BBI Contributing Editor

ORLANDO, Florida – The market for devices used in cardiology is one of the most rapidly growing segments of the medical products market, and continues to offer opportunities for major suppliers as well as new ventures. A wide range of new developments in the cardiovascular device market was presented at the 50th annual scientific sessions of the American College of Cardiology (ACC, Bethesda, Maryland), held here in mid-March.

The results of studies of new devices for prevention of restenosis attracted considerable attention, including new information on devices used for intravascular brachytherapy as well as drug-coated stents. Progress also is continuing in the electrophysiology device segment, particularly with new dual-site pacing techniques for the treatment of atrial fibrillation in patients with heart failure. The treatment of heart failure represents a major and growing area of application for new devices and drugs, with new devices employing mechanical technologies now entering the market. Longer term, emerging approaches including tissue engineering and angiogenesis may provide even more effective treatments for heart failure and coronary artery disease.

There also is continuing progress in technologies for the diagnosis and monitoring of patients with cardiovascular disease. A new test for heart failure was just introduced that promises to allow a considerable improvement in early diagnosis, perhaps allowing existing treatments to be initiated sooner to avoid or at least delay the onset of serious disease. New drugs such as ReoPro from Centocor (Malvern, Pennsylvania), a unit of Johnson & Johnson (New Brunswick, New Jersey), and other inhibitors of platelet function are proving highly effective in allowing patients to avoid additional adverse events following a heart attack, and recently introduced monitoring systems for point-of-care use are proving valuable in optimizing such therapy. Point-of-care (POC) technologies are becoming important in other aspects of the diagnosis and management of cardiovascular disease, including POC imaging devices to allow more convenient and widespread access to diagnostic images.

Advances in brachytherapy, coated stents

Intravascular brachytherapy was approved by the FDA in November 2000 for the treatment of in-stent restenosis, and physicians have already adopted the technology in numerous sites in both the U.S. and Europe. Two systems are approved in the U.S., including the Checkmate from the Cordis (Miami Lakes Florida) unit of Johnson & Johnson and the Beta-Cath from Novoste (Norcross, Georgia). More than 5,000 patients have now been treated with the Novoste system, and over 1,000 have been treated in the U.S. with the Checkmate system. Although neither system currently addresses the prevention of restenosis in de novo lesions, they both address a significant worldwide market opportunity approaching $2 billion, as shown in Table 1. A number of systems are under development by other companies, including the Galileo system from Guidant (Indianapolis, Indiana), the RDX radioactive balloon system using beta radiation from Radiance Medical Systems (Irvine, California), the RadioCath liquid-filled beta irradiation balloon system from Mallinckrodt Medical (St. Louis, Missouri), the Gammamed system from Boston Scientific (Natick, Massachusetts), and three types of soft X-ray systems (using low energy gamma irradiation), including one from Medtronic/Interventional Innovations (Minneapolis, Minneapolis).

Table 1
Worldwide Market Potential for Restenosis Treatment
Patient
Category
Annual
Procedures
Restenosis
Rate*
Est. Restenosis
Procedures
Potential
Market
Coronary Stents
1,200,000
20%-30%
435,000
$1.1 billion
PTCA Patients
400,000
40%-50%
160,000
$400 million
Peripheral
Angioplasty/
Stent Patients
500,000
20%-50%
175,000
$435 million
Total
770,000
$1.9 billion
*Within five years of original procedure
Assumes $2,500 per procedure in product sales

