CDU Contributing Editor
ATLANTA – The 55th Annual Scientific Sessions of the American College of Cardiology (ACC; Bethesda, Maryland), held here in mid-March, showcased new developments in a wide range of diagnostic and therapeutic technologies applicable to cardiovascular disease, including interventional device technologies, invasive imaging and diagnosis, technologies for diagnosis and treatment of heart rhythm disorders, and new technologies for stroke treatment.
Perhaps the most important new developments unveiled at the conference, however, are in the areas of noninvasive imaging technologies for cardiovascular diagnosis, as well as in advanced patient monitoring technologies that promise to greatly enhance the ability of physicians to manage patients more efficiently both within and outside of the hospital. Another area of growing interest is new technologies for management of heart failure, one of the most rapidly growing disease segments in the medical device market and one where considerable unmet needs exist.
Still another closely related area is technologies for diagnosis and therapy of sleep disorders, which are often present in patients with heart failure and can exacerbate the deterioration of heart function as well as diminish quality of life for congestive heart failure patients. The link between sleep apnea and heart disease is helping to drive growth in the sleep diagnosis and therapy products market. New developments in stem cell therapy were also described at the ACC conference that may impact the market in the long term, both for treatment of heart failure and vascular disease.
Rapid growth in noninvasive imaging
The use of noninvasive imaging technologies such as computed tomography (CT) and MRI for analysis of coronary artery disease is beginning to grow rapidly, based on information obtained in interviews with suppliers and clinicians at the ACC conference. In particular, CT angiography, a noninvasive modality for assessing the coronary arteries as well as the peripheral vessels, is rapidly gaining acceptance. While image quality and resolution of 0.6-0.7 mm for the latest 64-slice CT systems still falls somewhat short of that obtainable with state-of-the-art conventional angiography systems, CT adds the capability to acquire three-dimensional images, providing an enhanced perspective on the actual morphology of a vessel lumen that can be difficult to obtain via biplane angiography.
CT also provides information on the tissues surrounding the vessel, which is valuable in studies aimed at identifying vulnerable plaque, and allows detection of vessel narrowing in patients with diffuse atherosclerosis who do not exhibit a focal lesion. Conventional angiography may not readily reveal diffuse narrowing, and only provides information on the vessel lumen. According to Kim Williams, MD, of the University of Chicago Hospitals, 68% of myocardial infarctions are associated with non-flow limiting unstable lesions, which are not easily identified via conventional angiography.
CT angiography is particularly useful in lower-risk patients, that is, those who present with mild symptoms and non-STEMI ECGs, and its use results in shorter length of stay and lower cost of care in such patients, according to studies discussed by Raymond Kim, MD, at Duke University Medical Center (Durham, North Carolina). Kim also cited studies showing that 64-slice multi-dimensional CT imaging detects more patients at risk for myocardial infarction than ECG stress testing, currently one of the standard tests used for cardiovascular disease risk assessment. The radiation dose for a CT angiography exam is the same as for conventional angiography.
CT in strong uptake
The increasing utility of CT angiography has resulted in dramatic growth in adoption, according to suppliers. Companies such as Philips Medical (Best, The Netherlands), which markets the Brilliance 64-slice CT system as well as the XPER CT which allows integration of CT angiography images with conventional angiography, estimate that overall growth in the CT angiography market could be in excess of 40%-50% per year in the U.S. That growth rate is confirmed by suppliers of ancillary equipment used in CT angiography, such as Mallinckrodt (St. Louis, Missouri), which recently launched a contrast injector designed for use in CT angiography procedures.
Some centers now perform more CT angiography exams than conventional angiograms. Reimbursement remains an issue in some areas, since reimbursement levels of $650-$700 per exam are lower than for alternatives such as nuclear testing (reimbursed at $1,200-$1,300) or angiography. In addition, CT angiography is not appropriate for STEMI patients or others with obvious acute coronary syndrome symptoms, since it is highly likely that the patient will be transferred to the cath lab for interventional treatment and an additional CT scan would use up valuable time that could translate into lost heart tissue.
For low-risk patients, however, CT angiography can provide a lower-cost alternative to angiography or nuclear scans for assessing the status of the coronary arteries, including assessment of plaque characteristics and vessel morphology. The increasing use of CT angiography is expected to drive additional growth in the market for CT systems. As shown in Table 1, the worldwide market is expected to exceed $4.2 billion by 2009, growing at 7.4% annually.
