CDU Washington Editor

WASHINGTON While the approval of drug-eluting stents is practically a certainty, interventional radiologists and cardiologists alike are wasting no time in looking to the future and what it may hold in terms of breakthrough treatments. That future could be one without the drug-coated stent. Participants at last month's Cardiovascular Revascularization Therapy (CRT) conference, sponsored by the Cardiovascular Research Institute at the Washington Hospital Center, learned that the future of vascular therapy involves more than the drug-coated or drug-eluting stent, which in the pre-clearance stage has reached panacea-like hype. Hailed as the biggest breakthrough in treating vascular ailments, the drug/stent device could lose significant luster even before it gains FDA approval, based on presentations by researchers speaking at a session titled "Pharma, Devices and a Glimpse to the Future."

The overriding theme of the session was stated succinctly by David Holmes, Jr., MD, an interventional cardiologist at the Mayo Clinic (Rochester, Minnesota), as he warned participants that lessons could be learned from the George Orwell novel, Animal Farm. "Some drug-eluting stents, as in animals, are more equal than others," Holmes said. The premise that this type of product can reduce restenosis rates consistently hasn't yet been proven, he argued. "You have to read the fine print on these trials, and most physicians want to go to the last line, or conclusion, without reading the smaller print at the beginning. So if you immediately rush to the last line, you may miss something," he added.

Holmes said that interventional radiologists need to take a more pragmatic view of drug-eluting stents. "We are incredibly enthusiastic as interventional radiologists when it comes to these stents, and we're really not going to ultimately help our patients until we learn that these [stent trials] are exploratory studies," he cautioned.

The effectiveness of drug-eluting stents does not prevent patients from experiencing inflammation and cell proliferation, said Andrew Farb, MD, a pathologist at the Armed Forces Institute of Pathology (Washington). He cited morphologic insights from patients with bare stents that will require drug-eluting stents to reach what he termed a "morphologic balance" between plaque and inflammation within patients. Farb and other researchers at the Armed Forces Institute of Pathology have examined more than 400 stent recipients post-mortem. "There's a delicate balance that the stent will have to achieve once implanted, and it's clear that the results from the DELIVER trial [a clinical study involving the paclitaxel-coated Achieve stent from Guidant, Indianapolis, Indiana] won't meet expectations, which means we still haven't found that balance," he said.

Another alternative to the drug/stent combination is the development of a "living" stent, which could be a "very viable option," said Andrew Carter, DO, a cardiologist at Providence Heart Institute (Portland, Oregon). "By creating a bio-mimic effect, whereby we create an environment of passivation at the occluded site, we can reduce restenosis and enhance biocompatibility," he said.

Carter and researchers at his facility are attempting to produce a stent that combines mechanical abilities with biological activity. "The idea is to create a living stent that couples mechanical properties with biologic activity, so that we provide a scaffolding or barrier, the mechanical component, with the biological tissue that can replace and regenerate, and in turn inhibit neointimal formation," he said.

The concept behind the institute's research is the use of elastin. "Elastin has a biologic function of guiding cells. Some are guided to be contractile, and others are sent to migrate elsewhere," Carter explained. The institute is developing such a device as a conduit that can become a "living artery," which Carter claimed could be an ideal therapy of the future because it is not dependent on the possible toxicity of pharmacology.

Vascular inroads by ice, light, bubbles

Light, ice, and bubbles three properties more akin to the mystical powers of the blockbuster film The Lord of the Rings are making inroads into the man-made polymers and steel of vascular technology. In fact, researchers involved in cryotherapy, photodynamic therapy (PDT) and perfluorobunate gas microbubble carriers (PCMG) are eager to espouse the benefits of these quicker and in some cases cheaper treatments. The results of investigational in vivo and in vitro studies of the therapies were presented at the CRT conference.

Patients who agree to cryotherapy are ahead of the restenosis game, according to James Zidar, MD, associate professor of medicine at the Duke University Medical Center (Durham, North Carolina). "The procedure involves 20 seconds of inflation of a balloon device that converts a gas to extremely cold temperatures, but the entire procedure is over in less than a minute," he said. Zidar was involved in the clinical trials for Cryovascular Systems' (Los Gatos, California) PolarCath system which received FDA market clearance in September 2002. "Patients who enrolled in the trial later in the game benefited from device improvements that helped eventual outcome rates," he added.

