The State of Stents
by Sherree Geyer
April 2008
Drug-eluting stents have been under fire recently, but the medical community has yet to decide if the risks outweigh the rewards.
Photography by Zephyr/Photo Researchers, Inc.
In the four short years since the introduction of the first drug-eluting stent (DES)—the Cordis CYPHER in April 2003—the global market for stent sales reached more than US$5 billion. Based in part upon data showing reduced rates of re-stenosis, interventional cardiologists worldwide quickly adopted the CYPHER and its first competitor, the TAXUS system from Boston Scientific Corp. But amidst a whirlwind of conflicting clinical reports, negative press coverage, industry consolidation and regulatory ambiguity, both the market value and the number of percutaneous coronary interventions (PCI) that use DES has fallen. And with the next generation of stents rapidly approaching, clinical research that asks and answers the right questions will become paramount to their continued success in the marketplace.
Under Fire
In an open letter issued in January 2008, physicians at Boston Scientific called 2007 “one of the most difficult years in the history of percutaneous coronary intervention.” The letter—co-written by Drs. Donald Baim, the company’s executive vice president and chief medical and scientific officer, and Keith Dawkins, senior vice president and associate chief medical officer—blamed a “precipitous drop in PCI procedures” on “a handful of negative studies” that raised questions about the fundamental safety, effectiveness and appropriate use of DES, considered “one of the best studied medical procedures in history.”
Peer-reviewed articles corroborate this assertion. A January 2007 study published in the Canadian Medical Association Journal concluded that “comparative clinical trials have shown no difference in patient outcomes” between bare-metal stents and DES (CMAJ. 2007;176:199-205). Additionally, a March 2007 study in The New England Journal of Medicine, stated that “ST (stent thrombosis) after one year was more common with both sirolimus-eluting stents and paclitaxel-eluting stents than with BMS (bare-metal stents)” (NEJM. 2007;356:998-1008).
Some industry experts blame much of the adverse clinical results on conflicting regulatory standards and scientific data. In a January 2008 editorial in the Journal of the American Medical Association (JAMA), Drs. Debabrata Mukherjee and David J. Moliterno, researchers at the University of Kentucky in Lexington, Ky., USA, note “the current literature for DES can be challenging to interpret because of differing criteria for study enrollment, definitions for acute ST and other clinical endpoints.”
Despite the ambiguity regarding trial interpretation, however, regulatory authorities insist that the regulatory approval standards are the same regardless of the type of DES. Ashley Boam, acting deputy office director for science and regulatory policy in the Office of Device Evaluation at the U.S. Food and Drug Administration (FDA), in Silver Spring, Md., USA, says the agency’s recommendations for the design of clinical trials to support marketing approval are generally consistent across different DES.
Bringing DES to Market
To pass regulatory muster and bring DES to market, manufacturers must demonstrate “a reasonable assurance of safety and effectiveness,” Boam says. “This is typically accomplished through the submission of pre-clinical testing, such as bench testing, animal studies and clinical trials.” Although the same FDA regulations apply to all stents, she says, the amount of information needed to support approval of DES is generally greater due to the inclusion of coating and drug components.
“For DES, the FDA requests information specific to the drug, including chemical formulation, how it’s manufactured, levels of drug safety in several different animal models, how much drug is on the stent and how the drug is released from the implanted stent over time,” Boam says. The FDA also asks that the clinical trial be of sufficient duration to evaluate long-term effects of the drug and polymer stent components, she adds.
Scientific conferences, evaluation of peer-reviewed scientific literature and ongoing research conducted in the FDA’s Office of Science and Engineering Laboratories (OSEL) keeps the agency current on stent technology and applications, Boam says. The OSEL falls within the purview of the Center for Devices and Radiological Health, which reviews and regulates DES.
To be considered for FDA approval, DES makers must first develop a protocol specifying the types of patients to be included in clinical trials, Boam says. “Manufacturers request approval for a DES to be used in a specific patient population, such as those with certain coronary artery anatomy, vessels in diameter of 2.5 to 3.5 mm and lengths of 28 mm, and with certain types of heart disease, such as those with ischemic heart disease due to coronary blockage,” she says. The FDA then evaluates each protocol to ensure that the proposed intervention can potentially improve the outcomes of the designated patient populations. In other words, Boam says, “those for whom there is a reasonable expectation that the benefits will outweigh the risks of the device and procedure.”