The primary differentiating feature between the two systems now on the market is the type of radiation useded. The Checkmate system uses gamma radiation, which allows treatment of long lesions of up to 45 mm and is relatively forgiving in terms of the precision with which the radiation source must be positioned in the artery in order to achieve optimal results. However, because of the penetrating nature of gamma rays, shielding is required, exposure times are relatively long (15 to 30 minutes) and the operators must leave the room during the radiation procedure. However, patient outcome has been excellent in studies using gamma radiation so far, with target vessel revascularization rates of 10% vs. about 48% in controls in the WRIST study. Beta radiation does not require extensive shielding and uses shorter (3 to 5 minute) procedure times. But positioning of the radiation source is critical with beta, due to the rapid fall-off in radiation intensity. Results of studies for the treatment of in-stent restenosis using the Beta-Cath system have also demonstrated a significant beneficial effect, with restenosis rates in the analysis segment, i.e., over the entire region treated with the balloon and stent plus a 5 mm border on each end, of 28.8% vs. 45.2% in the placebo group, and target vessel revascularization rates of 16% vs. 24.1% in the placebo group.

For both gamma and beta, there were initially problems with subacute thrombosis following the procedure, an effect believed to be due to the ablative effect of radiation on endothelial cells, which prevents rapid coverage of the stent by cells, leaving the thrombogenic metal surfaces of the stent exposed to the bloodstream. However, thrombosis has been essentially eradicated by the use of extended anticoagulation and anti-platelet therapy. As a result, most experts now view both gamma and beta brachytherapy systems as providing a safe and effective therapy for in-stent restenosis. Beta systems have been particularly well-received in Europe. Cordis is focusing on training physicians to use the Checkmate gamma brachytherapy system at hospitals throughout the U.S. and Europe.

For de novo lesions, however, the most recent clinical trial results are not as promising, and in fact show a deleterious effect for beta radiation. As discussed by Richard Kuntz, MD, of Brigham and Women's Hospital (Boston, Massachusetts) at the ACC sessions, the results of the Beta-Cath trial in de novo lesions showed that restenosis was higher in the group treated with beta radiation than in the placebo group. The results were the opposite within the stent, indicating that beta irradiation can be effective in reducing restenosis, as already demonstrated in the START trial of in-stent restenosis treatment where a 34% reduction in target vessel revascularization was shown. However, in the analysis segment, which includes regions outside the stent, restenosis was higher at 44.9% vs. 35.3% in the placebo group. The higher restenosis rates are believed to be due to geographic miss (the edge effect) with the Beta-Cath system, wherein the source is not positioned properly to deliver a dose that inhibits cell proliferation to all segments of the vessel injured by the initial balloon or stent procedure. There were numerous catheter manipulations involved in the trial that probably resulted in less-than-optimal source position, and the trial was started before the critical nature of positioning was appreciated. The Beta-Cath was shown to be of some benefit for the prevention of restenosis following PTCA procedures, however, with a 31% restenosis rate in the analysis segment for the radiation group vs. 36% in the placebo branch.

A number of investigators at the ACC sessions said that they believe the edge effect problem with beta radiation can be solved. Ron Waksman, MD, of Washington Hospital Center (Washington), related results of a recent study showing positive results in de novo lesions with beta radiation if care is taken to position the radiation source precisely. On the other hand, a group of investigators at the University Clinic (Essen, Germany), led by Christoph Naber, MD, found that the results of treatment of in-stent restenosis did not vary between a group of patients with geographic miss during their treatment vs. a group with no geographic miss, leading them to question the importance of geographic miss for beta radiation treatment. Kuntz, the principal investigator for the Beta-Cath trial, said he believes that the use of direct stenting procedures, which should allow more precise alignment of the radiation catheter with the injured regions of the vessel, combined with use of an expanded radiation train, should solve the problems encountered in the trial of de novo lesion treatment. Novoste is analyzing the results of the study and has not yet announced its follow-on plans. Waksman is planning to initiate a trial using gamma radiation for prevention of restenosis in de novo lesions in diabetic patients and recommends using gamma radiation for treatment of in-stent restenosis. Waksman predicts that 300 cath labs will be using gamma-based intravascular brachytherapy within one year.

