At TCT, New Studies Support Drug-Eluting Stents 4823

After experiencing a serious downturn caused by concern over possible links between drug-eluting coronary stents and late-term thrombosis, the market for such products has been steadily recovering throughout 2008. That trend toward recovery received another boost earlier this month, with the release of new studies reported at the Transcatheter Cardiovascular Therapeutics Conference (TCT) in Washington, DC.

The clinical studies revealed at the conference generally concluded that drug-eluting stents are safe and do not increase the incidence of major adverse cardiac events (MACE) as compared with bare-metal stents. More importantly, the TCT studies generally affirmed the long-held belief of interventional cardiologists that drug-eluting stents are significantly more effective than their bare-metal counterparts for combating restenosis, or reclogging of the artery.

“These results provide definitive evidence that drug-eluting stents are superior in efficacy to bare-metal stents and have a comparable safety profile at one year,” said Gregg W. Stone, MD, professor of medicine and the director of research and education at the Center for Interventional Vascular Therapy at New York Presbyterian Hospital/Columbia University Medical Center.

Stone's comments were based on the results of the clinical study titled Harmonizing Outcomes with Revascularization and Stents in Acute Myocardial Infarction (HORIZONS AMI). The study was sponsored by the Cardiovascular Research Foundation (CRF; New York City), with research grant support from Boston Scientific Corp. (Natick, MA) and the Medicines Company (Parsippany, NJ), a developer of intravenous anticoagulants for use in patients undergoing coronary angioplasty. Stone is the chairman of CRF, which organizes the annual TCT conference.

Both of the stents used in the HORIZONS AMI study were supplied by Boston Scientific. In the heart-attack patients who were the subjects of the study, the company's Taxus paclitaxel-eluting stent demonstrated significantly reduced rates of target lesion revascularization and binary angiographic restenosis when compared with results using the company's bare-metal stent.

A Boston Scientific stent was also involved in another TCT-reported study that generated a good deal of interest from both clinicians and industry analysts. The Synergy between Percutaneous Coronary Intervention with Taxus and Cardiac Surgery (SYNTAX) study found no significant difference in treatment outcomes of patients who were stented compared with those who underwent coronary artery bypass grafting surgery. The company said the results reinforced previously announced data demonstrating no overall statistically significant differences between percutaneous coronary intervention (PCI) and coronary artery bypass grafting (CABG) in rates of death or myocardial infarction.

“The data announced today will provide important additional information for doctors as they evaluate treatment options for complex coronary patients,” said Keith Dawkins, MD, associate chief medical officer at Boston Scientific. “The comparable safety and efficacy outcomes with PCI and CABG in this trial indicate PCI is a good treatment alternative for this patient population.”

Additionally, Boston Scientific's next-generation Liberté stent, which recently received FDA approval, demonstrated solid indicators of safety and efficacy in treating patients with high-risk lesions or preexisting ‘comorbid conditions,' including prior incidence of stroke or heart attack, or chronic renal disease. Overall, the composite MACE rate for Liberté after one year was 4.4%, while in-stent thrombosis was reported as 0.8%. The stent also exhibited a very high implantation rate of 99.7%. The company's Taxus Atom stent, which is intended for small coronary vessels (up to 2.25 mm in diam), gained FDA approval late last month.

Almost certainly, the stent manufacturer with the most favorable news coming out of TCT was Abbott Vascular, a division of Abbott (Abbott Park, IL). In two clinical studies, Abbott's Xience V drug-eluting stent was found to outperform Boston Scientific's Taxus in both safety and efficacy.

“The pooled results from the SPIRIT II and SPIRIT III trials demonstrate that Xience V is safer and provides greater efficacy than Taxus at two years,” said CRF's Stone. “In the metaanalysis at two years, Xience V compared to Taxus demonstrated statistically significant reductions in the combined measure of all-cause death or heart attack, as well as further reducing the need for repeat cardiac procedures—reinforcing that Xience V is a true second-generation stent, which results in improved patient outcomes.”

John M. Capek, PhD, Abbott's executive vice president for medical devices, said, “With the subgroup analysis, we saw encouraging trends of lower event rates between one and two years for patients treated with Xience V compared to patients treated with Taxus, regardless of patient or lesion complexity.”

Abbott also reported positive news on its as-yet-unnamed bioabsorbable drug-eluting stent. In the ABSORB clinical trial reported at TCT, the stent demonstrated success in effectively treating coronary artery disease. Two years after treatment, the blood vessels were described as moving and functioning in a manner similar to unstented arteries. Patients who received Abbott's bioabsorbable drug-eluting coronary stent experienced no in-stent thrombosis during the two years after treatment, and experienced no new major adverse cardiac events in the period from six months to two years after treatment. Abbott said the results confirmed the clinical results at one year, which had been reported previously.

