CDU Contributing Editor

VIENNA — Cardiovascular disease remains the No. 1 cause of death in Europe, making the market for products used in diagnosing, monitoring and treating heart disease and stroke one of the largest segments of the medical device market in the region.

While the market has faced challenges over the past year related to safety issues with interventional devices, significant opportunities are continuing to emerge, not only in the developed markets in Western Europe but increasingly in the growing markets in Eastern Europe.

One of the most important disease segments in cardiology, and the focus of this year's Congress of the European Society of Cardiology (ESC; Sophia Antipolis, France), is heart failure, affecting 6.5 million in Europe and 5 million in the U.S. (with some sources quoting nearly 14 million with heart failure in Europe, nearly 23 million worldwide).

Effective device-based therapy for heart failure is now widely available in Europe, although rates of utilization are well below those in the U.S., as shown in Table 1, and vary significantly by country. Increasingly, heart failure patients are also being managed with the use of advanced remote telemonitoring technologies to improve early detection of changes in disease status and to enable better control of symptoms.

Drug-eluting stent (DES) technology for the coronary vasculature remains a controversial area in cardiology, with new data presented at the ESC congress showing better long-term safety than in prior trials.

But other new studies continue to indicate a higher long-term adverse event rate compared to bare metal stents (BMS). In particular, treatment of acute coronary syndrome patients with DES appears to result in higher rates of stent thrombosis.

Additional developments were described at the ESC congress in vulnerable plaque detection, treatment of structural heart disease, and minimally invasive therapy for heat valve disorders. New developments in imaging technology unveiled in Vienna are expected to play an important role in guidance of interventional procedures, driving expansion of the market.

Device-based telemonitoring

One of the most rapidly growing applications in the heart failure management sector in Europe is the use of remote telemonitoring to track patient status and detect deteriorating conditions at an early stage to avoid the need for frequent and costly hospitalizations. A number of device-based solutions for telemonitoring of heart failure patients are now on the market in Europe, and new competitors are continuing to enter the market.

At ESC, Dr. Uta Hoppe of the University of Cologne (Cologne, Germany) described results of the PAPIRUS II study using the RemonCHF device being developed by Remon Medical Technologies (Caesarea, Israel), a company in the process of being acquired by Boston Scientific (Natick, Massachusetts).

The Remon CHF is an implantable pulmonary artery pressure monitor that can detect fluid overload, a key symptom of decompensation in heart failure patients. It consists of the ImPressure self-expandable stent which includes an integrated pressure sensor, a battery, and a handheld readout unit that non-invasively monitors intracardiac pressure, activating an alarm if adverse trends are detected.

The device can be implanted along with an ICD or CRT device, avoiding the need for a separate implant procedure. It has the potential to provide an earlier indication of decompensation compared to less sophisticated measures such as body weight. In the PAPIRUS I study, a 40-patient trial designed to assess safety, there were only two minor adverse events, including a contrast allergic reaction and a mis-sizing of the device requiring explant.

Hoppe said that the RemonCHF is safe for monitoring of heart failure patients and believes that it could give an earlier indication of decompensation than existing monitoring methods. In addition to monitoring of heart failure patients, the device also may have applications in telemonitoring of patients with pulmonary hypertension.

Another implantable device designed for detection of decompensation in heart failure patients has been available since late 2004 from Medtronic (Minneapolis). OptiVol Fluid Status Monitoring is a feature of the Medtronic InSync Sentry CRT-D system and will soon be available on the company's CRT-P platform. It monitors impedance between the outer metal enclosure of a CRT device and the tip of the implanted defibrillator lead.

Changes in water content of a patient's lungs indicate fluid load and are reflected in the impedance measured by the device, and can be used to detect trends that predict decompensation.

As discussed by Martin Cowie, MD, of Imperial College (London) at the ESC sessions, the OptiVol monitor can detect an impending decompensation event about two weeks prior to the development of serious symptoms, allowing intervention to prevent further deterioration and thereby avoiding a hospitalization. This type of assessment is critical in the heart failure sector since early symptoms often are late indicators of cardiovascular problems.

According to Cowie, recent experience with the OptiVol shows that impedance monitoring is highly predictive, with only one false alarm generated per year of monitoring. When the impedance change reaches threshold, an alarm is generated and transmitted wirelessly to the Sentry Check, a handheld device used by the patient to self-check fluid status.