The field of brachytherapy may be eclipsed in the long term, however, by the introduction of coated stents for prevention of restenosis. Very promising results have been obtained in a pilot study using a rapamycin-coated stent from Cordis. In that study, conducted in Brazil and the Netherlands on a total of 45 patients with in-stent restenosis, no restenosis has yet been observed in follow-up periods ranging up to 12 months. As discussed by Patrick Serruys, MD, of the Thoraxcenter (Rotterdam, the Netherlands) at the ACC sessions, the new type of coating used on the Bx Velocity stent has eliminated problems with previous technologies that could not withstand the expansion of the stent. The Sirolimus coating used by Cordis was developed by Surmodics (Eden Prairie, Minnesota) and contains the drug Rapamune, licensed exclusively by Cordis from Wyeth-Ayerst Laboratories for use in stent coatings. Importantly, Rapamune is a cytostatic, not a cytotoxic, drug, which allows endothelial cells to grow to cover the metal stent surface but limits formation of neointima within the stent to essentially zero. Cordis introduced a heparin-coated stent in November 2000 for use in the treatment of abrupt or threatened vessel closure.

A number of other companies are developing coated stents, as shown in on page 116. The results of studies with coated stents, although preliminary, represent a considerable improvement over brachytherapy, leading some physicians to question if radiation treatments for restenosis will have a long-term role in the cath lab. However, companies involved in the commercialization of both modalities point out that in-stent restenosis remains a major problem at present because of the large number of patients who have been treated with conventional stents. While there has been some experimental work on using coated stents to treat in-stent restenosis using the stent-in-stent technique, brachytherapy is of proven benefit for in-stent restenosis and is FDA-approved.

Table 2
Development-Stage Coated Stents
Company/Institution Coating/Technology Development Status
Abbott Laboratories
(Abbott Park, Illinois)
Coronary stent coated using Biocompatibles'
PC Technology containing anti-proliferative
agent
In trials at Mayo Clinic. Preclinical data indi-
cate 43% reduction in neointimal formation
and no significant inflammation.
Biocompatibles Ltd.
(Farnham, Surrey, UK)
BiodivYsio stent coated with Batimastat;
partnership with British Biotech Ltd. for
drug technology
Clinical trials planned for mid-2001, with
commercial launch targeted within 24 months
Chonnam National
University Hospital
(Kwang Ju, South Korea)
ReoPro-coated stent Animal (porcine artery) studies demonstrate
inhibition of neointimal cell proliferation and
restenosis
Cook (Bloomington,
Indiana)
Hydrocarbon polymer coating loaded with
VEGF. Acts to stimulate endothelial cell gro-
wth to cover stent, improve biocompatibility

Paclitaxel-coated Logic stent

In vitro studies of sterilized stents demon-
strate eluted VEGF can stimulate cell growth

In clinical trials in Europea and Asia; app-
roval to begin clinical trials in the
U.S. received March 12, 2001

Cordis
(Miami Lakes, Florida)
Sirolimus/Rapamycin coating. Acts as cyto-
static agent to inhibit cell proliferation and
neointima formation post-stenting

Carmeda (heparin) coating for Bx Velocity
stent

Enrollment of 220 patients in RAVEL trial in
Europe completed December 2000. SIRIUS
trial with 1,100 patients at 50 sites in U.S.
started March 2001

Introduced in November 2000 in the U.S. and
Europe

Guidant (Indianapolis,
Indiana)
PHARMA-LINK Actinomycin-D coated
stent with timed-release coating
Clinical trials planned for Q2 2001
Medtronic/AVE
(Santa Rosa, California)
Hepamed (heparin)-coated BeStent Evaluated in 74 patients vs. PTCA; restenosis
rate (per protocol) of 6.3% vs. 24.2% for PTCA
at six months
Shiga Medical Center
(Moriyama, Japan)
Igaki-Tamai PLLA self-expanding biodegrad-
able stent
Evaluated in 50 patients with complex
lesions; 14% repeat intervention at 12 months.
Planning to develop drug-eluting version
Precision Cutting
Systems (Kalken, Belgium)
ELUT drug delivery stent. Laser-cut holes in
metal framework serve as controllable reserv-
oirs for drugs loaded in polymer matrix.
In vitro studies using methylprednisolone in
polymer matrix demonstrate higher local drug
concentration in ELUT vs.controls, and signifi-
cant prolongation of drug release
Quanam/
Boston Scientific
(Natick, Massachusetts)
Polymer-coated stent employing paclitaxel
derivative as active agent
No restenosis at two-year follow-up in pilot
studies; clinical experience includes over 200
patients. Now in pivotal trials in Europe
Boston Scientific Paclitaxel-coated stent employing technolo-
gy licensed from Angiotech Pharmaceuticals
(Vancouver, British Columbia)
60 patients enrolled in Phase I trial in Ger-
many