The most recent advances in CT imaging technology are expected to expand applications in cardiovascular imaging, by improving resolution and image acquisition time, thus closing the gap between conventional x-ray angiography and CTA. For example, Toshiba Medical (Tokyo) is developing a 256-slice CT system that allows imaging of the entire heart in a single 1.5 second scan, requiring only a single breath hold to acquire the image. The 2nd Spec 256-Multislice CT scanner allows a high-resolution image of the entire heart to be obtained without moving the patient table, and produces the same radiation dose as a conventional CT system. A key advantage is the ability to image patients with irregular heartbeats, since the image is acquired in a single heartbeat. Spatial resolution is equivalent to that for a 64-slice scanner.
Growing uses of MRI
MRI is another technology that is being developed for use in angiographic applications, including plaque characterization to identify patients at risk for an acute event. While the spatial resolution of MR imaging is not as high as for CT scans, MR can provide more detailed information on tissue characteristics including lipid content and fibrosis. A study described by Xue-Qiao Zhao, MD, of the University of Washington (Seattle) at the ACC conference that employed high-resolution MRI demonstrated that this imaging modality can enable quantitative assessment of plaque characteristics, allowing clinicians to monitor changes over time that can occur as a result of lipid-lowering therapies.
Using a 1.5 Tesla Signa Horizon Echospeed 5.8 whole-body MR scanner from GE Healthcare (Waukesha, Wisconsin), Zhao has demonstrated the ability to measure quantitative reductions in plaque lipid volume resulting from high-dose statin therapy. A negative correlation was also demonstrated between changes in HDL cholesterol levels and plaque lipid burden, and a positive correlation was found with LDL/HDL ratio.
The ability of MR to identify tissue characteristics also allows more sensitive detection of heart attacks. Andrew Arai, MD, of the National Institutes of Health (NIH; Bethesda, Maryland), presented results from the Age, Gene/Environment Susceptibility Study being conducted in Reykjavik, Iceland, showing that contrast-enhanced MRI detects more heart attacks than ECG.
The prevalence of unrecognized myocardial infarction detected by MR imaging in the study was 12.5%. Only 6.7% of the patients had MI based on ECG criteria, and 13.9% had MI based on hospital records, clinical criteria, or ECG. However, 21.7% of patients had experienced MI based on MRI criteria, indicating the greater sensitivity of MRI in detecting cardiac damage due to MI, and the possibility that MI prevalence is considerably underestimated in the population.
Imaging in three dimensions
A unique new technology for imaging of the heart was exhibited at the ACC conference by HeartView (Palm Beach Gardens, Florida). The HeartVue 6S system provides a 3-D portrait of the heart in 60 seconds using a technique called ECG fluctuation analysis. Instead of analyzing the electrostatic characteristics of ECG signals – as in a conventional ECG analysis – the HeartVue technique analyzes the electromagnetic characteristics of the heart using differential measurement techniques. The results are displayed as a 3D color-coded image of the heart that depicts regions of ischemia.
In a pilot study evaluating the device performed at Maimonides Medical Center (Brooklyn, New York) by Andre Giannakopoulos, MD, and colleagues, the HeartVue system demonstrated higher sensitivity and equivalent specificity for detection of cardiac ischemia compared to ECG. According to HeartVue, the sensitivity and specificity for detection of heart disease when using the system for screening is 95%/90%, considerably higher than conventional ECG analysis. The analysis requires one minute, and uses a four-lead configuration. The HeartVue system is not yet approved for sale in the U.S. or Europe but is marketed in Southeast Asia at a price of about $6,000.
Management, monitoring remotely
New developments in monitoring of patients with heart disease were also highlighted at the ACC conference. Remote monitoring of ECGs, as well as monitoring of therapeutic devices such as ICDs, is growing in importance as patients are increasingly managed outside of the hospital.
iCardia (Lake Forest, Illinoi) exhibited a new, disposable ECG event recorder at the ACC exhibition that can be used for 30 days and then thrown away. Because it is disposable, the device does not need to be returned by the patient, battery replacement is not required, and there is no risk of cross-infection. Reliability is also enhanced since the device is not subjected to extended wear. The device is patient-actuated whenever an arrhythmia event is suspected, and stores up to two events of single-channel ECG data starting 40 seconds before activation and lasting 40 seconds after activation. The data is then transmitted via phone lines to a monitoring center.