Devices such as the OptiVol and the RemonCHF monitor are thought to enable patients to become involved in managing their own condition, improving control of their disease and minimizing adverse events.

Cardiac rhythm telemonitoring

Telemonitoring of cardiac rhythm is another rapidly growing application in Europe, using both implanted monitors for patients with rhythm control devices such as CRT devices, ICDs, and pacemakers, as well as non-invasive telemonitoring systems.

There is also growing acceptance of implantable monitors such as the Medtronic Chronicle, which can be used to evaluate patients with serious rhythm disorders to determine their priority for heart transplants.

In Germany, for example, 80% of heart transplants are now performed on an urgent basis, and 16.5% of patients on the heart transplant list die awaiting a transplant. Devices such as the Chronicle can detect deterioration of the heart's condition and allow patients to move up the transplant priority list. The Chronicle can detect both atrial and ventricular fibrillation as well as sleep apnea.

Devices that can monitor patients at home and in other non-clinic settings are growing in popularity in Europe because they enable closer monitoring of patients than do periodic visits to the clinic and also allow costs to be reduced.

Arnaud Lazarus, MD, of InParys Clinical Research Group (Saint Cloud, France), discussed his experience with the CardioMessenger home telemonitoring system that is an integral feature of ICDs manufactured by Biotronik (Berlin), including the newly launched Lumax ICD that provides extended device longevity of nearly 10 years. Lazarus cited data showing that adverse trends in patient status are detected an average of 154 days earlier with home telemonitoring compared to a typical schedule of in-person clinic visits every six months.

The Biotronik CardioMessenger II performs routine transmission of data automatically via a wireless interface to a standard modem link to the company's service center in Germany. In case a significant adverse event is detected, an immediate transmission occurs to the Biotronik monitoring center. Alarm messages are forwarded to the patient's physician, and routine data transmissions are stored on a physician-accessible website. Over 70,000 Biotronik home monitoring systems have been installed worldwide in 35 countries, and more than 5 million data transmissions have been recorded since the CardioMessenger service was initiated.

At present, over 14,000 transmissions are sent daily, and more than 1,600 clinics are using the system. About 40% of all Biotronik transmissions are sent from patients in the U.S., and 50% are sent from Europe. Growth in adoption of the system in the U.K. has been particularly strong.

Device implants there increased 140% from 2000 to 2005, and 160% growth is predicted from 2005 to 2010. Every day 50 to 60 patients are monitored in the UK via telemonitoring, compared to 18 per day with in-office visits.

Another leading supplier of ICD and CRT-D devices, Boston Scientific, released data following the ESC congress on its implantable telemonitoring system, the LATITUDE Patient Management System.

More than 60,000 patients are enrolled on the system at more than 1,300 clinics across the U.S. Data from the first 15,000 patients to be monitored with the system over a seven-month follow-up period showed that at least one event of sustained atrial arrhythmia lasting for more than 24 hours was detected in 948 patients.

As with other wireless implantable monitoring systems, the immediate detection of arrhythmia events allows physicians to intervene early to prevent strokes. In addition, the LATITUDE system can perform monitoring of body weight and blood pressure using wireless external devices, allowing physicians to improve management of heart failure patients.

Very necessary: show 'em the money

One limiter of utilization of cardiac telemonitoring in Europe at present is lack of physician reimbursement.

As discussed by Hein Heidbuchel, MD, of the University of Leuven (Belgium), a team required to manage patients via telemonitoring typically includes a heart failure nurse, an electrophysiology device nurse and a physician. But physicians are not paid for their time reviewing electronic patient data.

Results from a number of recent and ongoing studies indicate that telemonitoring is able to reduce hospitalizations and mortality from heart failure, and so the physician loses revenue to the extent that in-person patient visits and hospitalizations are reduced.

Thus, lack of reimbursement works against the goal. In response, some physicians in Europe are developing biometric models based on their actual experience with telemonitoring to establish new reimbursement policies.

