CD&D Contributing Editor

CHICAGO — Developments (and controversies) concerning drug-eluting stents (DES) — first and second-generation devices and those to come — weren't the only newsworthy topics at this year's scientific session of the American College of Cardiology (Washington).

The latest developments in devices for closure of heart defects such as Patent Foramen Ovale (PFO, considered by some a primary source of migraine), atrial septal defects (ASDs), and ventricular septal defects (VSDs), were also of increasing interest at this gathering, the ACC's 57th, because of their major market opportunity in the sector.

A large number of devices for heart defect closure have been introduced or are under development, as shown in Table 1 .

Horst Sievert, MD, of Cardiovascular Center (Frankfurt, Germany), described the Solysafe Septal Occluder, a system under development by Carag (Baar, Switzerland), consisting of two polyethylene patches connected by eight wires to form dual umbrellas that are used to seal a septal defect in a highly controlled manner.

An initial clinical trial in 44 patients resulted in a 100% success rate in initial closure, and a complication rate of just 2%. The Solysafe received the CE mark in 2007 and is now in ongoing clinical trials in the U.S.

Another device, the Nitocclud PFO from Produkte fur de Medizin (PFM; Cologne, Germany), has been used in first-in-man (FIM) studies in Europe in 10 patients with good results, and a clinical trial is now being planned. The device is formed from a single nitinol wire.

The SeptRx PFO closure device is also showing promise in initial trials. The SeptRx device closes the PFO tunnel from within, leaving a minimal amount of material outside the PFO. In clinical experience with the device in 13 patients, technical success was achieved in 11 cases, and the closure success rate was 100% at six month follow-up, with no complications reported.

Coherex Medical (Salt Lake City) is developing the FlatStent PFO Closure system, which entered a FIM trial in October 2007, and it has been implanted in a total of 33 patients. Sievert said that to date no complications have been encountered and that all procedures have resulted in successful closure.

The trend in the market, according to Sievert, is to move toward bioabsorbable implants, or closure methods such as radio frequency coaptation, which eliminates the need for a long-term implant in the heart.

LAA closure a stroke treatment

An emerging segment of the market is targeted at closure of the left atrial appendage (LAA), an organ that is believed to play a significant role in increasing the risk of stroke in patients with atrial fibrillation (AF). Five million people worldwide and 2 million in the U.S. suffer from AF, according to estimates from Atritech (Plymouth, Minnesota), one of the companies developing LAA closure devices.

As discussed by Maurice Buchbinder, MD, of the Cardiac Foundation Clinic (La Jolla, California) at the ACC sessions, about 20% of all strokes are related to the presence of AF, and half of those strokes are fatal or result in severe neurological complications. According to Buchbinder, the stroke risk in the AF population is elevated by six-fold over the non-AF population.

The current approach used to prevent stroke in AF patients is the prescribing of Coumadin to prevent thrombus formation, but 80% of patients are under-treated, leaving them at elevated risk of stroke. Between 91% and 98% of the thrombi found in AF patients occur in the LAA, thus making it a prime target for stroke prevention therapies.

Atritech is developing the Watchman device for percutaneous closure of the LAA, enabling minimally invasive preventative therapy in place of lifelong Coumadin treatment. The device consists of a nitinol frame with a polyethylene terephthalate cap containing small orifices that become occluded by cell ingrowth. The device is placed into the orifice of the LAA and released, resulting in sealing of the channels within the LAA and elimination of the risk of clot formation.

Two feasibility trials have been completed that demonstrated good results, with zero strokes, deaths, or embolic events at three to five year follow-up. The Watchman is now undergoing a pivotal U.S. clinical trial in the PROTECT AF study, and a total of 747 patients had been enrolled as of March 19.

Although no long-term follow-up data is available yet, at six months 90% of the patients who were intended to come off Coumadin therapy had done so. Enrollment in the trial is scheduled to be complete by August 2008.

Plaque imaging, image-guided therapy

Imaging technologies are playing an increasingly important role in cardiology, both for screening and diagnosis as well as in therapy guidance. Detection of vulnerable plaque is one application that is drawing increasing attention, as new image-based methods for analyzing coronary arteries become available that provide a more powerful means of characterizing plaque.

According to Volcano (San Diego), a leading supplier of intravascular ultrasound devices used for in vivo imaging of coronary arteries, 86% of the 2 million heart attacks experienced annually, worldwide, are attributable to vulnerable plaques.

And often, the vulnerable plaque which causes a heart attack is not the one detected as a tight stenosis via angiography. In fact, as discussed by Robert Wilensky, MD, of the University of Pennsylvania School of Medicine (Philadelphia) at the sessions, 68% of myocardial infarction patients do not have a high-grade lesion that can be detected via angiography.

Clearly, improved diagnostic techniques are needed to enable clinicians to target for therapy those patients who are at high risk for myocardial infarction and to identify the lesions most likely to cause an infarct. This would provide a path for the use of prophylactic treatment such as stents to be delivered to the site of the true vulnerable lesion.

