CDU Contributing Editor

STOCKHOLM, Sweden – Cardiovascular disease represents a major public health issue in Europe, and one that is expected to become even more important in the future. As described here by presenters at the 23rd congress of the European Society of Cardiology (ESC; Sophia Antipolis, France), ischemic heart disease is the leading cause of death worldwide and is projected to remain number one through 2020. However, in part because of better methods to treat cardiovascular disease that have improved survival, ischemic heart disease also is becoming an increasingly important cause of disability, rising from the No. 5 cause in 1990 to No. 1 by 2020. In Europe, the changes in death and disability rates will not be uniform throughout the region, in keeping with the heterogeneity of the market for cardiovascular products.

Deaths from ischemic cardiovascular disease are projected to double in the low-income countries in Europe as the population grows rapidly in those areas. Aging of the population will contribute to increasing rates of cardiovascular disease in the more developed countries as the proportion of the population over the age of 60 grows from 10% in 1999 to 22% by 2050. Budgetary issues in health care are also impacting the approach to treating cardiovascular disease in Europe. Most countries operate on fixed health care budgets now, forcing physicians to choose the therapy they believe is most cost-effective and often limiting the number of treatment options available to patients. Acceptance of higher-cost products is not precluded, but it must be demonstrated that overall health care costs can be reduced if such products are adopted.

Risk assessment and risk reduction for cardiovascular disease are becoming increasingly important in health care systems throughout Europe. The introduction of effective drugs, such as statins, has increased the importance of early detection of disease. The increasing number of effective options for treatment also makes patient triage and therapy selection more important, to improve patient outcome as well as to optimize cost effectiveness.

Among the most promising of the new therapies highlighted at the ESC congress was the Cypher drug-eluting stent from Cordis/Johnson & Johnson (Miami Lakes, Florida), the subject of sensational results reported from the RAVEL (RAndomized study with the sirolimus-eluting VELocity balloon-expandable stent) trial. The Cypher stent not only represents a significant advance in interventional cardiology, but is also likely to drive a major restructuring of market share in the coronary stent market worldwide. Although largely overshadowed by the advance announced by Cordis, a number of other important new developments were described at the congress in both diagnostic and interventional cardiology. Progress is continuing in the development of brachytherapy to treat in-stent restenosis, with some new players developing promising technologies. The treatment of heart failure is attracting increased interest in Europe, as prevalence of the condition expands and new therapies provide opportunities to improve patient outcome and to control the costs of managing the disease. Other topics discussed at the ESC congress included advances in surgical treatments for coronary artery disease, emerging approaches to improve outcome for patients with myocardial infarction, new methods for detection of vulnerable plaques, advances in coatings for stents, carotid stenting and endovascular grafts for aneurysm treatment.

Cardiovascular disease still No. 1

Table 1 describes recent patterns in cardiovascular disease in Europe. Although the total population in Europe is larger than in the U.S., many countries have lower rates of coronary artery disease, particularly France, Spain and Italy. Rates are also stable or declining in many Western European countries with a high standard of living, due to improving lifestyles and preventative treatments. In the less-developed countries in Eastern Europe, however, cardiovascular disease rates are increasing. One reason is the increase in the population living in urban areas vs. rural areas. Recent studies show that risk factors for cardiovascular disease are higher in urban populations, and between now and 2050 the percentage of the population living in urban settings is projected to rise from 40% to 60%, with much of the change occurring in less developed countries. Overall, the number of individuals with cardiovascular disease is projected to increase in Europe at least through 2020, creating increased demand for products used in diagnosis and treatment.

The market will not rise in proportion to growth in the number of patients, however, because of the lack of funding for health care in the developing countries. Per-capita spending for health care in the countries in Eastern Europe, for example, averages $277 per year, vs. $1,693 per year in the European Union countries and $3,724 in the U.S. Those figures indicate that, although the population of Europe as a whole is 2.3 times as large as the population in Western Europe, the potential market is only about 9% larger. Nevertheless, over the long term, the developing countries in Europe will represent a major growth opportunity for product suppliers because of growth in population and improving economic status.