One of those improvements made of stepped-up inflation period when the nitrous oxide, or cooling agent, was inserted into the balloon. As a result, patients didn't experience a noticeable sensation during the therapy, Zidar said. Another improvement was a change in the balloon material to a more pliable material that did not fold as easily, he added. "The device involves a simple nitrous oxide cartridge, which the company actually is buying from Starbucks [Seattle, Washington], and Starbucks is especially happy with that additional order every week," he said.

Two photodynamic (PTD) therapeutic systems, with similar results but different modes of action, also were presented at the conference. The PhotoPoint system by Miravant Medical Technologies (Santa Barbara, California) involves a pharmacologic dose followed by lumen therapy. "The reason we are excited about this therapy is that we've worked out the light/drug dosimetry for the treatment," said investigator Ron Waksman, MD, course director for CRT and director of experimental angioplasty and vascular brachytherapy at the Washington Hospital Center. The treatment also provides a mechanism of action incorporating apoptosis whereby cells are effectively killed through the drug/light combination, resulting in much-reduced restenosis. "The future of this technology is that it will be used for thermography and optical computed topography, with the possibility of further expanded uses," Waksman said.

The second PDT therapy, involving motexafin lutetium, uses a diode laser and optical fiber and was presented by Dean Kereiakes, MD, medical director of the Linder Center (Cincinnati) and professor of clinical medicine at Ohio State University (Columbus, Ohio). The clinical trial endpoints include two stages using the therapy: a dosimetry evaluation and a light evaluation, he said. "The future of this type of therapy is that it can be activated through chemoactivation, so there's no need for the light aspect," he added. Both the cryotherapeutic and photodynamic methods incorporate the apoptosis method of cell death, where the invading cell tissue is robbed of necessary elements, thereby serving to kill the offending cells.

The PCMG therapy was presented as a cost-effective alternative to persistent restenosis, even though preliminary human studies aren't scheduled to begin until this summer. "There is a dark side to drug-eluting stents, and the persistent restenosis as well as the cost-effectiveness of multiple stents will make this therapy more attractive," said Nicholas Kipshidze, MD, a cardiologist at Lenox Hill Heart and Vascular Institute (New York).

PCMG is a therapy whereby medications can be administered intravascularly, similar to the drug-eluting stent, he said. He is involved in clinical trials using the PCMG method to deliver rapamycin to affected vascular areas. The therapy is scheduled to receive a National Institutes of Health (Bethesda, Maryland) grant later this summer for a human clinical trial, he said. "This is the type of treatment ideal for persistent restenosis and patients who are determined to be unstentable," Kipshidze added.

Study: Stent benefits worth costs

Stents are not cost-effective in the long run, but the benefits to patients are worth the costs that's the general conclusion from researchers who conducted the first economic study on stents. The study used standard analytic files from more than 12,000 Medicare patients between 1998 and 2000, according to David Cohen, MD, director of interventional cardiovascular research at Beth Israel Deaconness Hospital (Boston, Massachusetts). The take-home message from the study, Cohen said, is that restenosis has an overall direct cost between $8,000 and $28,000 and adds between $1,500 to $8,000 to the individual patient's costs. Costs for clinical trials are higher, researchers found. A total of five stent clinical trials showed a range in overall costs per patient from a low of $8,200 to a high of $23,300. Costs for patients ranged from $1,800 to $8,150.

Patient histories were tracked for a 12-month period to include mortality and repeat revascularization. "What we found was that each episode of revascularization increased overall costs by $19,000 and costs the patient an added $1,850 for each event," Cohen said. The study has some limitations, he noted. The patients were from a highly selected group with single-lesion PCIs combined with angiographic follow-up. Additionally, the data were limited to patients with bare stents. "In order to conduct a study on multiple stents in single patients, we need better data that we don't have right now," he said, adding, "You have to go after the low-hanging fruit first before reaching higher."

Cohen and his team developed a prospective analytical formula to determine a spending threshold for repeat revascularizations for drug-eluting stents. Based on inclusion of factors such as diabetes and myocardial infarction, the researchers determined that drug-eluting stents likely will include a spending threshold of $10,000. The study then went further to determine how much a patient is willing to pay to prevent restenosis following an initial revascularization procedure. "We estimate that patients would be willing to pay $2,800 more for the use of a drug-eluting stent vs. a bare metal stent," Cohen said.