In addition, recent data from Europe, published by Christian Zugck, Janis Radeleff, and Lutz Frankenstein of the Medical Center of the University Heidelberg, shows that the mean total cost for management of heart failure patients using telemedical care is less than half that for patients managed with standard care (€2,739 vs. €5,873.50 for a three-month observation period). The lower cost for patients managed with telemonitoring is primarily due to a reduction in hospitalizations.

A large randomized trial, PRECEDE-HF, is now underway in the U.S. under sponsorship of Medtronic to determine if a significant improvement in patient survival is achieved with telemonitoring.

Growth in telemonitoring

A number of other applications of telemedicine were described at the ESC congress that promise to expand the role of remote electronic monitoring in cardiology.

For example, Dr. M. Brzozowska-Kiszka of the University of Kopernika (Krakow, Poland) described use of the TensioCare home telemedicine blood pressure monitoring system to improve management of patients with hypertension. The TensioCare system, developed by TensioMed (Budapest, Hungary), enables a patient to perform self-testing of blood pressure and then transmit the data to a physician via a standard telephone link.

Brzozowska-Kiszka reported results of a study with the TensioCare system comparing home telemonitoring with regular self-testing of blood pressure in patients with hypertension. After two weeks of monitoring, a drop in blood pressure was seen in the TensioCare-managed group. The difference was not maintained at three months, but the precision of blood pressure control remained better for the patients using TensioCare, and compliance with hypertension control measures was improved.

Natale Brunetti, MD, of the University of Foggia (Foggia, Italy), described the use of telemedicine to improve time to diagnosis for MI patients in a regional healthcare network in Italy. A fleet of 150 ambulances serving both metropolitan and isolated rural areas was equipped with the Cardiovox P12 ECG system from Aerotel Medical Systems (Holon, Israel), which was interfaced via the cellular telephone network to the nearest hospital.

Patients who experienced symptoms of a heart attack called an emergency telephone number to summon an ambulance. The patient was then diagnosed via consultation with a physician at the hospital viewing the 12-lead ECG via the cellular link. The system proved particularly valuable for the 20% of patients with ST-segment elevation MI who did not experience chest pain, and thus might not have been taken to the hospital in the absence of real-time ECG data.

The study showed that the sensitivity of chest pain as a diagnostic parameter for MI drops dramatically with age, with the number needed to treat, in order to show a benefit for the use of on-site 12-lead ECG, dropping from 10 for patients in their 60's to three for patients in their 80's, and 2 for those patients in their 90's. Using the Cardiovox P12 allowed a definitive diagnosis to be obtained in about half of the patients in less than 30 minutes.

Another study presented at the ESC congress compared survival of patients following a heart attack for a group managed with telecardiology provided by SHL Telemedicine (Tel Aviv, Israel) to a conventionally managed patient group from the ACSIS survey, a biennial survey covering all patients with acute coronary syndromes in CCUs in Israel.

The SHL network employs wireless Cardiobeepers to allow patients to contact a call center when in need of medical attention, along with a customized ECG monitor that provides transmission of 12-lead ECG data to the call center via the cellular network. The network reduces the time for treatment to be initiated if patients suffer a second heart attack.

As discussed by Arie Roth, MD, of Tel Aviv Sourasky Medical Center at the ESC, the group managed with the SHL network had a mortality rate that was, at one year, less than half that of patients in the ACSIS survey (4.4% for the SHL patients vs. 9.7% for the ACSIS patients), an improvement that was attributed to more frequent contact with the SHL patients and greater motivation to seek timely medical assistance.

While the two patient groups were not equivalent in terms of cardiovascular risk and size, if a comparison of an equivalent risk group from the ACSIS survey were performed, it is likely that the improvement in mortality would be even greater for the SHL group, Roth said. SHL recently received FDA clearance of a new wireless cellular cardiac looping monitor for use in home monitoring of cardiac arrhythmia patients.

DES debate goes on and on

Another congress feature was the latest developments with DES, including new data on safety and the results of trials of next-generation stents employing bioabsorbable materials. DES issues remain unresolved, given the conflicting results of ongoing studies.

The most recent data from the Western Denmark study, providing data for diabetic patients treated with DES vs. BMS at three high-volume centers in that country, found that the rate of stent thrombosis was higher for BMS devices throughout the study, and that target lesion revascularization rates for DES-implanted patients were roughly half those BMS-treated (5% vs. 9%). Mortality as well as MI rates also favored DES or were equivalent for the two stent types.