An important factor that will drive growth in the market for products used to treat cardiovascular disease in Europe is the expanded use of new tools to help identify individuals who require treatment and to aid in selecting the most appropriate therapy. Risk assessment for cardiovascular disease is changing in Europe as it is in the U.S. New guidelines regarding acceptable levels of total cholesterol, LDL and HDL, and other lipoprotein subpopulations are being implemented that will result in a three-fold increase in the number of patients who are candidates for statin therapy. The new recommendations for intervention depend on the number of risk factors an individual has as well as on age. An estimated 36.5 million people in the U.S. now fall into the high-risk category and are eligible for treatment with statin drugs, and more than 65 million are candidates for diet control. Patients with certain metabolic syndromes may also be candidates for therapy. Similar numbers of new patients are likely to require treatment in Europe.

A variety of new technologies for determining which patients require preventative therapy with statins or other modalities were described at the ESC congress. CRP is attracting considerable interest in Europe as a risk marker for cardiovascular disease. Evidence is growing that inflammation is a key factor in the creation of vulnerable plaque, and CRP is emerging as a highly sensitive marker of inflammation that can help to indicate which individuals are at high risk for myocardial infarction, as well as serving as a predictor of outcome for patients with acute coronary syndromes and for patients undergoing interventional therapy. A number of presentations at the ESC gathering described the use of CRP in risk assessment and in predicting outcome. For example, a group led by N. Danchin, MD, of Paris, found that the relative risk for a major adverse cardiac event at one month following low-risk percutaneous coronary intervention was 10.5, and the relative risk of death or myocardial infarction was 12.2, for patients with elevated CRP. Other studies of CRP presented at the congress showed that CRP elevations also predicted worse outcome for patients at six months following percutaneous intervention.

Other risk assessment modalities described at ESC included intravascular ultrasound, intravascular thermography, magnetic resonance angiography (MRA) and electron-beam-computed tomography (EBCT). Intravascular ultrasound (IVUS) and thermography are invasive methods that have shown promise in detection of vulnerable plaque. For example, as described by Valentin Fuster, MD, of Mt. Sinai Medical Center (New York), IVUS exams often show build-up of plaque in arteries that appear clear via conventional X-ray angiography. However, the technique has not yet been refined to allow its use in predicting adverse events, largely due to the complex nature of myocardial infarction. As shown in an IVUS study presented by H. Kawakami, MD, of Ehime Prefectural Imabari Hospital in Japan, cavities indicative of plaque rupture are not always associated with the culprit lesion in patients with myocardial infarction. In fact, only 40% of the patients studied had evidence of plaque rupture. In the remaining 60% of patients, the researchers attributed the infarction to severe calcification with negative remodeling of the vessel. A group led by C. Stefanadis, MD, of Ippokration Hospital (Athens, Greece) presented new data at the meeting showing that the presence of plaques with higher temperatures is correlated with higher adverse cardiac events post-intervention. The odds ratio for an adverse event at approximately 18 months for patients having plaques with elevated temperatures relative to the normal vessel wall (as measured during an interventional procedure) was 1.92, which was larger than any other measured risk factor with the exception of left ventricular dysfunction. In principle, a thermographic analysis could be performed in conjunction with diagnostic angiography to help identify areas requiring treatment, including those that may not be detected via conventional angiography.

Both IVUS and thermography are invasive modalities, however, limiting their utility in detecting at-risk individuals in the general population. For that application, noninvasive techniques obviously would be preferable. CRP measurement is one approach that is being actively investigated, but imaging modalities such as MRA and EBCT also show promise. MRA has been shown to allow detection of significant occlusive disease in patients with arteries that appear normal on conventional angiograms. In fact, in 70% of all patients with acute coronary syndromes, the event occurs in vessels that have less than 50% closure when measured via X-ray angiography. Studies have shown that MRA measurements correlate with pathology exams in vessels including the carotid arteries and the thoracic aorta. One advantage of a noninvasive method such as MRA is that it can be used in a serial fashion to monitor disease progression, or to monitor regression of atherosclerosis in response to statin therapy. The major barriers to the use of MRA in detecting vulnerable plaque include cardiac and respiratory motion artifacts and the non-linear nature and small size of the coronary arteries. However, continuing improvements in the speed of image acquisition and in the resolution of MRA have allowed those barriers to be reduced, and researchers involved with the technique believe that it offers the best potential for development of a noninvasive method for detection of vulnerable plaque. Leading suppliers of magnetic resonance imaging systems with applications in coronary angiography include GE Medical Systems (Waukesha, Wisconsin), Philips Medical Systems (Best, the Netherlands), Siemens Medical (Erlangen, Germany) and Toshiba Medical Systems (Tokyo).