The original version of the iCardia recorder was cleared by the FDA in 2004, but a new version that does not require connection to the phone line for transmission but instead mounts to the phone handset is about to be approved. The company plans a full launch in the U.S. market later this year. The device will be priced at $199.
A number of suppliers of ECG monitoring equipment are developing new systems that allow wireless transmission of data for storage in an electronic patient record.
Delmar Reynolds Medical (Hertford, UK) is developing the Voyager, a new wireless ECG system that is awaiting FDA clearance in the U.S. The Voyager will allow integration of data from Holter testing, stress testing, event recording, and blood pressure monitoring, along with a wireless interface to Delmar’s Sentinel clinical information system.
Another leading supplier in the ECG monitoring market, Mortara Instrument (Milwaukee, Wisconsin), described an initiative to incorporate a DICOM interface into all its ECG equipment, allowing data to be transmitted to any clinical information system that is DICOM compatible. Data analysis software running on the clinical information system, such as software available from Cerner (Kansas City, Missouri), can then be used to store and analyze the data, avoiding the need for a separate ECG data management system. The company estimates that a monitor with the added DICOM capability will cost about $1,500 more than existing monitors.
The goal is to provide standards-based interoperability of ECG data and image data via the DICOM interface, so that hospitals can choose the ECG system that is best for their needs while still having the advantage of computerized data interface and electronic record-keeping.
Welch Allyn (Skaneateles Falls, New York) exhibited the SmartLink Wireless System, a new 12-lead ECG system that allows data to be sent digitally using a PDA or Internet-enabled cellular phone to speed analysis of patient condition and expedite therapy. For example, ECG data can be transmitted to a cardiologist by a paramedic in the field for an MI or cardiac arrhythmia patient, allowing diagnosis to be performed while the patient is in transit, so that appropriate treatment can begin as soon as the patient reaches the hospital.
Omron (Kyoto, Japan) also is developing a wireless ECG monitor for use by ambulatory patients, the HCG-801, which is undergoing FDA review and is expected to be available in the U.S. in about two months. It will be priced at around $300, and will be available by prescription.
Monitoring what’s implantable
Implementation of advanced monitoring capability is also a key trend in the implantable device arena, and in particular in the rapidly growing ICD market.
Medtronic (Minneapolis) has marketed the CareLink system since 2002, allowing remote monitoring of implantable cardiac devices such as ICDs. And within the past few months, competitors such as Guidant (Indianapolis) and St. Jude Medical (St. Paul, Minnesota) have introduced remote monitoring technology with advanced features.
Guidant introduced the Latitude system in late 2005 which provides continuous automatic wireless monitoring of ICDs in the patient’s home to detect arrhythmias as well as device malfunctions and sends the data to a call center. The system also allows daily and weekly patient evaluations to be performed, including monitoring of body weight, blood pressure, and patient activity level. Data from the implanted device is transmitted wirelessly to a station in the home, which is connected via modem to an 800 number for Guidant’s Latitude monitoring center.
If problems are detected, the patient’s physician and a Guidant representative are paged. Automatic checks of lead impedance are performed each day at 6 am, and a broader check is performed each week to assess arrhythmia and lead capacitance. The patient also responds to questions displayed on the base station once a week to provide information on symptoms, drug use, and other patient management parameters. Body weight is input from an electronic scale, and blood pressure is acquired from an electronic meter. Patient activity can be tracked using parameters from implanted devices. Since the system was introduced, about 2,500 patients with Guidant ICDs have begun using the service, which is included in the price of the ICD. Devices for weight and blood pressure monitoring are provided for an added charge.
Medtronic is now developing a similar automated wireless monitoring system, Conexus, for its implantable device patients, which will be available in about a year. The third major player in the U.S. ICD market, St. Jude Medical, markets the Housecall Plus remote monitoring system, which has features that are similar to those of the Medtronic CareLink.
