Medical Device Link.

Between 1987 and 1993, a large number of interventional devices were invented and perfected. Coronary stents—small metallic coil-like devices used to hold vessels open following angioplasty—stand out as the most influential devices of the 1990s. In the period from 1993 to 1997, stents became commonplace. They are now used in approximately 80% of all angioplasty procedures. Stents have eliminated many complications associated with percutaneous angioplasty, such as abrupt and unpredictable closure of the vessel, which leads to emergency bypass surgery.

According to the latest statistics from the American Heart Association (Dallas), from 1979 to 1998 the number of cardiac catheterizations performed in the United States for diagnosis and treatment purposes increased 332%. In 1998, an estimated 1.29 million inpatient cardiac catheterizations were performed, making it the most common medical intervention in the world. An estimated 539,000 percutaneous transluminal coronary angioplasty procedures were performed for the treatment of atherosclerosis in the United States in 1998, and from 1987 to 1998, the number of procedures increased 248% and the number of patients increased 190%. This number continues to rise as researchers, device makers, and interventional cardiologists perfect the procedures, devices, and visualization tools associated with interventional cardiology, with the ultimate hope of achieving excellent outcomes for all patients.

Since 1998, the IC community has been busy gaining experience with innovative procedures, devices, and delivery systems; advancing techniques to treat multivessel, small-vessel, bifurcated, and other more difficult cases; and gathering clinical data. It is now looking toward the as-yet-unreachable goal of conquering restenosis, or the proliferation of cell growth that occurs following any IC procedure and often leads to the need for repeat interventions. According to Jeffrey Popma, MD, director of interventional cardiology at Brigham and Women's Hospital (Boston), stent coatings and radiation therapy are among the most promising approaches currently under investigation for the treatment of restenosis.

"This is a very exciting time for us," says Popma. "The idea is to one day be able to prevent restenosis in the first place." In addition, Popma believes that embolic protection provided during IC procedures—via the use of occlusion balloons and filters that trap emboli before they travel downstream to vital organs—is a third technology that is especially exciting, as it is just evolving.

The current status and future direction of these three promising technologies in IC—coated stents, radiation therapy, and embolic protection—are discussed in the following sections.

Coated Stents

The prominent surgeon Patrick W. Serruys, MD, of Erasmus University (Rotterdam, The Netherlands) has called drug-coated stents the beginning of a new revolution in IC . However, the technology has been beset by numerous challenges, not the least of which has been the difficulty of getting potentially useful agents to cross the cell membrane into target cells. Researchers are now working with new technologies to expand the types of agents that can cross the cell membrane—either via a stent coating or local delivery—and are looking to gene therapy for additional means to localize treatment.

Figure 2. The sirolimus-coated Bx Velocity coronary stent by Cordis.

Sirolimus Coatings. The sirolimus-coated stent is one of the more-successful local drug-delivery endeavors. Sirolimus is manufactured by Wyeth-Ayerst Laboratories (Radnor, PA). It is a cytostatic immunosuppressant which is commonly used for the treatment of renal transplant rejection. It inhibits enzymes called cyclin-dependent kinases in order to cause cell-cycle arrest. Sirolimus has been shown in vitro to block smooth muscle cell proliferation, which is a major component of restenosis.

Cordis Corp. (Miami), a Johnson & Johnson (New Brunswick, NJ) company, is currently the only manufacturer of sirolimus-coated stents (see Figure 2). The company licenses the drug from Wyeth-Ayerst. As of February 2001, the company has begun a pivotal clinical study in the United States of its sirolimus-coated Bx Velocity coronary stent (see Figure 3). Known as the Sirius study, the trial is scheduled to enroll 1100 patients. According to data collected thus far in Europe, use of the device has resulted in no deaths or other adverse events such myocardial infarctions, stent thromboses, or repeat revascularization. Repeat patient assessment is planned at 18 months and at two years.

"There is a significant amount of excitement in the medical community regarding sirolimus," says Jesse Penn, president of Cordis Cardiology U.S. "The Bx platform has been well received and continues to gain physician acceptance and market share due to its wide range of parameters. Results of clinical trials have also been positive."