Electron beam computed tomography (EBCT) is another noninvasive imaging technique that also is capable of detecting atherosclerosis at an early stage, although it operates somewhat indirectly by detecting calcification that often is associated with plaque build-ups. Studies have demonstrated that calcification of vessels is associated with the occurrence of an acute coronary syndrome in between 50% and 70% of cases. Although the sensitivity for detection of pathological atherosclerosis is not 100%, there is a high correlation of the presence of calcification with coronary artery disease and also between the amount of calcification and the severity of disease. At present, Imatron (South San Francisco, California) is the only supplier of EBCT systems. As of August, the company's system was in use in 150 hospitals worldwide. For the six-month period ended June 30, Imatron's revenues were up 45% to $38.9 million. Although the EBCT technique is not completely noninvasive, since it requires injection of a contrast agent, it avoids the femoral artery puncture needed for conventional angiography.

Once coronary artery disease is detected, the focus turns to treatment. Medical therapy, including the use of statin drugs, is employed in the majority of patients. However, if the disease has progressed to the point of a clinically significant stenosis or occlusion, percutaneous intervention or surgery is indicated. In addition, for some patients with more serious disease who are not candidates for surgical or interventional treatment, there is some re-emergence of interest in systems for blood processing, which can be used to help lower lipid levels. Baxter Healthcare (Deerfield, Illinois) was among the first companies to enter that segment, with a selective apheresis system that eliminated LDL and certain immunoglobulins from the blood. The Baxter system was eventually taken off the market, however. Recently, PlasmaSelect AG (Teterow, Germany) has re-introduced the system under the Therasorb label, and has developed new applications, including an immunoadsorption technique for the treatment of idiopathic dilated cardiomyopathy (IDC). IDC, which is a leading cause of heart failure, often progresses rapidly in affected patients and is one of the principle diseases that lead to heart transplantation. The PlasmaSelect product uses columns containing antibodies that specifically bind and remove autoantibodies that react against cardiac cellular proteins that have been implicated in the initiation and progression of IDC. Studies with the Therasorb system have demonstrated major improvements in parameters such as left ventricular ejection fraction in treated patients. The system also includes columns for the removal of LDL, fibrinogen and beta-1 receptor autoantibodies. The market opportunity is substantial, since the cost of a single treatment ranges from about $750 to $2,250 in Germany. Another supplier of plasma apheresis systems, B. Braun Melsungen AG (Melsungen, Germany), has installed about 150 systems worldwide, and about 180,000 treatment procedures have been performed with the Braun H.E.L.P. system since its launch more than 16 years ago.

Interventional market restructuring likely

The most important development discussed at the ESC congress, however, was a major breakthrough in interventional cardiology, namely the complete elimination of restenosis in a group of patients receiving a new drug-eluting coronary stent developed by Cordis. As reported earlier this year, Cordis already had obtained promising results (no restenosis) in a total of 45 patients treated with a rapamycin-eluting stent in studies conducted in Brazil and the Netherlands at one-year follow-up. At the ESC congress, the results of a larger study, the RAVEL (RAndomized study with the sirolimus-eluting VELocity balloon-expandable stent) trial, were presented that reinforce the findings of the pilot study. The trial, which is being conducted at 19 centers in Europe and Latin America on a total of 237 patients with de novo lesions, is comparing the Cordis Cypher rapamycin-eluting stent with a bare stent. At 210 days, no restenosis has been observed, and only 3.3% of patients receiving the Cypher stent suffered an acute coronary event of any kind, vs. 26% of the patients who received a bare Cordis BX Velocity stent. The six-month results are significant since most restenosis usually occurs within that period. In addition, the unique mechanism of action of the drug, which has cytostatic rather than cytotoxic effects, is intended to inhibit cell growth during the period when DNA synthesis typically occurs in proliferative tissues that cause restenosis. That period usually lasts for about 40 to 45 days after stent implantation. Since the drug appears to inhibit neointimal cell proliferation leading to restenosis during that period, Cordis researchers said they believe that it provides a long-term solution to restenosis.