Heart failure treatments growing

The treatment of heart failure is another major area of focus for both medical device and pharmaceutical companies. According to the American Heart Association (Dallas, Texas), there are about 4.7 million people in the U.S. with congestive heart failure (CHF), and the condition is the cause of about 47,000 deaths per year. The estimated prevalence of the disease in the U.S. has almost doubled in the past 10 years. About 550,000 new cases occur each year, and deaths due to CHF increased 135% between 1979 and 1998. Today, treatment centers on the use of a variety of drugs including diuretics, ACE inhibitors, beta blockers, vasodilators, digoxin, anticoagulants and others. Antiarrhythmic drugs also play a role, since up to one-third of CHF patients have atrial fibrillation, a condition that increases the risk of stroke by 4.5-fold. A number of new non-pharmacologic approaches are under development to treat the disease, along with new approaches to management of patients that have proven to provide significant improvement in outcome.

Acorn Cardiovascular (St. Paul, Minnesota) is an example of one of a number of companies developing mechanical devices for heart failure treatment. Acorn is developing the Cardiac Support Device, a polyester sac that is placed over the heart to provide mechanical support to relieve the distension of the heart characteristic of CHF. About 60 implants of the device have been performed so far at five centers. One potential benefit of the device is that the reduced strain on the heart muscle will allow cardiac myocytes to recover or regenerate, reversing the loss of cardiac muscle tissue that is one of the key pathophysiological aspects of the disease. There is some evidence that recovery is occurring in the patients studied to date. Once the device is approved for marketing, it will probably be priced at about the same level as a high-quality heart valve. At present, however, it remains experimental.

The next generation of treatments for heart failure may employ tissue engineering technology in order to regenerate cardiac muscle tissues. The first successful implant of myocytes for cardiac muscle regeneration was performed in France in late 2000, and procedures are now being performed at the Thoraxcenter by a group including Serruys as part of the clinical program sponsored by Bioheart (Weston, Florida). Serruys described a procedure that involves expansion of cells at a facility in Baltimore, and subsequent shipment of the cells to Rotterdam for implant in a patient. Tissue engineering offers the first approach, other than heart transplantation, that could provide a cure for CHF, as opposed to drug therapies that primarily treat the symptoms of the disease.

Another important advance with applications in the treatment of patients with CHF has been developed by Medtronic (Minneapolis, Minnesota). As discussed by Sanjeev Saksena, MD, of the Cardiac Institute-Atlantic Health System (Millburn, New Jersey) at the ACC conference, up to one-third of all CHF patients have atrial fibrillation, and arrhythmias are the primary cause of death in most heart failure patients. Medtronic has developed a dual-site atrial pacing system for the prevention of atrial fibrillation, a condition that afflicts about 2.2 million patients in the U.S. alone. Furthermore, atrial fibrillation has a prevalence of 8% to 10% in individuals in the 80-plus age group, so the problem is likely to become more widespread as the population ages. As described by Saksena, the Medtronic technique uses two pacemakers applying pacing signals to dual sites and results in a more effective stimulation of the heart than does single-lead pacing, at least in CHF patients who are also undergoing drug treatment. The dual-site pacing technology could potentially address between 350,000 and 400,000 patients in the U.S. alone if proven effective. In the AFFIRM trial using the Medtronic dual-site pacing devices, patients with both bradycardia and tachycardia are being studied. Although the devices being used in the trial are already FDA-cleared for pacing applications, use for dual-site pacing would be an off-label application until Medtronic obtains specific clearance to promote the dual-site technique. Dual-site pacing already has been shown to be more effective than single site pacing for ventricular defibrillation, and the Medtronic study has now shown that the same is true for atrial fibrillation. The technique also requires less energy.