Cordis has initiated two additional studies for its sirolimus-coated Bx Velocity stent. The first, being conducted jointly in São Paulo by Eduardo Sousa, MD, and in The Netherlands by Dr. Serruys, has reached the 12-month angiographic follow-up point for the first 45 patients. At press time, the company expected to present the results of this study at the annual meeting of the American College of Cardiology (Bethesda, MD) in March. Cordis has also completed enrollment for 220 patients in a multicenter European trial, with results scheduled to be presented in May.

Batimastat Coatings. Other coatings are also being tested as possible restenosis inhibitors. Biocompatibles International plc (London) and British Biotech plc (also London) are collaborating to develop and commercialize batimastat-coated stents. Batimastat is one of British Biotech's broad-spectrum matrix metalloproteinase inhibitors (MMPIs), agents designed to reduce restenosis. During the body's repair of injury at the stented site, there is remodeling of the extracellular matrix that involves matrix metalloproteinases. According to the companies, MMPIs such as batimastat inhibit matrix degradation and subsequent cell migration. The drug may also inhibit the deposit of collagen and the remodeling that may contribute to restenosis. In vitro work showed that batimastat can be applied to and delivered from Biocompatibles International's BiodivYsio stent. Initial preclinical studies indicated that the batimastat BiodivYsio stent is well tolerated and reduces restenosis more than the drug-free version. The batimastat-coated version of the BiodivYsio stent is expected to enter clinical trials in mid-2001, with market launch to come within two years.

Figure 3. The photo on the left shows a coronary vessel prior to implantation with the Bx Velocity stent by Cordis, at the spot where the vessel branches in two. The photo taken following implantation (right) shows this vessel expanded.

Drug-Eluting Stents. Guidant Corp. (Indianapolis) has reported promising results from a series of preclinical studies with its Pharma-Link stent system. The system consists of the Multi-Link Tetra coronary stent and a proprietary delivery technology. The stent is coated with a timed-release polymer containing Actinomycin D, an antineoplastic drug developed by Merck & Co. (Whitehouse Station, NJ). According to a company release, the Pharma-Link system was designed for exceptional deliverability and to offer the highest levels of scaffolding, flexibility, conformability, and visibility.

Preliminary angiographic and intravascular ultrasound results announced in February 2001 demonstrated a marked reduction in the growth of cells at the site of the drug-eluting stent in comparison with stent placement without a drug. Histologic data also indicated a significant reduction in hyperplasia, or the regrowth of cells at the treated site, when compared with the control stent. Guidant's drug-eluting stent system is currently in the research and development phase. The company expects to begin human clinical studies in the second quarter of 2001.

"We don't take for granted the stent and the delivery system, which are important components of the whole local drug-delivery system," says Brian O'Connell, vice president and general manager of Guidant's stent business unit. "Together, the whole system gives us a basis for product comparison. We have the number one stent in the marketplace today, the Multi-Link Tetra coronary stent, which leaves us in a favorable position when the drug has eluted off the stent. We feel that our coating will give us a good foundation for future generations of the Pharma-Link stent system. Users can expect to see multiple generations of this device."

He adds, "There is a lot of justified excitement about coated stents, but they haven't been proven yet. Restenosis can be reduced, but to do so, more trials need to be performed on patients with all different types of lesions."

Heparin Coatings. During last year's American Heart Association scientific sessions conference, Cordis Cardiology announced the introduction of a heparin-coated stent called the Bx Velocity coronary stent with Hepacoat. The stent is designed to improve coronary luminal diameter in the treatment of abrupt or threatened vessel closure. It is approved for use with patients having lesions less than or equal to 30 mm in length with reference diameters ranging from 2.25 to 4 mm, who have previously undergone failed interventional therapy.

The Bx Velocity stent with Hepacoat was approved for use in the United States and Europe in 2000. Known as Carmeda bioactive surface (CBAS), the proprietary heparin coating on the device retains its properties for several months when implanted into blood vessels. CBAS was developed by Carmeda (Stockholm), a developer of heparin biomaterials.