The Volcano Virtual Histology (VH) IVUS technique for analysis of vulnerable plaque is one potential candidate. VH analyzes certain components of the IVUS image to obtain parameters that can be correlated with plaque composition. VH IVUS is to be evaluated clinically in the SECRITT 1 trial, in which lesions identified by VH but classified as low-grade (40% to 50% stenosis by quantitative coronary angiography, or with a normal fractional flow reserve and normal appearance on optical coherence tomography) will be randomized to treatment with either a self-expanding stent or with medical therapy. A four-year follow-up is planned to compare clinical outcome.

The increased interest in IVUS as a means to provide a more complete diagnosis and detect vulnerable lesions that go undetected using conventional angiography, along with the increasing use of IVUS to guide stent placement, is deriving rapid growth in IVUS utilization, as shown in Table 2.

The growth in IVUS use is occurring in spite of a decline in overall percutaneous coronary intervention (PCI) procedures. In 3Q07, Volcano's sales of IVUS disposables increased 28% compared to 3Q06, although PCI procedure volume declined 10% over that same period. And Volcano projects that 90% of catheterization laboratories will have integrated angiography/IVUS capability by 2012.

IVUS has also been shown to have value in tracking response to medical therapy in studies such as the Pioglitazone Effect on Regression of Intravascular Sonographic Coronary Obstruction Prospective Evaluation (PERISCOPE) trial. PERISCOPE data demonstrated that the oral anti-diabetic drug Actos, manufactured by the Japanese company Takeda Pharmaceutical (Osaka), reduced atherosclerotic burden in the coronary arteries compared to glimepiride, and that IVUS imaging provides an effective method to track changes in plaque volume in response to drug therapy.

Other intravascular imaging technologies that may complete with or complement IVUS and VH in analyzing vulnerable plaque include Optical Coherence Tomography (OCT), which also is being commercialized by Volcano; near infrared imaging, a technology being developed by InfraReDx (Burlington, Massachusetts); and intravascular MRI.

Volcano is developing OCT technology, which it acquired with its purchase of CardioSpectra (San Antonio) this past December, and the company says that it plans to initiate first-in-man studies, initially with a stand-alone OCT system, sometime this month. OCT also is proving useful method for assessment of stent placement, for assessment of tears and hematoma in blood vessel walls, and for characterization of thrombus.

NIR intravascular imaging technology is also nearing commercialization. A 510(k) submission for the InfraReDx NIR Imaging System has been filed, and the company expects to receive clearance in the near future.

In contrast to other optical techniques for plaque imaging such as OCT, NIR imaging can be performed without stopping blood flow, making it a more convenient method for vulnerable plaque characterization. Intravascular MRI is being developed by TopSpin Medical (Lod, Israel) and is being used to measure the lipid content of vulnerable plaques.

The TopSpin system is being evaluated in the TOPIMAGE trial in patients with unstable angina, and has been used in 104 patients in that study with a success rate of 88% and only one major adverse event. IV-MRI has demonstrated the presence of lipid-rich plaques in two-thirds of the patients in the trial.

New modalities further out

Longer term, non-invasive imaging modalities are expected to become increasingly important for detection of vulnerable plaque and risk assessment in cardiology.

For example, a new high-resolution MRI technique employing Ultra-Small Particles of Iron Oxide (USPIO) as a targeted contrast agent has been found to be a sensitive method for detection of vascular inflammation and emboli in patients undergoing lipid-lowering therapy in a study described at the ACC sessions by Jonathan Gillard, MD, of Cambridge University (Cambridge, UK).

The USPIO agent used in the study, Combidex, was developed by AMAG Pharmaceuticals (Cambridge, Massachusetts), and has been used in a wide variety of imaging applications including tumor detection. The study conducted by Gillard showed that contrast-enhanced MRI using an agent that targets inflammation in the carotid arteries allows patient response to high-dose statin therapy to be measured non-invasively. In principle, the technique can be used to determine which patients will benefit from aggressive therapy in advance, enabling a personalized medicine strategy to be used.

Other non-invasive imaging modalities showing promise for vulnerable plaque assessment and risk assessment in cardiology include CT angiography (CTA), MR angiography and tissue Doppler imaging.

CTA has been demonstrated as a highly specific technique for initial evaluation of patients with chest pain, as described by Michael Poon, MD, of Mount Sinai Medical Center (New York).

Poon quoted specificity of 96% for CTA in detection of MI in patients with chest pain, and he noted that the modality is particularly valuable in patients with a non-diagnostic ECG or an equivocal nuclear scan. In the future — perhaps the near future — Poon predicted that CTA will become the first imaging exam performed for chest pain patients.

Lesions detected via CTA, as well as others that are classified as harboring vulnerable plaque, can then be treated in the cath lab or evaluated using invasive methods, such as IVUS, to determine if PCI is warranted.

Although the use of CTA and multi-slice CT imaging in cardiology has come under scrutiny from the Centers for Medicare & Medicaid Services recently because of its potential for over-use — as have many imaging modalities — the decision in March to leave Medicare local coverage determination policies in place for CTA is viewed by clinicians and industry as a positive development.

