CDU Contributing Editor
ORLANDO, Florida The annual conference of the American College of Cardiology (ACC, Bethesda, Maryland), held here in early March, provided a forum for the announcement of a number of important new developments in the global cardiovascular device market. The results of major clinical trials involving head-to-head comparisons of the two leading drug-eluting stents on the market were reported at the conference, along with data on trials of new combination drug therapies for myocardial infarction patients that provide a significant reduction in deaths, recurrent myocardial infarction, and vessel re-occlusion in MI patients.
Continued advances in the less-invasive treatment of heart valve disease were described at the ACC conference, as well as new developments in device therapy for the treatment of aneurysms. Device-based treatments for heart failure and cardiac arrhythmias also were in the spotlight, where advances in implantable sensor technology promise to improve the effectiveness of ICD and ICD-CRT devices and improve the efficiency of patient management, and to potentially save the lives of patients whose ICDs fail after implant.
The latest results of cell transplant therapy and various new biotherapy approaches were described at the conference, as well as advances in technologies for detection of vulnerable plaque. Diagnostic imaging technologies are also becoming increasingly important in cardiology, with emerging molecular imaging modalities promising major advances in risk assessment and in the ability to characterize tissues for therapy guidance.
New findings in drug-eluting stent trials
The results of the first head-to-head studies of the two leading drug-eluting stents on the market the Taxus stent from Boston Scientific (Natick, Massachusetts) and the Cypher from the Cordis (Miami Lakes, Florida) unit of Johnson & Johnson (New Brunswick, New Jersey) confirmed earlier data from independent studies demonstrating the efficacy of the devices in reducing restenosis, but did not demonstrate an across-the-board advantage for either stent. Eight-month results from the Cordis-sponsored REALITY trial, involving 1,386 patients at 90 hospital centers in Europe, Asia, and Latin America, were presented at the ACC sessions by Marie-Claude Morice, MD, of Institut Jacques Cartier (Massy, France). To the surprise of many cardiologists at the conference, the study failed to demonstrate a statistically significant advantage for the Cypher in terms of in-lesion restenosis rate (9.2% for Cypher vs. 11.1% for Taxus) or major adverse cardiac events (9.2% for Cypher vs. 10.6% for Taxus).
One key parameter analyzed in the study of great interest to physicians was the stent thrombosis rate observed with each device. While the rate of thrombosis was not significantly different at 0.6% for Cypher vs. 1.6% for Taxus in the intent-to-treat group, rates based on actual treatment received were significantly different (0.4% vs. 1.8%). The relatively high thrombosis rate observed for Taxus could not be ascribed to a failure to comply with anti-coagulation therapy, since there was 99% documented compliance with the drug regimen for the Taxus group and 97% compliance for the Cypher group. Maurice concluded that further investigation of the thrombosis issue would be warranted.
Two other trials comparing the Taxus and Cypher stents, the SIRTAX and TAXI studies involving more than 1,200 patients, also failed to show any statistically significant difference in the two devices with respect to restenosis rates or target lesion revascularization rates, although there was a trend favoring the Cypher in the SIRTAX trial.
Another head-to-head trial of Cypher and Taxus, the ISAR-DESIRE trial, also produced some surprising findings based on results of previous studies. As discussed by Adnan Kastrati, MD, of Deutsches Herzzentrum in Germany, the trial involved a total of 250 diabetic patients, 125 in each arm, who received either the Taxus or the Cypher drug-eluting stent. At six- to eight-month follow-up, the angiographic restenosis rate was 16.5% for the Taxus group vs. 6.9% for the Cypher group, and the respective target lesion revascularization rates were 19% for Taxus and 8% for Cypher. The results demonstrated that the Cypher is more effective in preventing restenosis in diabetic patients, who are highly prone to restenosis following percutaneous intervention. Some smaller prior studies had indicated the opposite.
Another observation noted in many trials comparing Cypher and Taxus is that the lesions which develop within the stent when restenosis occurs tend to be focal and thus easy to treat with Cypher, whereas with Taxus they are more diffuse. In addition, the late loss for the two stents, which is the amount of vessel re-narrowing occurring after stent implantation, is higher for Taxus, although as shown by the comparison trials that difference does not translate into a statistically significant difference in restenosis or revascularization rates.