"The heparin coating on our Bx Velocity stent with Hepacoat consists of end-point attached heparin that freely interacts with the bloodstream. Due to covalent bonding, the heparin is firmly attached to the stent," explains Penn. "Utilization of the Bx Velocity with Hepacoat is strong. It is the first drug-coated stent approved for marketing in the United States."

Meanwhile, to protect patients from developing blood clots, STS Biopolymers (Henrietta, NY) is working on the development of longer-lasting heparin coatings for the surfaces of stents and other medical devices. A grant of $100,000 from the National Institutes of Health (Bethesda, MD) will enable the company to conduct research on how to develop stent coatings that will remain active until the stent becomes absorbed into the blood vessel wall and coated with naturally protective endothelial cells, a process that can take several months.

Questions still remain as to which patients will benefit from drug-eluting stents. In diseased-vessel posttreatment, the effectiveness of drug delivery is likely to be highly variable, depending on the type of vessel being treated and the extent of vessel-wall damage resulting from the stent procedure. Nevertheless, experts believe that such devices can potentially allow a greater number of patients to be treated with interventional techniques.

Intravascular Radiation

Figure 4. The Checkmate system by Cordis consists of a catheter (top) and a radiation delivery source (bottom).

Although there are numerous technologies under investigation for the treatment and prevention of coronary artery restenosis following percutaneous transluminal coronary angioplasty and stenting, intravascular radiation, or brachytherapy, is the closest to clinical reality. This technique has demonstrated effectiveness and remarkably low restenosis rates in several large trials, and has generated a great deal of interest among clinicians, who are cautious but optimistic about the technology. Analysts estimate that the total world market for such radiotherapy will eventually exceed $1 billion annually.

"This is a new field for practical use, and it is generating a lot of excitement in the catheterization lab," says Ron Waksman, MD, director of experimental angioplasty at Washington Hospital Center (Washington, DC) and associate professor of medicine at Georgetown University (also Washington, DC). "The expectation is that 200 labs will be performing brachytherapy by the end of 2001, while only 50 are doing so now. Sales for these products are expected to reach $60 million in the United States by the end of 2001."

"For in-stent restenosis, radiation is the best and only proven technology," Waksman says. "The lowest restenosis rate we've seen with brachytherapy is 3.9%, but this figure varies widely. We're still looking for consistent single-digit rates."

"Given the number of people who have had stents placed since their introduction in the mid-1990s and who may require retreatment, there is an ongoing need for more-effective treatment of restenosis," says Penn.

FDA Approvals

In November 2000, FDA approved the Checkmate system from Cordis and the Beta-Cath system from Novoste Corp. (Norcross, GA) for the treatment of patients with in-stent restenosis, launching the U.S. market for these devices with a head-to-head battle.

Gamma Radiation. The Checkmate system has an unsurpassed radiation safety record, says Paul Teirstein, MD, director of interventional cardiology at Scripps Clinic (La Jolla, CA) and an investigator in the system's clinical trials (see Figure 4). According to the company, among the more than 1000 patients treated in the United States with the Checkmate system, there have been no reportable events. The system uses the gamma-radiating source iridium 192 (Ir-192). Small Ir-192 seeds are encased in a source ribbon and delivered through a catheter to the blockage site (see Figure 1). The source ribbon is left in place for 15–20 minutes and is then withdrawn.

"In the aggregate, the Checkmate system can be used to treat a significantly broader range of patients than a system that uses beta radiation, as our product offers more in terms of treatment lengths," says Penn. "This is particularly true for those patients with longer, more-diffuse lesions and small vessels, such as diabetics." He continues, "The system uses Ir-192, which has more than a 40-year proven history of effectiveness in radiation oncology. The Checkmate is a closed-end monorail catheter-based system. While the dwell time is longer than that of a system using beta radiation, the overall case time is comparable. We will continue to explore enhancements to this technology."

