BB&T Executive Editor

NEW ORLEANS — The major media like what are called “bleeders” — news that indicates somebody, or something, is hurt or in trouble, preferably both — and they got it at the recent annual meeting of the American College of Cardiology (Washington). Elbowing aside a variety of interesting reports on new developments in stem cell technology and other emerging opportunities, the general media headlined the results of the Clinical Outcomes Utilizing Percutaneous Coronary Revascularization and Aggressive Guideline-Driven Drug Evaluation (COURAGE) trial which appeared to indicate that the use of drugs and other primary medical management systems are superior to percutaneous coronary intervention (PCI, a.k.a angioplasty/stenting) as a primary strategy for dealing with coronary artery disease. The study indicated that PCI does not reduce mortality, myocardial infarction or other major cardiovascular events “when added to optimal medical therapy.” The study, enrolling 2,287 heart disease patients in Canada and the U.S. between 1999 and 2004, appeared in the March 29 issue of the New England Journal of Medicine.

The mass media reports on COURAGE were generally interpreted by analysts as a one-day news wonder, with many pointing to the number of clinicians heavily committed to PCI and the strong profit motive built into the procedure. But the short story was that the Street wasn’t happy with the news. Shares of Boston Scientific (Natick, Massachusetts) and Johnson & Johnson (New Brunswick, New Jersey), makers of the two FDA-approved DES devices, dropped. Boston Scientific was hit hardest with nearly an 8% decline following the trial report, dropping to a four-and-one-half year low of $14.15.

In contrast, shares of Abbott Laboratories (Abbott Park, Illinois) rose nearly 5%. Abbott does not yet have an FDA-approved stent, but benefited from strong data for its Xience DES, rolled out at ACC, and the stent is expected to win that approval next year.

Counter-attack quickly launched

Following roll-out of the COURAGE data, stent manufacturers and clinician groups began their counter-attack on the report, zeroing in on various limitations of the study. Among the criticisms:

• Primary bare-metal stent use in the study. COURAGE enrollment came before the full roll-out of DES and so involved only 3% DES use in the study. Stent proponents immediately noted that broad use of the newer DES was likely to have shown a better result for stenting. And an editorial in the NEJM accompanying the study results noted that with more DES implants there might have been fewer repeat procedures and the symptom benefit of PCI larger.

• Patient pool limitations. Patients in the study came largely from hospitals treating veterans in the U.S. and Canada, a patient population with greater compliance to medication use because they are provided free, thus not representing the general population.

• Crossover population. Donald Baim, MD, chief technology officer for Boston Scientific, and others noted that about one-third of the patients in the drug group experienced worsened symptoms and over the five-year period of the study received a follow-on PCI or CABG.

• Limited stenting application. The Society for Cardiovascular Angiography and Interventions (SCAI; Washington), issued a statement saying that the chronic stable angina patient pool studied in COURAGE represents only about 30% of those treated with stenting. Gregory Dehmer, MD, president of SCAI, said, “We are concerned that many seem to be interpreting this study as part of a huge battle among cardiologists that will shift therapy in a dramatic way, but I don’t really see it shaping up that way. Although PCI is life-saving in the setting of a heart attack, it has never been promoted in any of the national treatment guidelines as saving lives or preventing heart attacks in patients with chronic stable angina. Although it is tempting to pick apart the COURAGE trial for its flaws, and there are some, doing so would remove the focus from how the results can best be used to improve patient care.” SCAI also positioned COURAGE as demonstrating the overall improved treatment of coronary artery disease.

Poised: newer stents, stenting

Against the backdrop of the ongoing debates concerning efficacy and safety issues related to stenting, the meeting served as a preview to new stent devices poised to come on line and challenge the two FDA-approved DES products: the Taxus from Boston Scientific and the Cypher from Cordis (Miami Lakes, Florida). The most important report came from Abbott Vascular, the vascular unit of Abbott Laboratories, which unveiled results of the SPIRIT III trial of its Xience V Everolimus-eluting Coronary Stent System. Based on earlier study results, Xience has been projected as the next big DES, and according to some analysts, likely to take No. 1 market share in this sector following approval.

