CDU Contributing Editor

Part 2 of 2

CHICAGO, Illinois The management of heart disease remains a high priority for the U.S. healthcare system, not only because heart disease is the No. 1 cause of death nationwide, but also because of the high cost of treating patients with chronic cardiovascular disease (CVD). As a result, there is a continuing focus on developing improved approaches to diagnosis of heart disease at an early stage to help minimize its long-term consequences, on devising new methods of monitoring patients to reduce the need for re-hospitalization and to improve outcome, and on developing new treatment modalities that are more effective, less invasive and lower in cost.

Important new developments in the diagnosis of cardiovascular disease were described during the annual scientific sessions of the American Heart Association (AHA, Dallas, Texas), held in Chicago's sprawling McCormick Place convention center in November, along with advances in monitoring technologies and minimally invasive therapy. While there have been some recent setbacks in certain areas, particularly in minimally invasive therapy for heart disease, the field as a whole is continuing to move forward and to attract new competitors.

New diagnostic markers for coronary artery disease, including markers that promise to allow earlier detection of myocardial infarction, were described that promise to improve the ability of physicians to identify individuals at risk for a heart attack and implement corrective measures. Those developments are using not only conventional technologies now used in the laboratory and at the point of care, but also emerging genomic analysis methods that add a new dimension to risk analysis.

Technology-based approaches for the management of chronic conditions, particularly congestive heart failure, also continue to attract attention, and are finding increased acceptance in the U.S., as clinicians become more aware of their benefits in reducing costs and the need for hospitalization.Information systems are beginning to play a more important role in heart disease management by helping to lower the cost of care and reduce errors.

In minimally invasive therapy, some technologies have recently encountered hurdles to adoption, both because of regulatory issues as well as findings that performance of the technology when implemented for widespread use has not equaled that achieved in clinical trials.Nevertheless, most segments of the market continue to expand, and prospects for growth of the overall market for minimally invasive devices to treat cardiovascular disease remain strong.

Diagnostic, monitoring technologies grow

One new diagnostic marker, high-sensitivity C-reactive protein (hs-CRP), has generated considerable interest within the research community and now is gaining a level of acceptance among clinicians. As discussed by the leading researcher in clinical studies that have assessed the marker, Paul Ridker, MD, of Brigham and Women's Hospital (Boston, Massachusetts), results of a new large-scale study of hs-CRP have laid the groundwork for a fundamental shift in the concept of the causes of vascular disease. CRP is already widely used as a general marker of inflammation, becoming strongly elevated when, for example, an infection is present. In coronary artery disease, the elevations in CRP level are much smaller, necessitating use of the high-sensitivity version of the test. Suppliers of hs-CRP assays in the U.S. include Dade Behring (Deerfield, Illinois); Beckman Coulter (Brea, California); Kamiya Biomedical (Seattle, Washington); Wako Chemicals USA (Richmond, Virginia); Roche Diagnostics (Indianapolis, Indiana); Diagnostic Products Corp. (Los Angeles, California); Pointe Scientific (Lincoln Park, Michigan) and ABX Diagnostics (Irvine, California). Many additional suppliers market hs-CRP kits, including tests that can be performed at the point of care, in Europe, and are likely to enter the U.S. market as it expands. Only about 130,000 hs-CRP tests were performed for clinical purposes in 2001 in the U.S., according to researchers presenting at the AHA sessions. As the role for the test expands, however, utilization is expected to grow rapidly.

Elevated levels of CRP as determined by high-sensitivity assays have been shown to be linked with an increased risk of heart attack, and, more recently, to allow prediction of outcomes after percutaneous revascularization. The marker appears to identify patients with inflamed arteries who are at higher-than-normal risk of a heart attack, and serves as an independent risk factor vs. established markers such as cholesterol, LDL and HDL. Moreover, the most recent evidence indicates that C-reactive protein may play a causative role in vascular inflammation, perhaps in combination with CD14, another marker of infection that measures levels of bacterial endotoxin. While the AHA does not yet recommend that hs-CRP be used routinely in assessment of the risk of coronary artery disease, such a recommendation is under consideration, according to Ridker. One of the factors that limits the need for the test is the lack of proven therapy to lower CRP levels associated with coronary artery disease. At present, an elevated reading is only useful as a motivator to induce a change in lifestyle.