Research also is continuing on fundamentally new methods to treat angina pain. Treatment with lasers using techniques such as transmyocardial laser revascularization has been highly controversial due to large placebo effects. In addition, experiments using angiogenesis agents have generally not produced definitive improvement. However, more recently, results from the FIRST trial using fibroblast growth factor 2 have shown an improvement in treated patients vs. the placebo group, although the primary endpoint of the trial was negative again due to major improvement in the placebo group. Other researchers studying the use of gene or growth factor therapy for angiogenesis have found a synergistic effect between P1Growth Factor and Vascular Endothelial Growth Factor (VEGF) in clinical trials. Another approach that is showing promise is the use of an electrical mapping technology called NOGA, marketed by the Biosense division of Cordis to assess the effect of various angiogenesis treatments on heart function. Jeffrey Isner, MD, of St. Elizabeth's Medical Center (Boston, Massachusetts), is using the NOGA system to assess recovery of hibernating myocardium following gene transfer. The most recent innovation is the addition of an injection lumen to the NOGA catheter, allowing areas of ischemia to be mapped, followed by targeted injection of gene therapy agents. So far, the results of gene therapy studies for inducing angiogenesis in patients with angina have not demonstrated a statistically significant benefit versus placebo, but some researchers believe that improved targeting of such therapy may improve its efficacy. Some new studies being conducted with drugs such as AdFGF-4 from Berlex Laboratories (Wayne, New Jersey) and HIV-1a NP16 from Genentech (South San Francisco, California) have looked promising according to Stephen Epstein, MD, of Washington Hospital Center. Studies of multiple injections of protein growth factors rather than genes have shown encouraging results, indicating that the timing and duration of the dose may be key factors. Gene therapy potentially can provide the ultimate form of sustained release dosing of angiogenesis factors if it can be targeted accurately and controlled properly. However, Epstein also said he believes that it is likely that no single factor will be capable of providing optimal angiogenesis and that ultimately cell-based therapies, which allow multiple factors to be expressed, will prove to be the key to success.

Imaging, information technologies for POC

The continuing improvement in therapeutic technologies for cardiovascular diseases such as coronary artery disease, congestive heart failure and cardiac arrhythmia is driving increased demand for diagnostic and monitoring techniques to select patients for treatment and guide therapy. One area of rapid growth is technologies for guidance of anti-platelet therapy. A number of products for monitoring of platelet function or monitoring of the effects of anti-platelet agents are now available, as shown in Table 3 on page 118. One device that is now used by many cardiologists for monitoring of anti-platelet drugs such as Centocor's (Malvern, Pennsylvania) ReoPro is the Accumetrics Ultegra system. The Ultegra is now in use in about 150 hospitals. A recent clinical study, the GOLD study (for Assessing Ultegra), evaluated the effect of the level of platelet inhibition as measured by the Ultegra on outcome of patients being treated with ReoPro and similar anti-platelet drugs such as Integrelin from COR Therapeutics (South San Francisco, California) and Aggrastat from Merck and Co. (Whitehouse Station, New Jersey).