Signals from sensors and antennae
Other implantable sensing devices for monitoring of patients with cardiovascular disease include the EndoSure Wireless AAA Pressure Measurement System from CardioMEMS (Atlanta) and the RemonCHF Implant from Remon Medical Technologies (Israel). The EndoSure sensor is a solid-state pressure sensor that is implanted along with a stent graft in the treatment of an abdominal aortic aneurysm. It is placed between the graft and the aorta wall, and is geometrically designed to sample a large volume of the sac formed between the graft and the vessel wall. The sensor is noninvasively interrogated via a hand-held RF antenna that is placed over the patient’s abdomen. Signals from the antenna are processed by a console that produces a view of the pressure waveform. The waveform allows monitoring for endoleaks, which can indicate failure of the graft to provide exclusion of the aneurysm.
Another version of the device is being developed for monitoring of pulmonary artery pressure in patients with congestive heart failure. Pulmonary artery diastolic pressure correlates with left ventricular end diastolic pressure, a hemodynamic parameter that can be used to detect decompensation events in heart failure. The sensor is delivered via a catheter-based procedure. The first human implant of the device was reported in late February 2006 by CardioMEMS.
The RemonCHF Implant is also designed for monitoring of pulmonary artery pressure, but is interrogated by ultrasound. Keyur Parikh, of the Heart Care Clinic (Ahmedabad, India), reported on the first human implants of the device in a poster presented at the ACC conference. Ten patients were included in the study. The Remon Implant is made of titanium, and consists of an energy exchanger, a control chip, a pressure sensor, and an energy reservoir with ultrasonic capabilities.
In the study reported by Parikh, a device was implanted percutaneously in the right main pulmonary artery. The sensor is held in position with an expandable nitinol anchor. To interrogate the device, a hand-held ultrasonic transducer is placed in contact with the chest, and the energy exchanger (a piezoelectric transducer) converts the ultrasonic energy into electrical energy. The control chip is then energized, interrogates the pressure sensor, and ultrasonically transmits the digital reading to an external receiver. In the 10-patient study, the RemonCHF sensor showed accurate readings compared to an indwelling pressure-monitoring catheter, and no adverse events were observed over a three month follow-up period.
As compared to existing implantable pressure sensors such as the Medtronic Chronicle, which measures right ventricular pressure and derives pulmonary artery diastolic pressure via an algorithm, the RemonCHF implant measures the pulmonary artery diastolic pressure directly.
Heart failure treatments expanding
In addition to the advances in heart failure monitoring described at the ACC conference, developments were also announced in CHF therapy.
A report on the Ultrafiltration versus IV Diuretics for Patients Hospitalized for Acute Decompensated Congestive Heart Failure trial (the UNLOAD trial), presented by Maria Rosa Costanzo, MD, of Midwest Heart Specialists (Naperville, Illinois), found that ultrafiltration using the Aquadex FlexFlow System 100 from CHF Solutions (Brooklyn Park, Minnesota) results in a lower rate of re-hospitalization over 90 days (18% vs. 32%), more than halves the number of re-hospitalizations per patient, reduces the number of re-hospitalization days per patient to 1.4 from 3.8, and reduces the percentage of patients having unscheduled office and ED visits to 21% from 44%.
The FlexFlow system is a catheter-based system that shunts a portion of the patient’s blood through an ultrafiltration cartridge, removing excess water from the blood and thereby reducing fluid overload. It is typically employed in a hospital setting for patients who have experienced a decompensation episode. While ultrafiltration for fluid removal in renal insufficiency has been available for over 50 years, the Aquadex system makes the procedure available for widespread use by packaging the pump, cartridge, and ancillary components in a compact, portable package. It also is simple to set up using a disposable blood circuit set.
The system was first introduced in 2002, and about 150 are in use. The console is priced at $19,500, and each disposable set costs $900. In addition to its ability to rapidly eliminate fluid overload in CHF patients, studies have shown that patients treated with ultrafiltration typically experience restoration of response to diuretic therapy.
Biophan in VAD sector
Another device developed for heart failure therapy, the MYOVAD Ventricular Assist Device (VAD), was exhibited at the conference by Biophan (West Henrietta, New York). The MYOVAD is a flexible polymer cup that is installed around the heart in about three minutes. The cup contains a pneumatically activated liner that is driven via a percutaneous control tube connected to a pump/controller. The device is intended for short-term support for bridge to recovery, bridge to transplant, acute resuscitation, or destination therapy. So far, the longest case using the MYOVAD has lasted 84 days.