An analysis presented by Christian Spaulding, MD, of Cochin Hospital (Paris), of three trials of the Cypher sirolimus-eluting DES from Johnson & Johnson/Cordis (Miami Lakes, Florida) — including the TYPHOON, STRATEGY and SESAMI — shows no significant difference in stent thrombosis at one-year follow-up in TYPHOON and SESAMI, and two-year follow-up in STRATEGY for DES.

Another study, described by Ron Waksman, MD of Washington Hospital Center (Washington) at the congress, compared the two stent types retrospectively in a wide range of off-label uses, including saphenous vein grafts, unprotected left main stenting, in-stent restenosis lesions, and similar applications.

All devices in the study were FDA-approved. At one year follow-up, target lesion revascularization rates were 8.5% for the DES, 13.9% for BMS, statistically non-significant. Rates of major adverse cardiovascular events were also equivalent. However, DES devices were superior in treating in-stent restenosis and ostial lesions.

Waksman said the data justifies the expansion of DES label indications for treating in-stent restenosis.

Additional DES results were presented by pathologist Renu Virmani, MD, of CVPath Institute (Gaithersburg, Maryland) at an ESC press conference. Virmani has been a leader in analyzing DES safety, assessing hundreds of cases of stent-implanted patient deaths.

As shown in Table 2, Virmani observed a significant drop in the number of cases in which stent thrombosis has occurred over time, perhaps resulting from changes in drug use, or other unknown factors. Virmani found more uncovered stent struts in patients with stent thrombosis, and that stents having a larger diameter also are more prone to thrombosis.

She raised the possibility that certain invasive imaging techniques such as Optical Coherence Tomography could be used to inspect stents post-implant to determine which patients need to continue with dual anti-platelet therapy. And she said that DES should not be used to treat acute MI patients, since they already are at increased risk for thrombosis.

Results from other studies presented at the congress confirm that with the current DES generation there is a significant increase in the risk of late stent thrombosis for MI patients.

Results from the Global Registry of Acute Coronary Events (GRACE) trial, presented at the congress by Gabriel Steg, MD, of Centre Hospitalier Bichat-Claude Bernard (Paris), show an overall increase in all-cause mortality at two-year follow-up after PCI with DES vs. BMS in acute coronary syndrome patients (those with ST-segment elevation myocardial infarction).

The increase was substantial — a death rate at 730-day follow-up of about 0.07 for DES, 0.035 for BMS. The registry excluded patients lost to follow-up and those who died in hospital.

In addition, registry data is not randomized, and the study did not employ information on the type of DES or BMS used or on angiographic lesion characteristics, which may impact outcomes. But the GRACE analysis prompted Steg to suggest that DES should be used cautiously in patients with STEMI until further evidence of long-term safety is accumulated.

A possible mechanism for increased risk of thrombosis in STEMI patients, offered by Patrick Serruys, MD, PhD, of Thoraxcenter (Rotterdam, the Netherlands) — in a presentation on results of the ARTS III study — is that the DES is implanted on top of a layer of thrombus when an MI has occurred, creating a space that creates long-term malapposition of the stent, leading to thrombosis.

A definitive answer regarding the risks of using DES in STEMI, typically comprising 25% to 30% of stent patients in hospitals in Europe, remains to be found, but the consensus of most cardiologists presenting at the congress was to avoid DES implantation in STEMI patients altogether or to use DES only in patients at very high risk for high-risk restenosis.

Treating PFOs and ASDs

Another segment of the interventional cardiology market highlighted at the ESC congress was devices for the treatment of structural heart disease such as patent foramen ovale (PFOs) and atrial-septal defects (ASDs).

A recent development in the segment is the receipt of the CE mark, as well as Canadian regulatory approval, for the BioSTAR atrial defect closure device developed by NMT Medical (Boston).

The BioSTAR device is the first bioabsorbable device to be approved for use in the heart, according to the company. It is also the first product to combine a drug, device and biologic material. The BioSTAR consists of a porcine intestinal collagen covering a metallic framework, plus a heparin coating to reduce thrombus formation. The device is 90% to 95% absorbed over two years, with the porcine collagen material replaced by host collagen.