The FDA regards coronary artery disease as “a heterogeneous disorder” with widely varying risks and lesions, Boam says. As such, device makers must demonstrate DES safety and efficacy through real-world clinical practice.
To illustrate a point about the depth and diversity of coronary clinical patients, Boam cites the SYNTAX trial conducted by Boston Scientific comparing paclitaxel-eluting stent results to those of cardiac surgery in patients. The trial enrolled more than 3,000 patients—including 1,800 with three-vessel and Left Main disease and 1,250 in nested registries tracking coronary artery bypass graft surgery and PCI outcomes—at 85 sites in Europe and the United States. Enrollment in the trial completed in 2007, and results are expected later this year.
Future of DES Technology
Although last year’s studies questioned the value of DES, current medical literature validates the reasons they remain the most common PCI procedure. A January 2008 study that compared sirolimus- to paclitaxel-eluting stents reported no significant differences in clinical outcomes such as heart attack or cardiac death in everyday clinical practice (JAMA. 2008;299:409-16). The study, which acknowledged that approval of DES was based on results of relatively small trials of selected patients, concluded that the use of DES in the general population may be safe.
New stent drugs promise rosier clinical results than previous DES. In their January 2008 JAMA editorial, Mukherjee and Moliterno predict that “in 2008, clinicians will have additional choices of drug-eluting stents with the availability of second-generation devices—namely, the everolimus-eluting stent, which yielded similar or fewer major adverse cardiac events among patients as compared with the paclitaxel-eluting stent.”
Web Extra: Bright Outlook for Bioabsorable Drug-Eluting Stent
A new type of stent might join the ranks of bare-metal and drug-eluting stents, based on initial trials.
According to a report published in the March 15 issue of The Lancet, ABSORB, a clinical trial of a fully bioabsorbable drug-eluting stent for the treatment of coronary artery disease, demonstrated no stent thrombosis, no clinically driven target lesion revascularizations (retreatment of a diseased lesion) and a low (3.3 percent) rate of major adverse cardiac events (MACE) in 30 patients out to one year (Lancet. 2008;371:899-907). These one-year results for Abbott Laboratory’s bioabsorbable everolimus-eluting stent were consistent with performance demonstrated by the system at six months, as previously reported in October 2007. Abbott’s prospective, non-randomized, ABSORB clinical trial is designed to evaluate the overall safety and performance of a fully bioabsorbable everolimus-eluting stent out to five years.
“The positive results from this clinical trial form a strong basis for the development of additional bioabsorbable stent platforms with the potential to eliminate some of the restrictions posed by metallic stents in areas such as vessel imaging and vessel remodeling,” said Dr. Patrick W. Serruys, co-principal investigator in the ABSORB study and professor of interventional cardiology at the Thoraxcenter, Erasmus University Hospital, in Rotterdam, the Netherlands.
“Patients and physicians like the idea of a stent that does its job and is then absorbed away,” said Dr. John A. Ormiston, cardiologist at Auckland City Hospital, in Auckland, New Zealand and principal investigator in the ABSORB trial. “Abbott’s bioabsorbable stent has the potential to hold an artery open long enough for healing to occur, and we would expect an artery that is healed to function as it did before it became diseased.”
Abbott’s bioabsorbable everolimus-eluting coronary stent is made of polylactic acid, a biocompatible material that is commonly used in medical implants such as dissolvable sutures. As with a metallic stent, Abbott’s bioabsorbable stent is designed to restore blood flow in clogged coronary arteries, and to provide mechanical support until the blood vessel heals. Unlike a metallic stent, however, a bioabsorbable stent is designed to be slowly metabolized by the body and completely absorbed over time.
“Abbott’s bioabsorbable drug-eluting stent system is a great example of scientific innovation leading to a breakthrough treatment for heart disease that has potential to improve patients’ lives,” said John M. Capek, Ph.D., executive vice president of medical devices at Abbott. “We look forward to continuing to evaluate the safety and effectiveness of our bioabsorbable stent platform in additional patients in the coming months.”
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