The trial’s primary endpoint was in-segment late loss (a key measure of vessel renarrowing) at eight months, and Xience V demonstrated superiority to Taxus with a 50% reduction in late loss compared to Taxus (0.14 0.41 mm Xience V, 0.28 0.48 mm TAXUS, p superior = 0.004). That was statistical significance with a large exclamation point.

Adding another exclamation point was Xience’s superiority over Taxus in its major secondary endpoint, target vessel failure (TVF) at nine months. Xience demonstrated non-inferiority to Taxus with a 21% reduction in TVF compared to Taxus (TVF being a measure of re-treatment anywhere within the target vessel and including cardiac death or heart attack.)

“Not only did the SPIRIT III trial meet its primary and major secondary endpoints, but it showed a statistically significant reduction in major adverse cardiac events, favoring Xience V,” said Gregg Stone, MD, of Columbia University Medical Center and the Cardiovascular Research Foundation (both New York), principal investigator of the SPIRIT III trial, in presenting the results. And in a not very thinly veiled reference to the current DES safety debate, Stone called Xience “an important advance” because of its “enhanced freedom from adverse event.”

Boston Scientific nevertheless mined good news from the SPIRIT III report, since it has a deal with Abbott for marketing rights to Xience, branded as Promus (the result of a distribution agreement developed last year).

Charles Rudnick, director of corporate communications for Boston Scientific, told Biomedical Business & Technology that half the Xience stents will be packaged and sold by it as Promus. The company’s margin on sales won’t be as large as Abbott’s, he acknowledged, but Boston Scientific will have a marketing edge by leveraging its position as having two DES products approved both in the U.S. and overseas.

Lawrence Biegelsen, analyst with Prudential Equity Group (New York), reported that he expects Abbott to file for Xience FDA approval in the first quarter of 2008, with potential market launch the following quarter.

The Xience V system uses the drug everolimus, which Abbott says “has been shown to reduce tissue proliferation in the coronary vessels following stent implantation and is based upon the highly deliverable and proven Multi-Link Vision coronary stent platform.” Xience was launched in Europe and Asia Pacific in 2006.

Abbott also provided a preview-type look at another group of stents poised to come on line —though more slowly and perhaps requiring a time line of three to four or more years — that of stents that are absorbed and completely disappear from the body.

“The encouraging results from the first 30 patients of ABSORB suggest that drug-eluting bioabsorbable stent technologies may be a promising future therapy option for physicians treating patients with heart disease,” said Patrick Serruys, MD, PhD, professor of interventional cardiology at the Thoraxcentre, Erasmus University Hospital (Rotterdam), co-principal investigator of the study. The company said that these results confirm a treatment effect of everolimus in the bioabsorbable stent similar to that seen in Abbott’s studies of metallic DES devices, with everolimus actively inhibiting tissue growth into the artery.

Abbott’s everolimus-eluting bioabsorbable stent is made of polylactic acid, a biocompatible material commonly used in medical implants such as dissolvable sutures.

“Based on these encouraging safety results, Abbott will continue to advance this technology by enrolling the next cohort of patients in the ABSORB study in Europe and New Zealand,” said John Capek, PhD, senior VP, Abbott Vascular. “The next phase of the ABSORB study will utilize a next-generation bioabsorbable everolimus-eluting stent that incorporates several advancements designed to improve strength and deliverability.”

Other stenting opportunities

The negatives concerning stenting coming from the ACC meeting are unlikely to prevent the expansion of stenting into other areas of the body.

For instance, researchers at Miami Children’s Hospital (Miami, Florida) reported on the use of stents to treat infants with congenital heart disease and concluded that “balloon extendable stent [BES] implantation in infants is safe and effective.

”They said the devices “can be enlarged through serial re-dilation to keep pace” with the child’s growth. The authors recommended use of stents with “adult diameter potential who do not require later surgery and that for those who will require follow-on surgery, “smaller stents can be used effectively and removed or ligated safely at a later date, if needed.”

The authors noted that the the BES strategy had been used previously but that there has been so far a lack of long-term follow-up data.