Another study, discussed at the AHA meeting by Michael Zairis, MD, of Tzanio Hospital (Piraeus, Greece), assessed the impact of moderate alcohol consumption on CRP levels in patients with heart disease. The GENERATION trial involved 4,835 patients treated for coronary syndromes including heart attack, chest pain or coronary artery disease, and assessed the rate of major adverse cardiac events in a cohort with moderate alcohol consumption versus patients who did not report moderate alcohol use. Alcohol use had no measurable effect for patients who had low CRP levels at the outset of the study, but reduced the event rate for patients with elevated CRP levels by almost a factor of two, from 40% to 23%.

Ischemia Technologies (Denver, Colorado) is developing a new marker for use in the diagnosis of acute coronary syndromes, including myocardial infarction, which will potentially improve patient triage and allow earlier identification of patients in need of treatment. The marker, ischemia modified albumin or IMA, is CE-marked for sale in Europe and is undergoing clinical trials to generate data for a premarket approval submission to the FDA. IMA is a marker for cardiac ischemia and has been shown to become elevated within minutes of the onset of ischemia. Recent studies by Ischemia Technologies have shown that combining IMA with cardiac Troponin I approximately doubles the sensitivity of detection of acute myocardial infarction within the first hour after onset of symptoms, from 23.9% with Troponin I to 55.9% with both markers. IMA alone provides a sensitivity of 39.1%. The IMA test is available in Europe as a clinical chemistry test kit that runs on commonly available chemistry analyzers. The test may help to reduce the occurrence of premature discharge of patients from the emergency department (ED) with an undetected myocardial infarction. About 8% of patients who visit the ED with chest pain or other symptoms of MI are misdiagnosed and discharged, with a significant incidence of associated mortality.

Products for improving the management of congestive heart failure are enjoying growing demand, both in the in vitro diagnostic sector, as well as for patient monitoring. Biosite Diagnostics (San Diego, California) reported high demand for its combination panel consisting of the Triage BNP and Cardiac Panel point-of-care assays for use in the emergency department and chest pain clinics. The test allows physicians to quickly make a differential diagnosis of heart failure vs. myocardial infarction. Biosite reported BNP sales of $9.8 million for 3Q02 and total product sales of $28.1 million for the quarter. BNP sales increased 987% over 3Q01. The Biosite BNP test, used in the diagnosis of heart failure, is now in use in more than 1,000 hospitals. In addition, suppliers of BNP tests for clinical lab use are experiencing growing demand for the assay. Biosite also is developing a panel of markers for the diagnosis of stroke and recently reported an agreement with ProteomeSciences (Surrey, UK) for the commercialization of stroke biomarkers.

The use of monitoring technologies outside the hospital to track the status of heart failure patients is another rapidly expanding market segment. A study described at the AHA meeting by Daniel Nul, MD, of Heart Failure Study Group (Buenos Aires, Argentina), evaluated the use of telephonic monitoring of heart failure patients in the randomized trial of telephonic intervention in chronic heart failure (DIAL trial). The trial involved 1,519 patients with stable congestive heart failure (CHF) who were monitored using a computerized telephone system that calls patients and connects them with nurses who ask questions about their symptoms. Key indicators of patient status in CHF include body weight and blood pressure. The study used trained nurses with physician oversight, and a computer program that adjusted the frequency of calls to a particular patient based on trends in their condition. The primary endpoints of the study were cardiovascular mortality and the number of hospitalizations.

The computerized calling system allows nurses to focus their monitoring efforts on patients who require the most intensive monitoring, improving efficiency. The study found that telephonic monitoring reduced total hospitalization by 29% and reduced hospital admissions by 15% (24% for admissions for cardiovascular problems). In addition, the monitored arm had a shorter length of stay when hospitalized as compared to controls.