As opposed to other heart assist devices, the MYOVAD provides support for the entire heart, can be installed quickly enough for use in acute resuscitation, can support a fully arrested heart, provides pulsatile flow and normal cardiac output, and shows evidence for producing remodeling of the heart. It is also considerably less expensive than percutaneous and implantable VADs at about $20,000 per unit, and the total cost for an implant procedure is only about $50,000, versus over $200,000 for implantable VADs.
Stem cells and cell therapies
The latest developments in stem cell therapy for heart disease were also discussed at the ACC conference. Dietmar Glogar, MD, of the Medical University of Vienna (Vienna, Austria), described a trial in which both intracoronary and intramyocardial injection of bone-marrow derived stem cells was employed for the treatment of heart failure. The aim of the study was to increase the number of stem cells delivered to the heart, since prior studies of stem cell therapy have used small numbers of cells, and the beneficial effect correlates with the number of cells successfully delivered, according to Glogar. About 30 million cells were delivered to each patient in Glogar’s study, and a substantial improvement in injection fraction from 33% to 39% was observed.
However, no controls were involved in the 17-patient Phase 1 study, so the true degree of improvement attributable to cell therapy cannot be quantified. As discussed by Patrick Serruys, MD, PhD, a total of nine trials completed to date have not demonstrated that cell therapy will have a meaningful impact on the treatment of heart failure. However, new approaches that allow more stem cells to be isolated and delivered could change that picture.
Cell therapy also may eventually play a role in treating other forms of cardiovascular disease. In particular, studies using endothelial progenitor cells in animals, described by Pascal Goldschmidt-Clermont at the conference, have shown that such treatment can help prevent atherosclerosis. Some success has been achieved in using cord blood containing progenitor cells in the treatment of children with Hurler Syndrome, which is associated with early atherosclerosis.
It is believed that endothelial progenitor cells can augment the repair process for damaged arterial tissue, thereby offsetting tissue injury that is the underlying cause of atherosclerosis.
In another study presented at the ACC conference by Hung-Fat Tse, MD, of the University of Hong Kong, the Prospective Randomized Trial of Direct Endomyocardial Implantation of Bone Marrow Cells for Therapeutic Angiogenesis in Coronary Artery Diseases (PROTECT-CAD), the ability of bone marrow-derived stem cells to induce angiogenesis in ischemic myocardial tissue was evaluated. As opposed to approaches that attempt to use stem cells to generate new cardiac muscle cells, which have so far not been proven to provide any long-term benefit, the PROTECT-CAD trial assessed the use of stem cells to generate new blood vessels to restore blood flow to damaged heart tissue.
Implantation of the cells in the PROTECT-CAD trial was performed using the NOGA catheter from the Biosense Webster unit of Johnson & Johnson (New Brunswick, New Jersey), which uses electromagnetic guidance to target deliver to specific regions of the heart. Twenty-eight no-option patients with severe coronary artery disease participated in the trial, including 19 who received implants of autologous bone-marrow derived stem cells and 9 controls who underwent a sham implant procedure.
Most stem cell therapy trials have shown a significant placebo effect, making sham controls mandatory in such studies. The treated patients exhibited a statistically significant improvement in ejection fraction, from 52% to 56%, versus a change of 48% to 49% in the placebo group. A 15% reduction in wall motion defect was also observed in the treated group.
The use of stem cell therapy to induce angiogenesis is a strategy that is the focus of development efforts at Arteriocyte (Cleveland), a company spun out of the Center for Stem Cell and Regenerative Medicine, a collaboration formed by Case Western Reserve University, the University Hospitals of Cleveland, and the Cleveland Clinic Foundation. The company has been funded by venture investment from the Case Technology Ventures Fund and by $1.4 million in grants from the NIH through the SBIR program.
The company initiated a Phase 1 trial of its stem cell technology in January of this year. While the PROTECT-CAD study employed bone-marrow derived stem cells, Arteriocyte’s goal is to use umbilical cord blood as a stem cell source. Cord blood provides a readily available and reasonably rich source of stem cells, as discussed by Sunichiro Miyoshi, MD of Keio University (Keio, Japan), at an ACC press conference. Miyoshi has also investigated the use of human menstrual blood as a stem cell source. Umbilical cord blood is the better source, yielding almost 30% more stem cells than menstrual blood.