Table 3
POC Systems for Platelet Function Monitoring
Supplier Product Key Features
Accumetrics (San
Diego, California)
Ultegra
System
Measures level of unblocked platelet glycoprotein IIb/IIIa receptors via
agglutination of fibrinogen-coated microparticles. For in vitro diagnostic use.
Dade Behring
(Deerfield, Illinois)
PFA-100 Bench-top platelet function analyzer; 8 minute turnaround time. Detects time
required for clot to form in aperture. Semi-quantitative indication of platelet
inhibition. 320 systems installed in the U.S.; $19,000 list price. FDA-cleared.
Helena Labs
(Beaumont, Texas)
Ichor
Plateletworks
Provides quantitative POC readings of both CBC and platelet aggregation in
five minutes. FDA-cleared. Responds to effects of multiple agents including
aspirin, plavix and platelet inhibitors.
Xylum (Scarsdale,
New York)
Clot Signature
Analyzer
Measures platelet functional activity in 4 to 8 minutes at bedside; also pro-
vides functional measurement of all coagulation mechanisms in 30 minutes.
Investigational use only in the U.S.

The data from the GOLD study indicate a significant drop in the rate of major adverse cardiac events when the level of inhibition rises from 70% to 80%. Further studies are expected to allow the optimum level of inhibition for each drug to be determined. However, the importance of measuring the inhibition level during treatment is now well established, at least over the first eight hours after an interventional procedure involving the use of platelet inhibitors. The other systems listed in Table 3 also can be used to monitor platelet function by assessing the level of platelet aggregation or the time required for a clot to form. However, the two FDA-cleared systems providing a quantitative indication of platelet inhibition are the Ultegra and the Ichor.

Visco Technologies (Exton, Pennsylvania) introduced another product at the ACC meeting that may have important applications in monitoring of hemostasis and in diagnosing hemostasis disorders. The company was founded by Kenneth Kensey, MD. Visco has developed a new system called the HEMOmeter that measures blood viscosity over a range of flow velocities at the bedside in four minutes. The system is currently available for investigational use only. According to Kensey, the ability of the HEMOmeter to measure blood viscosity as a function of velocity, and to relate the readings to heart rate and blood pressure, provides information that is of much greater clinical relevance and utility than blood viscosity readings taken only at one velocity. In addition to allowing evaluation of the effects of drugs on blood viscosity, the technology may have applications in predicting the risk of a cardiac event and in monitoring the results of preventative therapy.

Another important new test was described at the ACC exhibition by Biosite Diagnostics (San Diego, California). The company obtained FDA approval for its Triage BNP test in December 2000. The test measures levels of B-type natriuretic peptide, a cardiac hormone produced by the ventricles in response to ventricular volume expansion and pressure overload. Levels are elevated in patients with congestive heart failure, and studies have shown that the test more accurately correlates with the presentation of Class I to III CHF than do echocardiogram ejection fraction measurements. The test has a 98% to 99% negative predictive value for heart failure, according to data provided by Biosite. It is configured as a single-use disposable cartridge that can be read with the Triage Meter, also marketed by Biosite, at the bedside, at other ancillary testing sites outside the central lab, or in the main laboratory. The company is targeting the test initially at the emergency department where Biosite has established a strong presence with its drugs of abuse tests. The meter is priced at $3,500, and individual tests are priced at $25 to $26. Diagnosis of CHF, particularly in the early stages of the disease, has historically proven to be difficult since clinical assessment is subjective, and early stages are often asymptomatic and undetectable. Even in late-stage disease, patients may present with nonspecific signs and symptoms, and up to one-half of the diagnoses made in the primary health care setting may be incorrect, according to studies. However, early detection of CHF using a test such as the Triage BNP could have a significant impact, since early-stage diagnosis permits early intervention that may prevent the disease from advancing, or at least delay progression.

The BNP test will complement a new drug under development by Scios (Sunnyvale, California) for heart failure treatment. The Scios drug is a human recombinant form of BNP, identical to the human molecule. Studies have shown that elevations of endogenous BNP can promote coronary and systemic arterial vasodilation, contribute to reductions in fluid volume and perhaps decrease levels of vasoconstrictive hormones, combating a number of the adverse consequences of heart failure. The company is anticipating completion of the FDA's review of an amended clinical application for the drug, Natrecor, in July.

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