The study was conducted only in patients with single-vessel disease, so questions remain regarding the ability of the Cypher stent to eliminate restenosis in patients with more complex lesions. However, there is, in principle, no reason to expect that multiple stents will not work as well as single stents. The patient population studied included some with diseased vessels having reference diameters down to 2.6 mm, a more challenging population than for the BeneStent II trial, for example. Cordis has completed enrollment in a pivotal U.S. trial, SIRIUS, that will study a total of 1,100 patients, and hopes to launch the Cypher in 2Q02 in Europe and in 1Q03 in the U.S.

If the initial trial results continue to hold up in long-term studies, the coronary stent market in Europe and worldwide may well undergo a major revolution, including fundamental shifts in market share. As shown in Table 2, the coronary stent market in Europe is estimated at almost $280 million for 2001 and is approximately $2 billion worldwide, with most sales in the U.S.

Other suppliers of coronary stents – including Medtronic/AVE (Santa Rosa, California), Boston Scientific (Natick, Massachusetts), Cook (Bloomington, Indiana) and Guidant (Indianapolis, Indiana) – appear substantially behind Cordis in the development of drug-eluting stents. New entrants, including Quanam Medical (Santa Clara, California), now a Boston Scientific company, and Abbott Laboratories (Abbott Park, Illinois), also are developing drug-coated or drug-eluting stents. In late August, two Massachusetts companies, Implant Sciences (Wakefield) and CardioTech International (Woburn), reported that they are collaborating on development of a new drug-eluting, polymer-covered stent (see Product Pipeline, page 18). Coated stents, which differ from drug-eluting stents in that the active agents are intended to remain immobilized on the stent, have been developed by a number of companies including Cordis, but so far have not been shown to substantially limit restenosis.

Other new coronary stents described at the ESC congress include the Genic and Gendyl devices from Blue Medical Devices BV (Helmond, the Netherlands). The Gendyl is a unique stainless steel stent that incorporates both coil and slotted tube design features, and that is coated with Dylyn, a biocompatible composite of silicon, oxygen, carbon and hydrogen. The company is also developing a drug-eluting stent, but has not yet disclosed the drug being used, except to note that it is biodegradable and is active only for about 30 to 40 days. Biotronik GmbH & Co. (Berlin, Germany) described results of recent studies with its Rithron coronary stent system, which uses a silicon carbide coating to reduce restenosis. In a recent trial (TRUST), patients treated with the Rithron stent showed a 9.6% target lesion revascularization rate, and a major adverse cardiac events (MACE) rate of 4.7% vs. 15.3% for controls at six months. Biocompatibles (Farnhem, UK) is developing a version of its BioDivYsio stent that employs 17-beta estradiol as an active coating. The compound has been shown both to exert an antiproliferative effect on intima tissues and to accelerate endothelial cell repair in response to balloon injury in animal studies. Hexacath is another supplier of coated stents. The company's HeliStent includes a Titanox coating composed of nitric oxide and titanium to provide high biocompatibility. The helical design of the stent also provides high mechanical flexibility, and was rated No. 1 in that category in a comparison vs. other currently available stents including the Cordis Bx Velocity, the Boston Scientific NiRoyal, and the Guidant Tristar.

The potential breakthrough announced by Cordis in eliminating restenosis raises questions about the role of other technologies that have recently been developed either to prevent restenosis or to deal with restenosis in patients who have already been treated. Brachytherapy devices to help prevent or minimize restenosis are available in Europe from a number of suppliers, including Guidant, Novoste (Norcross, Georgia), Cordis and Boston Scientific, and systems are under development by Cook, Theragenics (Buford, Georgia) and Radiance Medical Systems (Irvine, California), among others. However, such systems have been primarily proven to be useful for the treatment of in-stent restenosis.

Results from the RENO (REgistry NOvoste) registry trial of procedures performed with Novoste s BetaCath device were released at the ESC meeting. They demonstrated outcomes that were essentially equivalent to those observed in the initial START clinical trial. The registry contained data for 1,098 patients treated at 47 centers who were not selected for a trial, but rather were treated for in-stent restenosis, restenosis, or de novo lesions under conditions and for indications encountered in routine practice. For the in-stent restenosis patients, the restenosis rate following brachytherapy was 17.7% vs. 18% achieved in the START trial, indicating that the results of the trial are translatable to routine practice. Philip Urban, MD, director of interventional cardiology at La Tour Hospital (Geneva, Switzerland) and principal investigator of the RENO trial, said the data "support vascular brachytherapy as the standard of care for in-stent restenosis."