Overall, 33 BES procedure were attempted in 27 patients, with the study group finally consisting of 22 patients with 26 BES implants. At the latest follow-up 21 patients were alive, with one mortality, a “late unrelated death 51 months after implantation,” according to the study abstract.

In another study, researchers used both DES and BMS to determine impact on renal insufficiency., finding no difference between the two types of stents.

Improvements in imaging and workflow

The big imaging companies were, as usual, in large-exhibit attendance at the meeting, highlighting what are being identified as crucial issues in the handling of heart disease: much more precise imaging of the heart for improved outcome, and greater workflow efficiency as a path to improved treatment.

• Royal Philips Electronics (Andover, Massachusetts) showcased its new portfolio of solutions that it said are designed to save time in the overall treatment of heart disease patients, especially in the critical first moments of care for heart attack patients. Integrating patient medical information across hospital care areas — from the ambulance to the emergency room, imaging, catheterization (cath) lab and critical care unit — to accelerate diagnosis and treatment and provide enhanced patient comfort and safety. new solutions introduced at the show included: HeartStart MRx Monitor/Defibrillator, designed to help hospitals realize the industry’s recommended 90-minute “door-to-balloon” protocol.

The HeartStart MRx Monitor/Defibrillator enables hospitals to organize their resources, before a patient even arrives. Pre-hospital transmission of the 12-Lead ECG helps avoid delays to treatment. With the MRx, a paramedic can quickly acquire and wirelessly transmit a suspected myocardial infarction patient’s ECG data to the emergency department and/or other locations, such as directly to the interventional cardiologist. Prior to the patient’s arrival, clinicians can use the transmitted ECG to assess, and if needed, prepare for lifesaving treatment such as PCI performed in the cath lab, or thrombolytic therapy. Beginning upon arrival, and as the patient is transported and awaiting treatment, this technology enables continuous surveillance of the patient’s waveforms and vital signs with an all-in-one device including advanced monitoring, built-in pacing, synchronized cardioversion and defibrillation capabilities.

Philips also demonstrated Xper Information Management, a new cardiovascular workflow solution featuring Philips’ physiomonitoring technology, and other innovations for reporting, scheduling, inventory and data management. Xper Information Management encompasses pre- and post-cath holding, physician review with reporting and administrative and systems management. With user-centric navigation and tools that enhance efficiency on multiple levels, this new solution simplifies workflow for all cardiovascular professionals so they can focus on delivering quality patient care.

• TomTec Imaging Systems (Munich, germany), focused on 3D and 4D echocardiography and echo information management systems, unveiled a solution for left ventricular analysis in cardiac magnetic resonance imaging (cMRI), calling it “the gold standard technique for precise measurements of left ventricular volumes, function and mass.”

The 4D LV-Analysis MR application, based on TomTec s successful 4D LV-Analysis software for echocardiography, uses MRI data sets to provide a functional analysis of the left ventricle. Results include volumes, ejection fraction and a quantification of dyssynchrony. It also offers innovative (patent pending) analysis options like 3D Parametric Imaging (3DPI), simplifying assessment of dyssynchrony and localizing areas with delayed myocardial contraction.

The 4D LV-Analysis MR application is designed to offer precise measurements, as well as recently established parameters for quantifying dyssynchrony, including dyssynchrony cut-off values, such as the Systolic Dyssynchrony Index (SDI), which aids in selecting those patients most likely to respond to Cardiac Resynchronization Therapy (CRT).

Martin Hyca, clinical marketing manager of TomTec, said, “The Systolic Dyssynchrony Index that TomTec developed with leading cardiologists is the first clinically validated parameter to separate responders from non-responders before pacemaker implantation. While this method was restricted until now to 3D ultrasound data, doctors may apply it in future even for patients that are difficult to examine with ultrasound, by using MR imaging. This may help even more patients benefit from this method.”

• Toshiba America Medical Systems (Tustin, California) showcased its Aplio XG ultrasound system including the latest innovations for diagnosing heart disease. Tissue Doppler Imaging Quantification (TDI-Q) — software that allows clinicians to perform various analyses for TDI images, measuring myocardial viability and aiding in the diagnosis of coronary artery disease.