Collectively, the data from the head-to-head trials are not expected to have a major impact on the relative utilization of Cypher vs. Taxus, according to most presenters at the conference, although in some patient subsets, such as diabetics, the Cypher may become the preferred device, and at least some cardiologists indicated that they may consider switching back to the Cypher. Cost may prove to be an important factor in switching, however, since Boston Scientific, having gained the leading position in the market, is pricing aggressively to retain existing accounts, offering discounts of as much as $500 per stent in the U.S. market to dissuade users from switching to Cypher. As shown in Table 1, prices for drug-eluting stents have been dropping steadily, although continued rapid growth in utilization is driving substantial growth in the market.
The next generation of drug-eluting stents promises to significantly expand the range of technologies available in the market, improving performance in complex lesions and allowing a wider range of vessel pathologies to be treated. One issue with existing devices that has been raised repeatedly by Renu Virmani, MD, of the Armed Forces Institute of Pathology (Washington), is adverse reactions to the drug-eluting polymers used to coat the stent. A poster presented at the ACC sessions by Marc Feldman of the University of Texas Health Science Center at San Antonio, along with Virmani and researchers from the University of Utah (Salt Lake City), analyzed the occurrence of hypersensitivity reactions which they hypothesize may be caused by the stent's polymer coating. Fifty hypersensitivity reactions had been reported to the FDA following introduction of the Cypher stent in the spring of 2003 through October of that year, vs. a total of about 390,000 Cypher stents implanted as of late-November 2003.
While the FDA concluded that the adverse reactions were due to the anti-coagulation medication used, Feldman's group observed patients who discontinued such medication but continued to suffer from hypersensitivity reactions, resulting in a difficult-to-treat condition since the stent cannot be explanted. In addition, as discussed by Patrick Serruys, MD, of Erasmus Medical Center (Rotterdam, the Netherlands), at least one case has been identified in the E-SIRIUS registry for the Cypher stent of a delayed hypersensitivity reaction that may have been the cause of a late thrombosis event resulting in death. The rate of occurrence of such reactions is quite low, considerably less than the rate of sub-acute thrombosis in the case of the Cypher stent, and corresponding to about 0.01% of the patients with implants, but nevertheless represents an issue that is attracting the attention of cardiologists.
A number of companies described new stents in development that use alternative coating technologies designed to minimize or eliminate such adverse reactions. For example, Orbus Neich (Fort Lauderdale, Florida) is developing the Genous stent, which use antibodies to the endothelial progenitor cell (EPC) marker CD34 to capture EPCs from the circulation following stent implantation, resulting in the formation of a biocompatible surface on the stent comprised of the patient's own cells. The antibodies are immobilized on a polysaccharide coating on the stent. Studies in animals have demonstrated that the Genous stent becomes completely coated in vivo within 48 hours.
In the initial human study with the device (HEALING I), a relatively high target vessel revascularization rate of 6.3% was reported at six months, and late loss was very high at 0.63 mm. The company has now altered the sterilization method from that used in the initial trials, performing gamma irradiation in a dry state, and achieved many-fold higher EPC binding. In the HEALING II study with the improved device, target vessel revascularization and major adverse event rates, as reported at the ACC meeting by Michael Kutryk of Erasmus Medical Center, were 0% at 30 days. Additional planned improvements include use of a humanized antibody and the possible addition of drugs.
Biosensors International's (Newport Beach, California) Occam unit is developing the BioMatrix stent, which features a bioresorbable polylactic acid coating and the company's S-Stent platform that elutes Biolimus A9, a rapamycin derivative. Polylactic acid is a widely used biocompatible material that is expected to elicit no adverse tissue response. In the STEALTH trial using the BioMatrix stent, as reported by Eberhard Grube. MD, of Heart Center Seigburg (Seigburg, Germany) at the ACC conference, in-stent restenosis at six months was 3.9%, and the target vessel revascularization rate was 1.3%. Late loss was also quite low at 0.14 mm. However, the restenosis rate for the bare-metal S-Stent used in the trial was also quite low at 7.7%.
Grube also reported on progress with the Axxess Plus system, under development by Devax (Irvine, California). Devax is collaborating with Biosensors to use Biolimus A9 in the Axxess Plus, which is a new self-expanding stent used for the treatment of bifurcation lesions, which can occur in up to 30% of patients. The Axxess is placed in the main branch, covering the vessel to the bifurcation, and drug-eluting stents such as the Cordis Cypher are placed in both branches of the bifurcation, overlapping the Axxess device. In initial studies, three stents have been used in 40% of procedures, two stents in 25%, and one Axxess stent in 33%, with no major adverse cardiac events observed at six months. The AXXENT trial using the new device began in February.