Results from the ECRIS II trial, presented at the ESC congress by M. Hoher, MD, of the University of Ulm (Ulm, Germany), were even more promising than those from RENO, with an 11.1% restenosis rate observed in patients treated with Guidant's beta-emitting rhenium-188 liquid-filled balloon vs. a 28.3% rate in controls.

However, E. Eeckhout, MD, of Centro Cuore Colombus (Milan, Italy), said at ESC that brachytherapy is likely to remain a secondary technique for restenosis prevention in Europe, and its impact will be limited. Even with some promising new systems such as the Theragenics palladium source wire, which does not require centering in the vessel, brachytherapy remains a delicate technique involving complicated logistics. Furthermore, in preliminary evaluations, the Cordis Cypher drug-eluting stent has appeared more effective than brachytherapy in treating in-stent restenosis, again completely eliminating restenosis in short-term follow-up. While there are currently a large number of patients treated with conventional stents who are likely to experience restenosis and would benefit from brachytherapy treatment, in the long term, low or zero rates of restenosis, including in-stent restenosis, may limit the market opportunity for brachytherapy systems.

Another important topic is the potential reduction in demand for surgical treatment of coronary artery disease if, as a result of the elimination of restenosis, long-term patient outcomes for minimally invasive percutaneous intervention become equivalent to those for surgery. Even in the absence of the new developments with drug-eluting stents, continued progress in percutaneous intervention is expanding the range of patients who can be treated with transcatheter techniques rather than bypass surgery. On the other hand, bypass surgery is evolving to become less invasive, including the possibility that bypass also can be performed via catheter-based methods. As discussed by P. Widimsky, MD, of Cardiocenter (Prague, Czech Republic), results from the ARTS and AWESOME studies comparing percutaneous intervention (PCI) and coronary artery bypass grafting (CABG) have shown that peri-procedural events are similar for both modalities, but that PCI requires only a one-day hospital stay (or can be performed as an outpatient procedure in some patients). Another study, conducted by Karch et al., favored CABG, but only because reintervention rates were much higher for PCI, a deficiency that may disappear with the advent of drug-eluting stents. Importantly, costs at one year for PCI are only 52% of those for CABG, but rise to 81% at the end of two years due to the need for reintervention in patients treated with percutaneous techniques. An equalization of reintervention rates for the two techniques would result in PCI having a wide cost advantage, with no compromise in long-term patient outcome. PCI also typically is associated with lower rates of procedural complications than surgery, providing another significant advantage. While the use of off-pump, beating heart surgery has helped to lower surgical complications, PCI is likely to remain superior in terms of procedure-related complications for the foreseeable future.

Nevertheless, some patients will remain poor candidates for percutaneous intervention, such as those with chronic total occlusions, left main coronary artery disease, ostial lesions, bifurcated lesions, and those with distal or severely calcified lesions. Experts presenting at the ESC congress estimated that at least 20% of those patients with occlusive coronary artery disease will continue to require surgical, rather than percutaneous, treatment. That rate already is being achieved by some centers in Europe (i.e., about 80% of all patients are being treated with PCI), but most are at about 50%. As indicated by data on relative numbers of PTCA and CABG procedures in Europe, PTCA accounts for about 73% of all procedures combined at present.

European cardiologists expand role

In addition to their growing role in treating patients with coronary artery disease, interventional cardiologists in Europe are expanding into a number of related applications of interventional technology. One important new segment is the treatment of carotid artery stenosis with stents. Studies in Europe as well as in Latin America have demonstrated good outcomes, particularly in later phases of the studies where embolic protection devices have been used and operators have become experienced in the procedure. The Wallstent from Boston Scientific has been widely used in studies of carotid stenting. For example, in an Argentine registry of carotid stenting, which includes 339 procedures performed over a six-year period in eight hospitals, 48% of the procedures used Wallstents in the most recent phase, while 18% used the Cordis SMART stent, 6% used the Cordis Palmaz stent, and the remainder used other stents. The rate for stroke and death in the registry dropped from 6.5% to 1.8% between the initial phase of the registry and the latter phase, and technical success for the procedure increased from 96.9% to 100%.