As part of the TDI-Q package, the Aplio XG offers Dysynchronous Imaging (DI), a technique that aids cardiologists in the quantification of left ventricular mechanical dyssynchrony by providing a color-coded display that demonstrates the timing of events within the myocardium of the heart. Early mechanical events are “green” and severely delayed events are displayed “red,” allowing clinicians to quickly identify the presence and severity of the patient’s dyssynchronous events. The DI method allows physicians to select the optimal candidates for cardiac resynchronization therapy because quantitative values are now available.

The Aplio XG’s TDI-Q software performs various analyses via the following features: Harmonic Tissue Doppler, allowing for clearer signal and more accurate data analysis; Angle Correction — Cardiologists have the ability to evaluate the synchronicity, not only longitudinally, but can use the short axis view to obtain radial information. Tissue Tracking — Allows for accurate tracking through the cardiac cycle of the myocardium to gauge thickening of the tissue.

Additionally, the system features Tissue Strain Imaging (TSI), an evaluation tool that clearly displays the regional myocardial strain quantitatively during systole. TSI, along with displacement imaging, also can be utilized for bi-ventricular pacing.

• Vital Images (Minneapolis), a provider of visualization and analysis solutions, featured enhancements to its ViTALCardia product, including a new EP planning tool and CathView, a new angiographic orientation, and intuitive protocols that automate workflow including automatic: segmenting, viewing, labeling, probing and quantifying of cardiovascular image data.

ViTALCardia’s CT Cardiac application probes, segments and labels the three main coronary arteries allowing for fast non-invasive evaluation, automatically segmenting the Left Anterior Descending artery, the Circumflex artery, and the Right Coronary artery. This preprocessing “facilitates a streamlined workflow,” according to Vital Images. A new cardiovascular report was designed to automatically populate as findings are obtained, thereby reducing the number of steps needed to compile a final report.

The Cardiac Functional Analysis (CFA) application automatically calculates end diastolic and end systolic volumes to compute ejection fraction. CFA segments the left ventricle, automatically calculates cardiac output, myocardial mass, myocardial volume, and analyzes wall motion with 4D cine reviews. The application provides full color polar plots charting quantitative wall motion data.

ViTALCardia software includes applications for the visualization and analysis of cardiovascular images, including coronary vessel analysis, cardiac functional analysis, calcium scoring, peripheral vessel analysis and SUREPlaque, coronary plaque characterization software. With the availability of higher resolution image data, Robert Schwartz, MD, of the Minneapolis Heart Institute and Foundation.

ViTAL EP, which is pending FDA clearance, automatically identifies anatomic landmarks, segments and probes the left atrium and the pulmonary veins to the first bifurcation. The application then creates a 3D model of the heart for super-imposing EP mapping. In addition, ViTAL EP has a streamlined integration with the St. Jude Medical EnSite System.

Technologies and applications abound

The ACC meeting offers the opportunity for looking at the broad range of technologies being developed in the cardiovascular sector, across a variety of applications and opportunities. Just a few examples:

Metabolic assessment. At the lower end of the high-tech spetrum, and emphasizing prevention perhaps more than therapy, BodyMedia (Pittsburgh) was featuring its SenseWear Body Monitoring System, focused on “lifestyle adjustments.”

The SenseWear is an armband-worn monitor, weighing a tad less than 3 ounces, that continuously gathers in data which can then be translated to information that a person, and that person’s physician, can use for understanding actual activity level what his or her body is doing, and doing metabolically, minute-to-minute, day-to-day.

Donna Wolf, PhD, clinical research manager for BodyMedia, noted that given engrained habits and the various claims on our attention, most people don’t really have a good idea of caloric input and energy output. And so the system provides an objective guide for making lifestyle alterations, and a clear alternative to draconian diet regimens. “It’s an education” that people can’t get in a lab or really any other way, she told BB&T.