Miyoshi is focusing on regeneration of heart muscle tissue and has developed a technique that induces stem cells to differentiate in culture into cells that beat when subjected to electrical stimulation as occurs in the heart.
Another new source of stem cells is subcutaneous adipose tissue. As compared to sources such as bone marrow, which typically produces less than 1% yield, subcutaneous fat gives a yield of 2%-10%, according to Eckhard Alt, MD, of Tulane University (New Orleans), or 100-fold more than bone marrow. The low yield may explain the variable results of experiments performed with stem cells for cardiac regeneration, according to Alt, since most have employed sources with low yields.
Sleep apnea: an awakening
Another strategy for improving outcomes for patients with heart failure and coronary artery disease that has attracted increased attention recently is sleep apnea therapy. The strategy is based on growing evidence that a large percentage of CHF patients are afflicted with sleep-disordered breathing, and that the disorder can act to worsen underlying heart problems, and accelerate the deterioration of cardiac function.
In particular, Cheyne-Stokes or central sleep apnea, one of the two forms of sleep apnea (the other being obstructive sleep apnea), affects about 25% of patients with CHF, according to suppliers of sleep diagnosis and therapy products, whereas the prevalence of the syndrome in the general population is less than 1%.
About 50% of sleep apnea in the CHF population is central sleep apnea. Obstructive sleep apnea, which comprises 90% of sleep apnea in the general population, has also been linked to heart disease.
Effective treatments for sleep apnea are available, primarily employing assisted breathing modalities such as CPAP. However, many CHF patients and other patients with heart disease are not treated for co-existing sleep disorders, since the syndrome is significantly under-diagnosed. It is estimated that 20 million - 30 million individuals in the U.S. have sleep apnea, but only about 10 million have been diagnosed.
As shown in Table 2, an increasing number of companies are now developing products for sleep apnea diagnosis, based on the potential for significant expansion of the market as the adverse effects of sleep-disordered breathing become more widely recognized. There are now about 2,500 sleep labs in the U.S., and the number is increasing 10%-15% annually. As an indicator of the growing interest in the link between sleep apnea and heart disease, a number of cardiologists have recently opened sleep labs, and the number of physician-operated labs is increasing at 20%-30% annually.
One of the leaders in the sleep apnea therapy arena, Resmed (Poway, California), introduced a new technology for treatment of central sleep apnea at the ACC conference called Adaptive Servo-Ventilation. The technology, incorporated in the company’s S8 CPAP device, automatically adjusts CPAP pressure based on dynamic measurement of breathing patterns. Resmed has also introduced a new device for home screening for sleep apnea called Apnea Link.
The system uses an unobtrusive nasal cannula and pressure sensor to monitor breathing patterns, and is typically purchased by a sleep lab or durable medical equipment provider and provided to physicians for use in screening for sleep disorders. The goal is to identify and treat the 10 million-20 million patients with sleep apnea who are currently undiagnosed.
Sleep disordered breathing growing also
Suppliers of medical equipment used in the home setting are particularly interested in such systems, since they may provide a means to offset the expected decline in revenues resulting from pending cuts for home oxygen therapy. The market for sleep disordered breathing products is expected to exceed $1 billion in 2006, and is growing at over 15% per year, as shown in Table 3.
One of the newer entrants in the market, Nexan (Atlanta), has recently introduced a new product, the NX-300, that provides sleep monitoring and Holter ECG monitoring capabilities in a single system designed for home use. The device monitors 2-lead ECG, respiratory impedance, and oxygen saturation and transmits the data wirelessly to a hand-held monitor. So far, about 30 systems have been installed. Equipment and supplies cost for a typical monitoring session is $125.
In addition to providing a tool that can simultaneously evaluate heart problems and sleep apnea, the combination of technologies allows physicians to obtain a higher level of reimbursement when performing a monitoring study. The development of lower-cost technologies for use in sleep screening is expected to be a key factor in expanding the sleep products market since the current high cost of a complete sleep lab study, which averages around $1,000 in the U.S., is a deterrent to widespread testing.