An Italian registry of carotid stenting shows similar results. In that registry, which is indicative of the evolution of use of carotid stents in Italy, a total of 830 elective procedures were performed in 57 centers from January 1998 through December 2000. As shown in Table 3, 90% of all procedures used the Wallstent, a self-expandable device, and only 10% used a different type of stent. The clinical success rate for all procedures was 96.4%, and complication rates were generally below 1%, with the exception of a 1.3% rate of major stroke and a 3.07% rate of transient ischemic attack. Restenosis is not a major issue for carotid stenting, with typical rates in registries of about 3.5%. The use of carotid stenting is growing rapidly in Italy. Procedures in the registry increased from 118 in 1998 to 265 in 1999 and 326 in 2000.

Another procedure that has been adopted by cardiologists in Europe is the implantation of endovascular grafts for the treatment of aneurysms and saphenous vein graft disease. The primary application for such grafts in aneurysm treatment at present is for abdominal aortic aneurysm (AAA). There is some controversy regarding the clinical utility of endovascular grafts in Europe because of the considerable number of late complications that have been observed, including some related to device failures. Although at least eight different devices for AAA treatment have been developed and used either clinically or in trials, all except for one, the Zenith device from Cook, have had recalls or product alerts issued as a result of mechanical failures. Since recent studies have not shown that the devices are significantly less expensive than surgical repair, or that patient outcome is improved, some clinicians have questioned whether endovascular grafts should be used except in certain special situations. As described by M. van Sambeek, MD, of Rotterdam, the Netherlands, at the ESC congress, if contemporary drug therapy (beta blockers) is used for patients with vascular aneurysms, only about 2% of patients are at high risk if treated surgically. For the remaining 98%, van Sambeek contended that the risk of major complications is no worse for surgical treatment than for endovascular graft repair.

However, as discussed by A. Nevelsteen, MD, of Leuven, Belgium, patients who have received endovascular graft implants are typically followed very closely, so that all complications are included when assessing adverse events, whereas the same may not be true for surgery, particularly for treatment performed in routine clinical practice. Nevelsteen's data indicate that the true death rate for surgically treated patients is about 7% to 8%, and that the rate of cardiac complications is 45% to 50%. Using the latest versions of commercial endovascular grafts, rates of rupture are less than 1%. It is becoming increasingly clear, however, that patient selection and proper graft sizing are critical to successful performance.

Another new device that is showing increasing promise is the Jostent Coronary Stent Graft from Jomed GmbH (Rangandingen, Germany). It is indicated for use in the treatment of diseased saphenous vein bypass grafts because of its ability to trap debris that might otherwise be released into the bloodstream during an interventional procedure. The STING clinical trial, now being conducted in Germany, involves an assessment of the device's safety and efficacy. Although some problems initially occurred with graft thrombosis, the addition of higher-dose drug therapy has resolved those issues, according to Jomed. The Jomed device has just been cleared for marketing in the U.S. It consists of a layer of PTFE sandwiched between two concentric flexible stainless steel stents and is priced at about $1,200 in Europe.

An emerging approach to treating patients with myocardial infarction (MI) is about to be launched in Europe by TherOx (Irvine, California). The TherOx AO System is designed to improve outcome for MI patients by helping to salvage the maximum amount of cardiac tissue in an infracted region. It uses aqueous oxygen, which is produced by mixing gaseous oxygen with Ringer's lactate solution in a specially designed chamber. The mixture is then mixed with the patient's blood to produce oxygen partial pressures of between 760 mm and 1,000 mm Hg, and delivered to the target tissues via a specialized catheter. Aqueous oxygen is typically delivered to the patient for about 90 minutes, as soon as possible after the onset of myocardial infarction. The treatment can provide benefits if delivered within a 20-hour window after an infarction by reviving stunned myocardial tissues that otherwise may become necrotic. The treatment is typically applied following revascularization by angioplasty and/or stenting. TherOx expected to receive a CE mark for the device sometime last month, and has completed a 30-patient Phase I trial in the U.S.