Another new stent for the treatment of bifurcations is under development by Boston Scientific, using technology acquired this year in the company's purchase of Advanced Stent Technologies (Pleasanton, California). The AST SLK-View stent, using Petal technology, also will allow combination of drug-eluting stents such as the Taxus with a device that ex-pands to cover the bifurcation region.
Other new devices highlighted at the ACC sessions include the Cordis Evolution drug-eluting stent, the Xicence V from Guidant (Indianapolis), the ZoMaxx from Abbott Vascular (Redwood City), the Endeavor from Medtronic (Minneapolis), the XC-121 and XC-441 stents from X-Cell Medical (New York) and the CoStar drug-eluting stent from Conor Med-systems (Menlo Park, California). The Cordis Evolution is a new, small-diameter drug-eluting stent for use in small vessels. The sirolimus-eluting device has a 0.7 mm unexpanded profile, uses a cobalt-chromium platform and includes a hepacoat. Six-month results with the device in vessels with a 2.15 mm reference diameter showed 10% in-stent restenosis, 12% in-lesion restenosis, and 13.5% a target lesion revascularization rate. While the rates appear high compared to results in larger vessels, they are very encouraging given the very small vessels treated in the study. Stent deliverability success was 98.1%.
Guidant's Xience V device from is an everolimus-eluting stent using the company's MultiLink Vision cobalt-chromium platform. Everolimus is an analog of sirolimus used outside the U.S. for similar indications and manufactured by Novartis (Basel, Switzerland). An "approvable" letter was recently received from the FDA for the drug. Everolimus also has been evaluated for use in drug-eluting stents in the FUTURE trial with good results. The Xience stent is being tested in the SPIRIT trials, as discussed by Cameron Rogers, MD, of Brigham & Women's Hospital (Boston) at the ACC sessions. Initial results from the SPIRIT FIRST trial, presented at the Transcatheter Cardiovascular Therapeutics conference in September 2004, were promising, with a 7.7% rate of major adverse cardiovascular events, late loss of 0.1 mm, and 0% restenosis. Three follow-on SPIRIT trials are being planned in the U.S., Europe and Japan.
The ZoMaxx stent uses the immunosuppressant drug ABT 578 on Abbott's TriMaxx stent platform that uses two stainless steel layers plus a thin middle layer of tantalum. A phosphorylcholine coating (Pharmacoat) serves as the drug reservoir. The stent struts are the thinnest available at .0029", and the device's crossing profile is .039" (1.0 mm). A key feature of the ZoMaxx is the highly lipophilic nature of ABT 578, which leads to better tissue penetration and less elution of drug into the bloodstream. The ZoMaxx stent is being evaluated in the ZOMAXX 1 trial, which will involve 200 patients. Seventy-four patients had been enrolled as of mid-February. The hydrophilic, non-thrombogenic nature of the Pharmacoat coating along with its low platelet adhesion is expected to result in a lower tendency for thrombosis to occur.
Medtronic's Endeavor stent also uses ABT-578 and a phosphorylcholine coating, but is based on the Driver stent platform. The device has been evaluated in the ENDEAVOR I trial enrolling 100 patients in Australia and New Zealand, with a 5.4% restenosis rate reported at one year, although two of the five patients were asymptomatic. The target lesion revascularization rate was 1%. A U.S. pivotal trial of the stent will begin in two to four months.
The X-Cell stent features the R-Stent platform developed by Orbus, and uses a polymer coating developed by SurModics (Eden Prairie, Minnesota), the company that developed the Cypher stent coating, along with 17-beta-estradiol as the eluted drug. The pro-healing characteristics of the drug may positively impact thrombosis, according to the company. A first-in-man study, the ETHOS trial, is planned starting in June, with completion targeted by 2Q06.