Cordis has also signed an exclusive agreement with Photoelectron Corp. (Lexington, MA), a developer of miniature x-ray technology, to develop and manufacture an intravascular radiation system based on Photoelectron's technology. The system will include an integrated disposable x-ray tube and catheter as well as a delivery and control device to administer intravascular radiation therapy.

Figure 5. The Beta-Cath system by Novoste Corp. (Norcross, GA) significantly reduces the risk of restenosis.

Beta Radiation. According to Novoste Corp., findings from the company's stents and radiation therapy (START) trial, a randomized placebo-controlled study of 476 patients, indicated that use of its Beta-Cath system significantly reduces the risk of restenosis and additional procedures intended to reopen stented coronary arteries (see Figure 5). The incidence of restenosis was 36–66% lower in patients treated with beta radiation than in those from the placebo group. In addition, patients treated with beta radiation had a 34% lower frequency of repeat revascularization procedures compared with patients who did not receive the radiation treatment. Furthermore, patients treated with the Beta-Cath system had a 31% lower rate of major adverse cardiac events than those in the placebo group.

To use the Beta-Cath system, cardiologists reopen the vessel with a catheter-based intervention method such as balloon angioplasty. The Beta-Cath system is positioned inside the artery at the site of the previous intervention. At this point, strontium 90 (beta radiation) seeds are hydraulically delivered to the treatment site at the end of the closed-end catheter, where they remain for three to five minutes before being completely withdrawn.

Other Radiation Systems

Figure 6. The Galileo system by Guidant (Indianapolis) includes a centering catheter (top), a beta-emitting phosphorous 32 source wire, and an automated source delivery unit (bottom).

In December 2000, Guidant filed with FDA for approval of its Galileo intravascular radiotherapy system, which is designed to prevent the recurrence of blockages in stented coronary arteries. The Galileo system, which was granted a CE mark in May 2000, is made up of three components: a centering catheter, a source wire, and a radiation-source delivery unit (see Figure 6). Following angioplasty or stenting, the physician advances the centering catheter through the artery until it reaches the treatment area. The source delivery unit automatically advances the source wire, which contains the radioisotope phosphorus 32, through the centering catheter to the diseased coronary artery. An automatically calculated dose of beta radiation is delivered to the area for a predetermined period, usually three to five minutes. The source wire is then automatically retracted into the source delivery unit to complete the procedure.

"Radiation has passed all the clinical hurdles," says Brian O'Connell of Guidant. "It is a viable therapy, a viable technology, and a potentially large marketplace. The opportunities are there, depending on reimbursement and longer-term results."

In January 2001, Radiance Medical Systems (Irvine, CA) received FDA approval to begin a Phase I safety study called beta radiation to combat in-stent restenosis for saphenous vein bypass grafts (BRITE-SVG). The study will be conducted to evaluate the company's RDX coronary radiation delivery system for the treatment of lesions in veins that were used in coronary artery bypass graft surgery. FDA also approved the commencement of BRITE II, a broader trial of the RDX system to treat in-stent restenosis after angioplasty. Phase I of that trial, involving 27 patients, yielded a 0% rate of restenosis, as measured six months after treatment with the beta radiation catheter.

The BRITE-SVG trial will involve 50 patients with previously untreated lesions and in-stent restenosis in leg veins that were surgically grafted to bypass blocked coronary arteries. Gregg Stone, MD, of Lenox Hill Hospital (New York City) will be the principal investigator for the BRITE-SVG study.

Phosphorous 32, the beta radiation source used in the RDX system, is incorporated into the balloon material of the delivery catheter so that it resembles a standard percutaneous transluminal coronary angioplasty catheter. When the balloon is inflated, it conforms to the shape of the vessel wall, centering the source within the vessel's interior. Radiance Medical Systems believes that this combination of shape and centering will optimize the radiation and maintain dose uniformity in the larger vessels, as compared with other device designs.