“Now you see it, now you don't. For the first time, we have data on patients showing that Abbott's bioabsorbable drug-eluting stent does its job treating diseased coronary arteries, and that it is absorbed by two years,” said John Ormiston, MD, medical director at Mercy Angiography (Auckland, New Zealand) and principal investigator in the ABSORB trial. “These are very exciting results that represent a potential major breakthrough in the future treatment of patients with coronary artery disease.”

Abbott's bioabsorbable everolimus-eluting coronary stent is made of polylactic acid, a biocompatible material that is commonly used in such medical implants as dissolvable sutures. In 2012, the company expects to apply for a CE mark that will permit it to enter the European market, and will follow with a submission to FDA shortly thereafter.

The stent manufacturer receiving the most disappointing news at TCT was perhaps Medtronic Inc. (Minneapolis). One study successfully demonstrated the safety of the company's Endeavor drug-eluting stent compared with its bare-metal version known as Driver. But another study raised serious safety concerns when Endeavor went head to head in a clinical trial with the Cypher drug-eluting stent from Cordis Corp. (Warren, NJ), a Johnson & Johnson company.

In the latter study, conducted in Denmark, the target lesion revascularization rate for the Endeavor stent was found to be 4.5%—considerably greater than the 1.0% rate for Cypher. The researchers noted that in an earlier study conducted at the same five centers, the in-stent thrombosis rate for Endeavor was 1.7%, as opposed to 0.2% for the Cypher stent.

“The data are confoundingly anomalous for Cypher,” said a Medtronic spokesperson. “They are at odds with every other study of this vintage drug-eluting stent ever conducted.” Although the study generated a few negative headlines for Medtronic, several cardiovascular market analysts agreed that the results might represent an outlier or reflect the presence of an unknown intervening variable.

Medtronic received better news from another source—a continent away from the TCT conference—when the federal court for the Northern District of California ordered the removal of an injunction that had denied the company access to a rapid-exchange stent delivery system patented by Abbott. The injunction had been in place since 2000. Although FDA granted market approval for Medtronic's Endeavor stent earlier this year, industry analysts had generally concluded that sales of the product would be adversely affected by not having access to a rapid-exchange delivery system. In a press release, Medtronic said that it would announce its commercial intent with regard to the rapid-exchange technology after the ordered end to the injunction on October 29.

At this year's TCT meeting, Cordis—the first company to market a drug-eluting stent—did not attract a great deal of attention from either industry analysts or the media. In study results announced at the meeting, the company's flagship Cypher sirolimus-eluting stent compared favorably in a head-to-head match-up with perennial rival Boston Scientific.

Looking to the future, Cordis demonstrated its development work on a new generation of reservoir-based drug-eluting stents called Nevo, a technology it acquired with its purchase of Conor Medsystems LLC (Menlo Park, CA) in late 2006.

The original Conor CoStar cobalt chromium stent suffered a serious setback in May 2007, when a major clinical study found a MACE rate of 11%, compared with 6.9% for Taxus. In response to the study, Johnson & Johnson immediately withdrew the Conor stent from the market. As indicated at that time, the company has continued to develop the Conor platform, replacing the drug compound paclitaxel in favor of sirolimus.

In spite of such ongoing R&D, Cordis is widely perceived as lagging in stent development, and a number of key executives have left the company over the past year. During TCT, the company announced some major additions to its corporate management team. According to Seth Fischer, worldwide franchise chairman, “Cordis Corp. continues to attract top talent both from within Johnson & Johnson and from across the healthcare industry.”

In addition to the big four U.S. market players—Abbott, Boston Scientific, Cordis, and Medtronic—many other coronary and vascular stent manufacturers also made news at TCT. The following sections describe this year's announcements by some of the emerging players in the field.

Capella Inc. (Galway, Ireland) bills itself as a developer of the “next generation of bifurcation stenting.” The company describes its Sideguard ostium protection device as “a novel solution for the treatment of ostial and bifurcated disease, which has demonstrated ease of use and excellent clinical results.” According to Capella, the Sideguard is an anatomically-shaped, self-expanding device with clinical results that are equal to those of conventional drug-eluting stents.

CeloNova BioSciences Inc. (Newnan, GA) is developing the Catania drug-eluting stent system, which features a surface that has been modified with highly lubricious Polyzene-F, a synthesized, inorganic, biocompatible polymer. According to the company, Polyzene F is antithrombotic, antiinflammatory, bacteria-resistant, and “essentially cloaks the device's presence from the body to promote healthy endothelial cell growth without stimulating platelet activation.” CeloNova says the unique combination of stent and surface treatment effectively creates a new and different stent option. The Catania system offers many of the clinical benefits of drug-eluting stents, while addressing some of the significant ongoing concerns with drug-eluting stent technology, such as the potential for thrombosis. The system is also intended to address challenges associated with costly long-term dual antiplatelet therapy following treatment, including patient compliance, bleeding risks, drug intolerance, and product cost.

Coherex Medical Inc. (Salt Lake City, UT) has developed the FlatStent patent foramen ovale (PFO) closure system, which “redefines the concept of a stent.” Instead of using the outward force generated by an expanded stent to open a structure, the FlatStent uses outward force to close a structure. The implantable device is part of a system that is designed to provide three distinct closure mechanisms.