Conor's CoStar stent is a second-generation device fabricated from cobalt-chromium with hundreds of small holes in the stent that are loaded with a drug-polymer matrix to provide drug elution capability without the need for a continuous surface coating. The version now in clinical trials uses a poly(lactic-co-glycolic acid) polymer loaded with paclitaxel. Two initial trials (PISCES and COSTAR I) evaluated the device at various drug doses and allowed optimization of the design, and enrollment in two trials in Europe (the EuroSTAR I and II studies) is complete. Six-month results of the EuroSTAR I trial show a 1.7% target lesion revascularization rate and 0.7% late thrombosis, with 4.7% in-segment restenosis. The CoStar design minimizes the exposure of polymer materials, theoretically reducing adverse reactions that could lead to stent thrombosis and possibly allowing a reduced need for anti-coagulant therapy following implantation. At present, patients are prescribed six months' treatment with aspirin and clopidigrel, but Keith Dawkins, MD, of Southampton University Hospital (Southampton, UK), an investigator involved in the EuroSTAR trial, is confident that the treatment period can be safely reduced to as little as three months. According to Dawkins, the CoStar stent provides the best combination of low late loss combined with low crossing profile of any drug-eluting stent now on the market or in late-stage development. Conor is preparing to begin the COSTAR II study, which will be a pivotal trial of the device involving 1,500 to 2,000 patients.
One issue with drug-eluting stents that continues to be a focus of clinical studies and of companies developing new DES technologies is stent thrombosis. Rates of stent thrombosis in clinical trial populations as well as in registries are about 0.4% to 0.7% for Cypher and 1.2% to 1.8% for Taxus. While the most recent data indicates that thrombosis rates for drug-eluting stents are similar to those for bare metal stents, at least for the Cypher stent, achieving those rates requires long-term dual anti-platelet therapy with aspirin and clopidigrel for three to six months, whereas such therapy is typically continued for only two to four weeks for bare-metal stents. Some cardiologists presenting at the ACC sessions now continue the therapy for one year for drug-eluting stents.
The heavy dependence on dual anti-platelet therapy can create problems when stent patients, who typically have a high prevalence of other disorders, must have surgery during the period of anti-platelet treatment. In some cases, patients must be admitted to the hospital for up to three days prior to surgery to undergo alternative anti-coagulant therapy, resulting in considerable added expense. Treatment with clopidigrel also increases the risk of serious bleeding to about 2%. While many cardiologists consider dual anti-platelet therapy to be relatively inexpensive, it can present a cost burden for some patients, particularly those in rural areas, leading to failure to take the drugs and a significant increase in risk of stent thrombosis. Further compounding the problem is the fact that up to 25% of patients are resistant to clopidigrel, and 27% are resistant to aspirin. When it occurs, stent thrombosis is a serious event, with mortality rates quoted at up to 80% by presenters at the conference. As a result, future generations of drug-eluting stents are likely to incorporate new materials or alternative technologies designed to reduce thrombogenic characteristics.
The new Endeavor stent, under development by Medtronic, shows promise for minimizing thrombosis based on results of the ENDEAVOR II trial of 1,200 patients presented at the ACC conference. The cumulative rate of stent thrombosis at nine months post-implant was reported at 0.2% vs. 0.9% for the bare-metal stent control, using only a three-month, dual anti-platelet treatment, and no stent thrombosis was observed beyond one month.
Risk assessment takes on new importance
With the growing availability of more effective minimally invasive treatments for coronary artery disease, the identification of individuals at high risk for an adverse cardiovascular event has taken on increased importance. Improved risk assessment methods can potentially identify those individuals who are most likely to suffer a heart attack at an early stage, allowing preventive treatment with stents or drugs. The development of methods to detect vulnerable plaque has as a result attracted considerable interest, using technologies such as MRI, computed tomography (CT), positron emission tomography (PET) scans, ultrasound and nuclear imaging.
In addition, a number of laboratory-based test methods, as well as point-of-care tests including skin cholesterol measurements, are being applied to improve risk assessment for cardiovascular disease. One such method is a new test for myeloperoxidase (MPO) levels in serum, conceived by researchers at the Cleveland Clinic Foundation (Cleveland) and now being commercialized as an automated laboratory assay by Abbott Diagnostics under a non-exclusive license. As discussed by Peter Libby, MD, at a satellite ACC symposium sponsored by CV Therapeutics (Palo Alto, California), MPO levels in chest pain patients appear to predict the risk of myocardial infarction, and indicate the need for implementing preventative therapy, which could include revascularization therapy with stents.