Radiation Cautions

Although the early message is that radiation seems to be working against restenosis, FDA officials and some physicians caution that more testing is needed to ensure that the benefits of intravascular radiation outweigh the risks, which may include thrombosis that could lead to an increased risk of heart attack. Additionally, the result is dose dependent. According to surgeon Martin B. Leon, MD, clinical professor of medicine at Georgetown University Medical Center, and director and CEO of the Cardiovascular Research Foundation (New York City), radiation should be reserved for the most resistant patients, such as those who have failed more-conventional therapies. Leon adds that he does not "advocate the use of radiation as a primary therapy or as an alternative to stents . . . because we don't know the long-term hazards associated with radiation, particularly in a nonstented artery."

In a January 2001 article published in the New England Journal of Medicine, FDA officials point out that although the agency recently approved two devices for the delivery of radiation to coronary arteries, more research is needed on the effects of radiation.¹

Embolic Protection Devices

Embolic protection during vascular procedures is a new technology in the field of interventional cardiology. Initially, an important focus in the development of embolic protection devices was that they could be used during a stent implant procedure in conjunction with carotid stenting to protect against the release of emboli that could cause a stroke. However, industry experts have realized that the potential range of applications for embolic protection devices is much broader and extends to most interventional procedures. Interventional treatment of saphenous vein grafts (SVGs), an increasingly common procedure due to its high survival rate, results in a 10–15% incidence of embolic events.

Enthusiasm for distal protection was summed up by Leon of the Cardiovascular Research Foundation after a presentation at the TransCatheter Therapeutics Conference in 1999: "I would venture to guess that within a very short time, these techniques will be fully assimilated, so that it would be unconscionable to treat patients (with SVGs) without proper distal protection."

Embolic protection devices consist of occlusion balloons or filters. Occlusion balloons serve to obstruct the target vessel distal from the site of percutaneous revascularization, thereby blocking the outflow of debris. The debris is then aspirated out of the vessel by an export catheter before the balloon is deflated. Filtering devices are attached to guidewires, and serve as basketlike devices to trap embolic material downstream from the interventional procedure.

A number of companies have developed or are now developing endovascular distal protection devices. These include Boston Scientific (Natick, MA); Cordis; Guidant; IntraTherapeutics (St. Paul, MN); MedNova Ltd. (Galway, Ireland); Microvena (White Bear Lake, MN); PercuSurge (Sunnyvale, CA), which is in the process of being acquired by Medtronic (Minneapolis); and Scion Cardiovascular (Miami).

Figure 7. The GuardWire Plus distal occlusion balloon and aspiration catheter system by PercuSurge (Sunnyvale, CA).

Balloon Occlusion. The PercuSurge/Medtronic GuardWire Plus distal occlusion balloon and aspiration catheter system uses a balloon-tipped guidewire that is inflated briefly to occlude blood flow and capture any material dislodged from the wall of the vessel during placement of a stent upstream (see Figure 7). Captured material is then withdrawn by using the export aspiration catheter before the balloon is deflated and blood flow restored. The device has been used in more than 5000 procedures since its release in Europe in 1999. According to PercuSurge representatives, the device is likely to be approved by FDA between March and May 2001 for use in vein graft procedures. The company believes that this market alone (constituting an estimated 225,000 interventional procedures per year worldwide) could generate annual revenues in the range of $250 million to $300 million.

The product's first targeted indication is for the treatment of degenerated SVGs that show signs of disease following heart bypass surgery. According to PercuSurge, the GuardWire Plus system has shown a 50% reduction in adverse events in SVGs, as demonstrated in the results of the company's recently concluded saphenous vein graft angioplasty free of emboli randomized (SAFER) trial. PercuSurge and Medtronic soon plan to launch a 550-patient trial, led by Gregg Stone, MD, of the Cardiovascular Research Foundation, on the use of the GuardWire Plus device during acute myocardial infarction where microemboli may be of critical importance.

