them to rule out coronary artery disease in chest pain patients without the need for performing a coronary angiogram.

Further improvement is expected with use of a new 16-slice CT system. It appears necessary, however, to use multiple imaging modalities such as CT combined with MR in order to achieve adequate accuracy, since a study described by Kaiser of University Hospital (Basel, Switzerland) at the ESC congress, using the Siemens Medical Solutions (Erlangen, Germany) Sensation 16-slice spiral CT system, found a positive predictive value of only 50% for CT alone. Other factors that now limit the use of such dual modality imaging include lack of reimbursement in Europe for cardiac MR and lack of FDA-approved contrast enhancement agents for MR in the U.S. Some sites in Europe are performing full-body MR screening exams for coronary artery disease and other diseases in Europe for patients willing to pay between EUR 3,000 and EUR 4,000, and some sites have replaced digital subtraction angiography with MR for some procedures, particularly for assessment of infarct area. But overall, adoption of MR for diagnosis and monitoring of cardiovascular disease remains very limited in Europe.

Another new technology for coronary artery lesion assessment is under development by IntraMedical Imaging (Los Angeles, California). IntraMedical has developed a miniaturized probe for imaging of emissions from infused 18F-deoxyglucose, a radioactive beta emitter. The compound preferentially deposits in inflamed plaques and consequently may provide a means to noninvasively image vulnerable plaque, although administration of a radioactive imaging agent will be required. IntraMedical, which is focused primarily in the area of cancer imaging, has formed a new company, Atheron, to develop and commercialize the technology for cardiovascular disease applications and is seeking additional funding for the venture.

Advances in heart failure treatment

Heart failure is a growing public health problem in Europe, as in the U.S. and worldwide. There were 5.3 million patients with congestive heart failure in Europe in 2000, and the number is expected to increase by at least 50% over the next 15 years. However, new technologies using stem cells to treat the disease are now showing promise, and advances in diagnosis are helping physicians to improve their management of heart failure. Three research teams reported progress in using stem cell therapy to regenerate heart tissue or improve its function, potentially providing a cure for heart failure rather than only to slow progression of the disease. One promising approach was described by Dr. Jurgen Hescheler, of the University of Cologne (Cologne, Germany), that involves genetic manipulation of embryonic stem cells to stimulate them to differentiate into cardiac precursor cells. The technique employs a genetic vector that only functions in cardiac precursor cells, and that also confers resistance to the antibiotic puromycin. Culturing of modified murine embryonic stem cells in the presence of the antibiotic results in a purified population of cardiac precursor cells which have been used in mice to produce a significant survival benefit in animals with induced heart failure. The researchers plan to proceed with studies using human embryonic stem cells, since Hescheler's lab is one of only three in Germany authorized to conduct studies with human embryonic stem cells. According to Hescheler, embryonic stem cells appear to have the capability to differentiate into cardiac cells, whereas adult stem cells being evaluated by other researchers for heart failure treatment do not.

A second group, led by Hans Dohmann, MD, of Pro-Cardisco Hospital (Rio de Janeiro, Brazil), is using a catheter delivery system developed by Johnson & Johnson to implant bone marrow cells into damaged cardiac muscle to generate new arteries and thereby improve blood flow to an infracted region. In a study involving 21 patients with end stage coronary artery disease, of whom 14 received autologous bone marrow cell implants, ejection fraction improved from 20 to 29 in the treated group, mechanical function of the heart improved and an improvement in heart oxygen consumption (VO2) was observed in 80% of patients following transplant. There was a significant 71% reduction of the area of impaired blood supply in the treatment group vs. controls. There were no adverse events related to the procedure, with two deaths occurring in the control group and two in the treatment group during the one-year follow-up period of the study. In a subgroup of five patients who were listed for heart transplant and were treated with the cell implant therapy, four had improved to the point that they no longer had sufficiently severe heart failure to be eligible for transplantation at six months post-procedure.

A third group, led by Lior Gepstein, MD, PhD, of Technion-Israel Institute of Technology (Haifa, Israel), reported on a new human embryonic stem cell differentiating system. Gepstein's group has demonstrated the capability not only to produce differentiated cardiac cells from embryonic stem cells in culture, but also that those cells can integrate in vitro with pre-existing cardiac cultures to form a small-scale functional section of spontaneously contracting tissue, indicating the potential for their integration and survival as functional cardiac tissue when used for cell implant therapy.

While stem cell therapy may represent the long-term future for heart failure treatment, cardiac resynchronization therapy is already on the market in Europe and is having a significant positive impact in reducing the cost of disease management while prolonging patient survival. Recent studies have demonstrated a 77% reduction in hospitalization and halving of the length of stay per hospitalization, from seven days to 3.4 days. Between 2,700 and 3,000 patients will have been treated worldwide with cardiac resynchronization therapy by the end of 2003, and projections are that about 3,800 will have received treatment by the end of 2004. Key suppliers of devices for cardiac resynchronization therapy include Medtronic and Guidant (Indianapolis, Indiana).