The National Coverage Decision being contemplated by CMS would have effectively eliminated Medicare coverage for CTA in the view of groups such as the Society of Cardiovascular Computed Tomography (Washington), which lobbied heavily against the change in policy. Now, the coverage decision appears to leave CTA in a position that will allow its growth to continue.

Another positive sign for the technology has been seen in a physician survey conducted in mid-2006 by Siemens Medical Solutions (Munich, Germany) and projecting CTA use to increase from 15% to 60% of patients undergoing cardiac diagnosis between 2006 and 2009.

Home/remote monitoring challenged

Another segment of the cardiology diagnostics market, home/remote monitoring of patients with heart failure, may not fare as well as CTA with respect to reimbursement decisions, based on the results of a study presented at the sessions by Ozlem Soran, MD, MPH, of the University of Pittsburgh.

Soran described results of the Heart Failure Home Care (HFHC) trial, designed to assess the cost-effectiveness of home heart failure monitoring in Medicare beneficiaries recently hospitalized for heart failure.

The study, sponsored by CMS, was a multi-center randomized trial of computer-based care vs. standard care. A total of 350 patients were included in the study, with 175 managed with computer-based care using the Alert Day Link Heart Failure Monitoring System from Alere Medical (Reno, Nevada), a company acquired by Inverness Medical Innovations (Waltham, Massachusetts) last November for $302 million.

The Day Link system includes an electronic home unit that asks preprogrammed questions scripted by a physician to patients regarding their clinical symptoms, and also tracks patient body weight via a digital scale. Readings are transmitted via modem to a central call center staffed by nurses, where the data is evaluated and used to manage the patient. The study period in the HFHC trial was six months.

Although some previous studies conducted with home monitoring systems for heart failure patients have shown savings in overall patient management cost due to reduced rates of hospitalization and reduced rates of adverse events requiring treatment, the HFHC study found a higher overall cost for the monitored group, which included a high ratio of elderly women and non-white males.

There were no statistically significant differences between the groups in death or re-hospitalization, and the mean length of stay for patients hospitalized was similar.

But the mean costs of monitoring the Medicare monitored patients was nearly $4,000 more than for the patients monitored by means of standard care — $17,837 vs. $13,866.

Costs — likely (hopefully) to come down

The higher cost was seen as the result of the greater expense for the electronic monitoring, a cost likely to come down with advanced generations and greater use of such systems, according to its advocates.

CMS has sponsored other studies of electronic home monitoring in the past, but has so far authorized only very limited Medicare coverage for home telehealth.

The results of the HFHC study do not support expanded reimbursement and utilization of telehealth, according to Soran, and may carry significantly more weight than previous studies, in future CMS decisions on telehealth reimbursement, since the study was sponsored by the agency.

In addition to Alere/Inverness Medical, other important players in the home telehealth market include Honeywell HomMed (Brookfield, Wisconsin), which has 50,000 monitoring systems installed worldwide and a cumulative total of 550,000 users of its service at rates ranging from $15 to $35 per month; Health Hero Network (Palo Alto, California), acquired by Robert Bosch (Stuttgart, Germany) in December 2007; American Telecare (Eden Prairie, Minnesota); Philips Medical (Best, the Netherlands); and Viterion Telehealthcare (Tarrytown, New York).

Another segment of the cardiology monitoring market is remote cardiac monitoring systems, such as those provided by Raytel Cardiac Services (Windsor, Connecticut), a unit of Philips Medical, and Aerotel Medical Systems (Holon, Israel), a provider of clinic/remote site ECG monitoring systems.

A positive study for this segment was completed recently in the UK, and reporting a savings of 46 million (about $90 million) through use of the Aerotel Medical monitoring system.

Continued growth nevertheless expected

The total market for health management services including services such as home monitoring at the payer level is substantial, totaling about $2 billion in the U.S. as shown in Table 3.

The market is expected to continue to grow, including increased expansion of the home health management segment, as payers search for more cost-effective approaches to managing patients with chronic diseases such as heart failure, respiratory conditions, and diabetes.

Ongoing evaluations of cost-effectiveness in specific patient populations and geographic regions will have an important impact on reimbursement and market growth, creating some winners and losers. Suppliers and providers will need to continue to refine their products and services to achieve the most cost-effective business models while optimizing patient outcomes.

A positive development for the home monitoring sector in the U.S. was the announcement in late March of expanded Medicare coverage for home International Normalized Ratio (INR) monitoring.

Previously, reimbursement for home INR monitoring was available from Medicare only for patients with mechanical heart valves to monitor their anti-coagulation status while undergoing warfarin therapy. In March, CMS decided to expand coverage to include patients on warfarin therapy with chronic atrial fibrillation or venous thromboembolism. The decision expands the potential market for home INR monitoring by a factor of eight to 10, according to suppliers of monitoring systems.

As of July 2007, about 26,000 patients in the U.S. performed home INR testing, but about 1.5 million were undergoing warfarin therapy, according to information from Roche Diagnostics (Indianapolis), the leading supplier of home coagulation monitoring products worldwide. Other suppliers of home INR monitors include HemoSense (San Jose, California), a unit of Inverness Medical; and International Technidyne (Edison, New Jersey), a unit of Thoratec (Pleasanton, California).