Abbott Laboratories (Abbott Park, IL) has entered into an exclusive, worldwide licensing agreement with Rubicon Medical (Salt Lake City), involving Rubicon's Guardian system, an occlusion balloon for embolization protection. The Guardian system uses a balloon that is inflated during a stent procedure in the vessels that feed blood to the heart, brain, and kidneys. An aspiration catheter is then used to remove any embolic material that may have been dislodged during the procedure. Rubicon and Perclose (Redwood City, CA), an Abbott subsidiary, are currently codeveloping the Guardian system.

Figure 8. The TriActiv system by Kensey Nash Corp. (Exton, PA) consists of a distal balloon (left), a catheter (center), and a drive console (right).

Another company exploring the balloon occlusion approach is Kensey Nash (Exton, PA). The company's TriActiv device is said to provide three actions in one—a distal balloon that can be inflated in two shorter occlusion phases, a catheter with a blunt whirring head to emulsify particles, and an automatic suction channel to vacuum away the debris (see Figure 8). Stents are meanwhile deployed over the central guidewire.

Figure 9. The Trap vascular filtration system by Microvena (White Bear Lake, MN) includes a nitinol braided basket.

Basket Design. In October 2000, Microvena was granted a CE mark for its Trap vascular filtration system, a nitinol braided basket that captures embolic material released during interventional procedures involving SVGs (see Figure 9). The company also received FDA approval to begin clinical trials of the device in the United States under investigational device exemption (IDE) status.

Filters. Guidant's embolic protection device is called the Accunet embolic protection system, and it is currently being tested in human feasibility studies for use in carotid stenting procedures. The company is also developing a coronary application for the device, although this is not yet in human clinical trials. The Accunet system consists of a guidewire with a filter that is developed to trap embolic material that may be generated during the stenting procedure. The filter is designed to allow normal blood flow during the procedure, while simultaneously trapping embolic particles before they can travel to the brain and potentially occlude blood vessels, causing the patient to have a stroke.

MedNova Ltd. also manufactures embolic protection filters. In February 2001, the company entered into a distribution agreement with Abbott Laboratories for its embolic filter and carotid stent products. MedNova's first-generation embolic filters, NeuroShield and CardioShield, are approved for use in Europe. The company is now beginning an SVG trial called Captive, with David Holmes, MD, of the Mayo Clinic (Rochester, MN) as the principal investigator.

Another company involved in the embolic filter arena is Boston Scientific. In February 2001, Boston Scientific agreed to acquire Embolic Protection Inc. (Campbell, CA), manufacturer of the Filterwire distal embolic protection device. The Filterwire device has already been approved for marketing in Europe, and in February 2001 received IDE status from FDA for a randomized trial in patients receiving SVGs that require stents.

Another hot contender in this area is Cordis Corp. The company has already received a CE mark for coronary use of its 0.014 AngioGuard Capture guidewire, which is tipped with an expandable, umbrellalike filter basket that is placed distal to the target lesion to capture and retrieve emboli throughout interventional procedures.

Conclusion

Interventional cardiologists are working to expand the range of patients who can be treated with interventional therapy and to perfect methods to make IC treatment as durable and effective for the long term as bypass surgery. A potentially large pool of candidates are those suffering from acute myocardial infarction, some of whom may benefit from immediate stent implantation. A number of studies have suggested that stent deployment during early reperfusion of an infarct-affected artery may confer added benefits over the use of a balloon alone. In addition, the use of embolic protection devices may allow more at-risk patients—those with unstable plaque or those who have suffered previous heart attacks—to receive stent implants or other interventional therapies.

Some surgeons view stents as a foundation for altering local vascular biology. Adjunctive therapy with stents and pharmacotherapy, including localized gene therapy, will therefore become very important in the future. In addition, new drugs are being tried and integrated all the time. As Martin Leon of Georgetown University concludes, "The future of interventional cardiology will not be based solely on the application of a bare metal prosthesis onto a vascular surface."

Tracy A. Schaaf is a freelance writer based in Southern California.

REFERENCE

1. W Sapirstein and B Zukerman, "FDA Approval of Coronary-Artery Brachytherapy," New England Journal of Medicine 344, no. 4 (2001): 297–299.