Another strategy employing laboratory analysis for risk assessment was discussed in the ACC presidential plenary lecture by Eric Topol, MD, also of the Cleveland Clinic Foundation. Topol is investigating genetic markers of coronary artery disease, and described three gene defects that may prove useful in risk prediction, including a mutation in Chromosome 1 that is linked to the risk for heart attack, the FLAP gene mutation shown to be linked to vascular inflammation, and the MEF2A mutation that affects susceptibility to myocardial infarction and coronary artery disease. While the markers do not identify all MI patients (2% of MI patients have MEF2A deletions), they may represent a new category of screening tests that could allow more precise identification of patients who will benefit from preventative therapy.
Non-invasive diagnostic imaging technologies also are becoming important tools for cardiovascular disease risk assessment. Modalities including CT, MRI, PET, ultrasound and nuclear imaging are already widely employed in the diagnosis of heart disease. In fact, more than 51% of all nuclear imaging scans are performed for cardiac diagnosis. As shown in Table 2, the total worldwide market for diagnostic imaging products of all types approached $23 billion in 2004, and is projected to exhibit attractive growth over the next five years. Much of the growth will occur in imaging procedures performed outside of the traditional hospital setting, in free-standing imaging centers and physician offices. For example, office-based nuclear imaging procedures are expanding at 30% per year, according to data presented at the ACC sessions.
As indicated by the data in Table 2, the introduction of new contrast agents is expected to drive growth in the diagnostic imaging market, including a number of agents that are showing promise for risk assessment in cardiovascular disease. The target population for use of such imaging modalities is patients who are at risk for cardiac events but who are asymptomatic. New non-invasive imaging techniques prom-ise to provide information on the burden of atherosclerotic plaque, tissue composition and on plaque molecular activity.
Existing imaging techniques for cardiovascular risk assessment include ultrasound exams to assess intimal media thickness (IMT) in the carotid arteries, and CT scans to measure coronary calcium score. IMT, in particular, provides a simple, low-cost approach for screening employing recent innovations in hand-held ultrasound scanners from companies such as SonoSite (Bothell, Washington) that now allow IMT screening exams to be performed in the office setting. If significant plaque build-up is found by qualitative imaging in the carotid arteries, quantitative testing can be performed to obtain a risk level. IMT measurements, however, do not provide information on plaque composition, which is important for assessing the vulnerability of plaque to rupture, and coronary calcium scores provide only limited information on plaque composition, showing the degree of calcification of plaque.
As discussed by Zahi Fayad, MD, of Mt. Sinai School of Medicine (New York), MRI using contrast agents offers a number of advantages for cardiovascular risk assessment compared to existing modalities, including whole body imaging capability, avoidance of hazardous radiation, minimal operator dependence, high spatial resolution (~1 mm), and the ability to characterize and differentiate tissues. Key anatomic targets for MR detection of cardiovascular pathologies include the aortic arch and the carotid bifurcation. Using contrast-enhanced MR imaging, Fayad has found that plaque structure can be analyzed to show relative amounts of fibrous cap vs. lipid core, and that differences in plaque burden as assessed by contrast-enhanced MR are correlated with the presence of coronary artery disease in patients who do not exhibit elevated risk as assessed by blood lipid testing.
In a poster presentation at the ACC conference by Il Rhee of Samsung Medical Center (Seoul, South Korea), it was shown that high-resolution, contrast-enhanced MRI could detect changes in plaque composition in patients undergoing statin therapy indicative of plaque stabilization. At present, however, the diagnostic utility of MR imaging in the coronary arteries is limited by its relatively low spatial resolution as compared to angiography or CT imaging. CT, for example, provides 0.5 mm resolution vs. 1 mm available with MRI, and that difference is crucial when imaging vessels that may be 2.5 mm or less in diameter. The use of targeted contrast agents may provide a significant improvement in the diagnostic power of MR imaging in the future, based on research studies reported at the ACC sessions. Fayad described studies with a new Gadofluorine agent under development by Schering (Berlin) that allows differentiation between early stage and advanced plaque.
Fayad also has studied a new MR contrast agent being developed by Epix Pharmaceuticals (Cambridge, Massachusetts) that binds specifically to fibrin, and which can identify blood clots. The agent allows differentiation between acute and chronic thrombus. Other companies pursing development of new contrast agents include GE Healthcare (Waukesha, Wisconsin), developing new contrast agents through its Amersham unit, acquired by GE last year.