A number of companies in the U.S. also are marketing computerized systems for monitoring of CHF patients at home via telephone lines. Those systems employ not only call center monitoring by nurses who can interactively assess patient condition, but also equipment in the home that measures body weight, blood pressure, pulse rate, and other parameters, with the data automatically transmitted to the nurse for review. Physicians can in most cases access the data via the Internet from the call center. Leading suppliers of such systems in the U.S. include HomMed (Brookfield, Wisconsin), Alere Medical (Reno, Nevada), American TeleCare (Eden Prairie, Minnesota), Health Hero Network (Mountain View, California), Cybernet Medical (Ann Arbor, Michigan), LifeLink Monitoring (Bearsville, New York) and Philips Medical Systems (Best, the Netherlands).

HomMed's monitoring devices were used in the management of more than 20,000 patients during the first nine months of 2002, and the company projects that more than 50,000 patients will be monitored during 2003 based on the current growth rate. Alere Medical also has continued to expand its position in the market and is partnering with PacifiCare Health Systems (Santa Ana, California) in a demonstration project sponsored by the Centers for Medicare & Medicaid Services (Baltimore, Maryland) that will involve monitoring of 15,000 patients with chronic disease.

Another important technology used in the management of CHF patients is cardiac output monitoring. There has been a revolution in that area over the past few years as noninvasive technologies have become more widely adopted, allowing cardiac output to be monitored in a variety of sites outside the hospital including physician offices and the home. The leading supplier of noninvasive systems for cardiac output monitoring is CardioDynamics International (San Diego, California). As shown in Table 1, CardioDynamics achieved sales growth averaging more than 100% per year over the period from 1998 to 2001. Another supplier of noninvasive cardiac output monitoring products, Sorba Medical Systems (Brookfield, Wisconsin), entered the market earlier in 2002 and exhibited its new Steorra ICG system at the AHA meeting. The company developed noninvasive impedance cardiography technology for research applications in the early 1990s, and has placed a number of its CIC1000 research units, but decided to enter the clinical market when impedance cardiography became reimbursable (at $37 per exam) through Medicare. The Steorra ICG system is priced in the mid-$20,000 range, with cost dependent on options selected. The system uses R-wave triggered ensemble averaging as an enhancement to basic impedance cardiography, providing an improved signal-to-noise ratio. The Steorra provides full disclosure output, and a measurement requires about 20 seconds. The system can automatically group patients by New York Heart Association class. It also provides measurements of systemic vascular resistance and thoracic fluid volume index.

As shown in Table 2, the market for noninvasive hemodynamic monitoring products is expected to grow rapidly over the next five years, while the overall market, comprised of both invasive catheter-based monitors and a variety of noninvasive monitors, grows at only about 5% per year. The noninvasive segment includes impedance cardiography, pulse contour analysis, partial rebreathing monitors, and Doppler ultrasound monitors, but is dominated at present by impedance cardiography products. The market is expanding in large part because noninvasive monitors are allowing hemodynamic measurements to be performed in a wide range of alternate sites including the physician's office, home healthcare, heart failure clinics and the emergency department, whereas the use of invasive monitoring is mainly confined to the critical-care setting in the hospital. Noninvasive monitoring is even beginning to make inroads in the hospital due to its reduced cost as compared to invasive monitoring and reduced risk of complications.

CardioDynamics is expanding into products for noninvasive ambulatory monitoring of hypertension, a new segment of noninvasive monitoring that also has become commercially attractive as a result of changes in reimbursement. In fact, the company estimates that the total number of potential monitoring procedures for hypertension is 25 million annually, vs. 20 million per year for congestive heart failure. CardioDynamics introduced at the AHA gathering its Oscar2 ambulatory blood pressure monitoring system, which allows physicians to check for white-coat hypertension, a condition that may affect up to 20% of individuals who are diagnosed with hypertension. The $2,995 Oscar2 was developed by Suntech Medical (Raleigh, North Carolina) and is targeted at users in cardiology and internal medicine clinics, as well as family practice physicians. Once a patient is qualified for monitoring by a series of spot blood pressure readings taken both in the office and at home, ambulatory monitoring is reimbursable at a rate of $36.19 per exam.