The monitor collects four kinds of data — temperature of the skin, galvanic skin response, heat flux, and a measurement of motion via an accelerometer — which are then massaged by company-developed algorithms that translate these measurements into descriptors of energy expenditures, such as duration of activity, the number of steps a person takes, the time spent lying down and duration of sleep.

Requiring just two standard AA batteries, the monitor is worn continuously and can help to tell how well you sleep, even when you turn over during the night, according to Wolf. The device can collect up to two weeks of such data, with the information then exportable to a computer for analysis. Analysis is made explainable via reports and “graphical” presentations. The entire data can be analyzed or particular time periods can be examined for a closer look.

SenseWear was first developed as a research tool and is now being marketed to physicians. At the ACC sessions, the company was also introducing a new accessory to the system, a trendy-looking device — looking, and worn like, a watch — that wirelessly captures the data from the monitor to provide the wearer a real-time sense of the data being gathered.

Hypertension control. CVRx (Minneapolis) bannered preliminary data from European and U.S. trials for its Rheos system — which it says is the first implantable device designed to control hypertension — presented by principal investigator Peter de Leeuw, professor of medicine/ hypertension at the University of Maastricht (Maastricht, the Netherlands). The company said the findings show a significant reduction in blood pressure in patients with drug-resistant hypertension who have a systolic blood pressure of 160 mmHg or greater, despite being on at least three anti-hypertension medications, including a diuretic. The trials are assessing the safety and clinical efficacy of the Rheos System.

CVRx describes the Rheos system as an external device that electronically activates the baroreflex, which sends signals to the brain suggesting a blood pressure increase. Then, the brain acts to lower blood pressure by sending signals to various parts of the body to reduce blood pressure, including the blood vessels, heart and kidneys. The system’s proprietary technology uses the body’s own natural blood pressure regulation system (baroreflex) to control blood pressure.

A small pulse generator is implanted under the collar bone, with two thin lead wires implanted at the left and right carotid arteries and connect to the pulse generator. The system provides, according to the compnay, a “physiological rational” method to reduce blood pressure.

The presentation reported on the following office cuff measurement results after six months of active Rheos therapy for the first 21 European and U.S. patients enrolled in these trials at 10 medical centers: Systolic blood pressure was reduced by an average of 21 mmHg (187 mmHg vs. 166 mmHg); and diastolic blood pressure was reduced by an average of 16 mmHg (112 mmHg vs. 96 mmHg).

Rheos implants were well tolerated, and there were no unanticipated adverse events related to the system or procedure.

“These favorable results are promising for the many people with drug-resistant hypertension,” said Nadim Yared, president/CEO of CVRx. “We are expanding the scope of the Rheos System evaluation with a pivotal trial that is now under way. We have begun enrolling patients and look forward to advancing our understanding of the Rheos System and therapy.” Findings from two pre-clinical studies that evaluated the Rheos System in canine subjects with heart failure were also presented. In both studies, the system was found to improve the function of the left ventricle, the heart’s main pumping chamber, in canines.

Holter monitoring advances. Spacelabs Healthcare (Issaquah, Washington), a division of OSI Systems (Hawthorne, California), launched the evo Digital Holter Recorder and Voyager 12-Lead Electrocardiogram (ECG) system, calling it an advancement in digital Holter monitoring.

The recorder features a Dynamic Energy Source technology that ensures that the evo is ready for use on the next patient, immediately following data download. It also eliminates the need for disposable batteries. Small, lightweight, evo can be concealed under patient clothing and offers 48 hours of recording time with pacer detection capability as well as an on-board display to check signal quality.

The Voyager 12Ci high-end ECG system incorporates 12-lead technology, intuitive design, and large color touch screen that displays patient’s 12-lead ECG in real time. The system can acquire, interpret and store up to 120 ECG records at any one time while also being able to print and send diagnostic ECG reports to Spacelabs’ recently launched Sentinel Cardiology Management System.

Deepak Chopra, CEO and chairman of OSI, said, “Our commitment to R&D since acquiring Del Mar Reynolds in July 2006 is exemplified in our recent launch of the Sentinel Cardiology Management System and in today’s . . . launch of evo and Voyager.