BBI Contributing Editor

ORLANDO, Florida The annual scientific sessions of the American College of Cardiology (ACC; Bethesda, Maryland), held here in March, provided a forum for a number of important new developments in the global cardiovascular device market. Considerable attention was paid to improvements in risk assessment for cardiac patients, partly a result of the growing availability and effectiveness of minimally invasive treatments for coronary artery disease. Such assessments are found in both the laboratory testing and diagnostic imaging sectors.

Diagnostic imaging technologies are 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. Advances in technologies for the detection of vulnerable plaque also drew attention, both in scientific sessions and on the Orange County Convention Center exhibit floor. The conference also included presentation of the latest results of cell transplant therapy and various new biotherapy approaches.

Continued advances in the less invasive treatment of heart valve disease also were described at the ACC gathering, 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.

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 used 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 1, 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 1, 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 more than 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 2, 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 overuse 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 imposition 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 more than $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 3, 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.