A potential barrier to the expanded use of diagnostic imaging in cardiology, however, is the recent focus by payers, particularly the Centers for Medicare & Medicaid Services, on perceived over-utilization of imaging by some physician specialties. In recent testimony before the U.S. House of Representatives, Mark Miller, PhD, executive director of the Medicare Payment Advisory Commission (MedPAC), presented recommendations for stricter controls on providers of imaging services to the Medicare program, based on concerns about the dramatic growth in Medicare spending in that area and concerns about inappropriate use and declines in the quality of such services. Medicare spending for imaging services paid under the physician fee schedule increased over 60%, from $5.7 billion to $9.3 billion, between 1999 and 2003, driven by a 45% increase in service volume, while volume for all physician services grew at half that rate (22%).
As shown in Table 3, growth in service volume was particularly high for MRI on parts of the body other than the head, CT scans on parts of the body other than the head, and nuclear medicine. In his testimony, Miller discussed physician self-referral as a possible factor underlying the increase, particularly for nuclear medicine services because they were excluded from the Stark law provisions when those rules were finalized.
In a recent editorial in the Journal of the American College of Cardiology, as well as in remarks made during an address at the ACC conference, Michael Wolk, MD, the current president of the organization, disputed the notion of inappropriate over- use of diagnostic imaging in cardiology, and also exhorted cardiologists to take a stand against efforts by radiologists to limit the ability of cardiologists and other non-radiology specialists to perform imaging procedures. The response of the Centers for Medicare & Medicaid Services to the MedPAC recommendations, as well as the success of cardiologists in preventing im-position of limits on their ability to perform imaging procedures, will have a significant impact on the future growth of the diagnostic imaging segment of the cardiology market.
Opportunities in implantable devices
Another segment of the cardiovascular device market experiencing rapid growth is implantable cardioverter defibrillators (ICDs) and combination ICD-cardiac resynchronization therapy (ICD-CRT) devices. The worldwide market for ICDs is estimated at over $3.1 billion for 2004, with growth projected at over 15% annually over the 2004-2009 interval. ICDs are the newest technology for the prevention of sudden cardiac death, which claims from 120,000 to 462,000 lives annually in the U.S., depending on the source of the estimate. CRT devices, either used alone or in combination with ICDs, have also proven effective in the treatment of patients with heart failure. An emerging area of development focus involves the use of implantable sensors used in conjunction with ICDs and ICD-CRT devices, as well as related stand-alone implantable sensors, for remotely tracking the condition of patients with heart failure and other cardiovascular conditions. As shown in Table 4, a variety of new implantable monitoring devices are under development.
Promising results in the COMPASS-HF (Chronicle Offers Management to Patients with Advanced Signs and Symptoms of Heart Failure) trial using Medtronic's Chronicle device, an implantable hemodynamic monitor designed to track the condition of patients with late-stage (New York Heart Association Class III and IV) heart failure, were presented at a late-breaking trials session at the ACC conference. The study involved weekly transmission of the logged sensor data from the implanted device to a physician, and use of that data to guide heart failure therapy. A 33% reduction in hospitalization and ER visits was reported vs. controls with the implant but for whom the data was not used in disease management.
The Savacor (Los Angeles) HeartPOD is another implantable monitor designed to improve the management of heart failure. The system includes an implantable sensor plus a Patient Advisor Module (PAM) that allows patients to download data to a PC for viewing by their physician. Sensor data is transmitted wirelessly to the PAM for readout. As discussed by Neil Eigler, MD, of Cedars-Sinai Medical Center (also Los Angeles) at the ACC sessions, the HeartPOD provides high-fidelity tracking of pressure waves in the heart, which is important to allow treatment changes to be properly prescribed, although it does not provide real-time telemetric readout. The device also monitors intra-cardiac ECG waveforms. In the future, Eigler envisions combining the HeartPOD with a CRT device. Transoma Medical (Arden Hills, Minnesota) is another company pursuing development of implantable sensors for monitoring of patients with heart failure.
In the future, the use of implantable sensors, combined in many cases with implantable therapeutic devices, will provide cardiologists with tools that allow comprehensive disease management for complex chronic conditions such as heart failure. New devices will provide a detailed history of events, records of therapeutic device activity, and device settings, all via remote telemetry so that changes in patient condition can be detected immediately, and appropriate therapy delivered either via an implantable device or by indication that hospitalization is required. Because of the large and growing number of patients with heart failure, totaling 22 million worldwide, the market is poised for continued expansion, creating opportunities for both established suppliers as well as emerging companies with advanced sensor and treatment technologies.