Promising news from the Centers for Medicare & Medicaid Services (CMS; Washington) followed Cohen's presentation. The agency confirmed that two diagnosis-related groups (DRGs) were created to accommodate drug-eluting stents. "The DRGs are there and ready for use April 1, but that all hinges on FDA approval of the device," said Joseph Chin, MD, a researcher in the coverage and analysis group at CMS. The codes DRG 526 (placed with myocardial infarction) and 527 (placed without myocardial infarction) will have higher reimbursement amounts to account for the new technology, Chin noted, but declined to specify an amount. A new ICD-9 code (36.07) should be used with angioplasty to include with the DRG for the proper reimbursement, he said. CMS also established an outpatient ambulatory patient classification (APC) code (0656) for drug-eluting stents.

If no product approval is announced by the FDA before April 1, the higher reimbursement would not take effect until the next quarterly update from CMS, which is in June, Chin added.

Although reimbursements will be higher, hospitals will still suffer, said Waksman. "We [Washington Hospital Center] are struggling with the current reimbursement, and when the drug-eluting stents are approved, we may have to take the step of limiting them to one per patient. Physicians would have to use bare stents for other occlusions," he said.

Chin confirmed that CMS would reimburse payments based on 1.5 stents per patient based on an average wholesale price from manufacturers. When asked about patients needing more than the allotted amount of stents, he said, "the payment is based on an average, and I have no good answer."

Device industry learning from stents

A joking analogy of the medical device industry that in the U.S. is not quite grown up and is more of a teenager became an overriding theme of a marathon afternoon session at the CRT gathering ending in little consensus regarding what lies ahead. The session, billed as a town hall meeting with the FDA, became more of a debate among cardiologists, interventional radiologists and industry representatives over lessons learned in clinical trials with bare stents and how trials should be designed in the post-Cypher stent era.

Medical devices, particularly drug-eluting stents, were praised by some medical representatives on a panel, but panned by others throughout the afternoon-long session. The analogy to the maturity of the industry stemmed from discussions over the design and enrollment of patients in clinical trials for devices compared to those for drugs.

"Maybe the device industry is growing up. It's now two-thirds as large as the pharmaceutical industry," said Robert Califf, MD, associate vice chancellor for clinical research at Duke University Medical Center, serving as moderator of the session. The statement was quickly defended by Azin Parhizgar, vice president for emerging ventures and regulatory science for Medtronic AVE (Santa Rosa, California), the sole industry representative on the panel. "The medical device industry is going through a paradigm shift toward looking at the cost-effectiveness of a technology, and the industry is not used to large 1,200- to 1,500-patient studies," she said. "You have to consider the development costs when looking at large-scale studies, especially for multi-layer technology such as a drug-eluting stent. The pharmaceutical industry has not been as cooperative as we'd like them to be when it comes to the drug-eluting stent." Parhizgar estimated the device industry to be "one-15th" the size of the pharmaceutical industry in terms of revenues.

One of the most vocal critics of the drug-eluting stent, Mitchell Krucoff, MD, director of interventional devices clinical trials and of the ischemia monitoring laboratory at Duke University Medical Center, said that there was no debate regarding drug-eluting stents. "I equate drug-eluting stents as 'breakthrough technology' vs. 'disruptive technology,'" he said. "Stents, including the drug-eluting variety, do two things: they affect local structural and biological manipulation. There's no debate. Do the work. Do the trials. They give us the answers." Krucoff suggested that drug-eluting stent manufacturers partner with pharmaceutical companies to "partner the burden" of financing large-scale clinical trials. "That should involve the insurers, academia and NIH [National Institutes of Health]," he added.

Panelist Spencer King III, MD, holder of the Fuqua chair of interventional cardiology in the Fuqua Heart Center at Piedmont Hospital (Atlanta, Georgia), voiced a more practical concern for cardiologists in the shadow of approved drug-eluting stents: Liability. "The medical malpractice premiums need to be fixed, and I'm hoping that will be addressed tonight [referring to President George Bush's State of the Union address, which was scheduled to be delivered that evening]. My biggest concern is with the liability of the drug-eluting stent. I foresee an environment where physicians tout themselves as 'No. 1 in drug-stent implants.' We can't afford to put them in everybody, so we need to put the energy only where it can have the greatest impact," King said.