Applications for the BioSTAR device include prevention of stroke and Transient Ischemic Attack (TIA) and, possibly, treatment of migraine headache.

Development of a bioabsorbable device may expand the range of applications of structural heart defect closure products, since a bioabsorbable device could greatly facilitate use in children where growth of the heart structures could otherwise require repeat interventions.

However, the latest study of PFO closure as a treatment modality for migraine failed to reach its endpoint. As discussed by Eric Eeckhout, MD, of Centre Hospitalier Universitaire Vaudois (Lausanne, Switzerland), details of the MIST1 trial results using the NMT STARFlex, a non-bioabsorbable closure device, have not yet been published, although results of the trial were presented in early 2006. According to Eeckhout, there are now eight trials under way to assess the treatment of migraine via PFO closure, and results should be available in about two years.

Other suppliers of PFO and atrial-septal defect closure devices include AGA Medical (Golden Valley, Minnesota), Cardia (Eagan, Minnesota), W.L. Gore (Flagstaff, Arizona), and St. Jude Medical (St. Paul, Minnesota).

According to Eeckhout, a limiter of expanded use of heart defect closure devices such as devices used for ASD closure is the complexity of the implant procedure. The procedure is performed on the beating heart and requires precise sizing and transcatheter placement of the closure device, typically under ultrasound guidance.

Advances in interventional imaging

A new development in imaging technology that could greatly facilitate device implant procedures and consequently increase utilization was introduced at the congress by Philips Medical Systems (Andover, Massachusetts). Philips has developed a real-time, 3D transesophageal echocardiography imaging system, the ie33, the first of its kind and providing unprecedented image detail and perspective promising to be particularly useful for guidance of interventional procedures in the chest, including the heart.

As shown in Table 3, the worldwide market for ultrasound imaging products in 2006 totaled roughly $3.9 billion, and about 25% of the market is attributable to cardiology imaging products.

Furthermore, development of emerging ultrasound imaging modalities such as 3D TEE is expected to enable expansion of the market into areas such as acute care, cardiovascular disease management, procedural guidance, and screening.

Suppliers of heart defect closure devices believe that 3D TEE could enable a major increase in device use by making it easier to correctly guide placement.

The new Philips 3D system allows accurate dimensional measurement of structures in the heart such as PFOs and heart valves, and can be used in the catheterization laboratory during interventional procedures.

It also allows a measurement of cardiac ejection fraction to be performed in less than one minute.

The technology is expected to be particularly useful for guidance of procedures such as percutaneous heart valve repair and closure of PFOs and atrial-septal defects. Although the 3D probe has a 2,500 element transducer, it is the same size as a 2D TEE probe. The new probe is priced at €50,000, compared to €15,000 for a 2D probe.

Other leading imaging suppliers are expected to introduce 3D TEE systems in the near future. For example, Siemens Medical Systems (SMS; Munich, Germany) is planning to introduce a new 3D TEE system at the EuroEcho 2007 conference in early December.

Competitive image systems

While new 3D ultrasound techniques show great promise for improving the guidance of interventional procedures, advances in other imaging modalities described at the ESC congress may provide some competition.

In particular, as discussed by Vivek Muthurangu at a conference symposium on new imaging technologies sponsored by SMS, interventional MRI has considerable potential for use in procedure guidance. MRI excels at structural imaging of soft tissues, and can provide highly accurate physiological information. In the past, the technique was not able to provide real-time images, making it impractical for interventional procedure guidance.

But continued advances in acquisition time and imaging processing technology have now enabled MRI to be as interactive as echocardiography, according to Muthurangu, with applications now including guidance of procedures such as transcatheter valve implantation in complex lesions.

Other applications of MRI showing promise in cardiology include the use of delayed enhancement imaging to identify vulnerable plaque, as discussed by Juhani Knuuti, MD, of the University of Turku (Turku, Finland), as well as weighted MRI, currently being evaluated as a non-invasive method to identify lipid-rich plaque, and perhaps particularly useful in targeting invasive imaging devices, such as OCT, virtual histology (an intravascular ultrasound imaging technology), intravascular Raman spectroscopy, or other emerging invasive imaging modalities for detection of vulnerable plaque.