Advances in therapy for heart failure

New treatments for heart failure also are beginning to gain acceptance. While there is considerable interest in experimental treatments employing cell transplants and tissue engineering, some existing approved device-based therapies are helping to improve the condition of patients with CHF. For example, Somanetics (Troy, Michigan) introduced the CorRestore System following receipt of FDA clearance in November 2001, and about 1,200 patients have now been treated with the device. CorRestore is indicated for patients with Stage III and IV heart failure who have exhausted the various pharmaceutical options for treatment. CorRestore is a patch manufactured from bovine pericardium that provides an off-the-shelf solution for surgeons performing the Surgical Ventricular Restoration (SVR) procedure. The SVR procedure changes the shape of an enlarged heart by reshaping the heart's apex and realigning the heart valves. An immediate increase in pumping efficiency of about two-fold is typically achieved, reducing the workload on the heart and allowing it to return toward normal size. In contrast to the typical heart failure scenario in which 40% of CHF patients are admitted to the hospital each year and 25% are admitted at least twice each year, only 10% of patients treated with the CorRestore have a hospital readmission in over three years. Treated patients generally revert to Stage I. As shown in Table 3 on page 5, the company estimates the market potential for CorRestore at about $200 million annually in the U.S. alone for treatment of new patients, plus an additional $1.6 billion spread over perhaps five to eight years for treatment of existing patients. Somanetics' device is priced at $3,950.

Surgical procedures such as SVR may help restore some of the losses in procedure volume being faced by cardiothoracic surgeons, who are experiencing a dwindling number of cases for their mainstay coronary artery bypass graft (CABG) procedure. Continued improvements in minimally invasive interventional technologies have eroded the patient base for cardiac surgeons. Efforts to develop less-invasive CABG surgery techniques have not succeeded in reversing the declining trend, since the techniques are still more invasive than transcatheter methods. Nevertheless, surgeons continue to be interested in developing improved less invasive methods, and a number of studies discussed at the AHA meeting described evaluations of devices used in minimally invasive cardiac surgery.

Terrence Yau, MD, of Toronto General Hospital (Toronto, Ontario), described his experience with the Symmetry Bypass System developed by St. Jude Medical (St. Paul, Minnesota), which features the company's Aortic Connector that allows the surgeon to attach a saphenous vein graft to the aorta without sutures. He was the first to deploy the device in patients. According to Yau, the main concern in using the device was the potential for damage to the graft's endothelium as a result of the mechanical action of the struts of the device during deployment. In a study of 26 patients, each receiving 3.1 grafts on average, the St. Jude device proved easy to use, with a loading time of about five minutes and a firing (attachment) time of less than 10 seconds. There were two failures during anastomosis, one of which was repaired with sutures. The second failure was possibly due to use of a vein that was too small to mate properly to the device, Yau said. At one-year follow-up, there were three cases of stenosis, all at the proximal end of the anastomosis, but none resulted in any symptoms and all the grafts remained patent.

Advantages of the St. Jude connector include minimization of manipulation of the aorta and avoidance of aortic clamping. The latter feature is particularly important, since clamping is often thought to result in the formation of emboli that can lead to downstream blockage of blood flow, particularly in the brain. A concern voiced by Yau is that the struts of the St. Jude device might create a problem if a re-operation in the area of the anastomosis is needed, but there is currently no data to substantiate that concern.

Paul Grunderman, MD, of UMCU (Utrecht, the Netherlands), discussed his experience with the EndoStarfish, a device developed by Medtronic (Minneapolis, Minnesota) for heart positioning during minimally invasive cardiac surgery procedures. The device was used along with the company's EndoOctopus tissue stabilizer in performing endoscopic surgery in a study conducted in pigs. The key finding was that the circumflex vessels could be exposed for access using the EndoStarfish. In fact, Grunderman found that a complete revascularization could be performed endoscopically, although five access ports were needed. The ultimate goal is to develop technologies that enable robotic coronary artery bypass surgery to be performed with endoscopic techniques. Demand for such techniques may increase in the future, at least as a percentage of total CABG cases, because the average age of bypass patients is increasing, causing a drop in the percentage of patients who qualify for conventional open-heart surgery.