Elixir Medical Corp. (Sunnyvale, CA) a nnounced positive first-in-man results in three studies involving the company's drug eluting coronary stent systems, Myolimus and Novolimus, which are designed to optimize localized drug delivery.

Micell Technologies (Raleigh, NC) is developing MiStent, which utilizes a bioresorbable polymer coating to deliver the therapeutic benefits of the drug during the healing process. The drug and polymer are both eliminated from the stent within 90 days following implantation. Micell says its technology is leading the way to a new generation of stents that can deliver a drug precisely, while safely eliminating the polymer faster than any other commercially available biodegradable coating.

MIV Therapeutics Inc. (Vancouver, BC, Canada) is a developer of next-generation coatings and advanced drug-delivery systems for cardiovascular stents and other implantable medical devices. At the TCT meeting, the company featured its Vestasync stent, which combines a stainless-steel platform with an ultra-thin hydroxyapatite surface coating impregnated with a polymer-free formulation that elutes drug for more than 40 days. Hydroxyapatite shows positive biocompatibility because it occurs naturally in the body. The Vestasync stent is also significantly thinner than any drug-eluting stent currently on the market. The company plans to seek CE marking for European marketing approval by mid-2010.

OrbusNeich (Hong Kong) presented 12-month follow-up data demonstrating “good safety and efficacy” in the real-world use of the company's Genous Bioengineered R stent. The company describes the stent as an antibody-coated device that is the first-ever stent to capture a patient's endothelial progenitor cells in order to accelerate the natural healing process following placement.

Palmaz Scientific Inc. (Dallas, TX) was formed earlier this month by Julio Palmaz, MD, who is widely credited with inventing the first commercially successful balloon-expandable intravascular stent. The Palmaz device was granted a U.S. patent in 1988 and was approved by FDA for use in coronary arteries in 1994. Palmaz Scientific will design, manufacture, and sell implantable bioprosthetic devices—including cardiovascular stents and related applications—developed from its 37 patented and 152 patent-pending technologies. The company will also enter into third-party product-distribution relationships and license technologies to third parties.

Stentys SAS (Paris, France) says it has developed the world's first next-generation stent dedicated to the treatment of blocked coronary artery bifurcations, offering a new option to patients for whom open-chest surgery was previously thought to be the only option. The Stentys bifurcated stent has been successfully implanted in patients, taking only routine interventional time to complete implantation. Patients were released from the intensive care unit within hours of implantation, and discharged from the hospital shortly after the procedure. The stent was successfully deployed in 39 of 40 patients, leading to a procedural success rate of 98%. The company says its stent has the potential to make the treatment of blocked coronary artery bifurcations as simple and effective as a conventional stenting procedure.

Trireme Medical Inc. (Pleasanton, CA) announced during TCT that its Antares coronary stent has received the CE mark for distribution in Europe. The company describes the Antares device as a unique main-vessel stent system specially designed for use at or near coronary bifurcations.

Xtent Inc. (Menlo Park, CA) reported positive long-term follow-up data, which the company says reinforces the efficacy of its Custom NX drug-eluting stent system. Custom NX is designed to enable a more personalized approach to the treatment of arterial disease based on the characteristics of each patient's individual lesions. The device features a delivery system that enables the interventional cardiologist to customize the length and diameter of the stent at the site of the lesion. The physician can separate the stent in six-mm segments, or combine segments to place up to 60 mm of stent. The stent has not yet been approved by any regulatory authority.

Interventional cardiologists are increasing calls for the use of antiplatelet drug therapy following implantation of a drug-eluting stent. The issue is no longer whether antiplatelet therapy should be used, but to what extent and to what duration. Addressing the simmering controversy at the TCT meeting, eight manufacturers involved in the drug-eluting stent market announced plans to study whether 12 months or 30 months of dual antiplatelet therapy is better for preventing in-stent thrombosis and major adverse cardiovascular and cerebrovascular events (MACCE). The underlying concept for such a study goes back to FDA's safety meeting with drug-eluting stent stakeholders in December 2006.

The Dual Antiplatelet Therapy Trial (DAPT) is expected to include 20,000 patients and cost at least $100 million. Companies funding the study include Abbott, Boston Scientific, Bristol-Myers Squibb Co. (New York City), Cordis, Daiichi-Sankyo (Tokyo), Eli Lilly and Co. (Indianapolis), Medtronic, and Sanofi-Aventis SA (Paris, France). The study will not compare the performance of different stent brands or different types of antiplatelet drugs.

Although the U.S. market for drug-eluting stents remains down sharply from the 85–90% penetration rate of just a few years ago, use of drug-eluting stents has climbed back to a rate around 70%. Current market value is thought to be about $2 billion, which represents a 40–50% decline from the peak in 2006.

With its Xience V drug-eluting stent, Abbott has captured just over 50% of the market, far exceeding even the most optimistic forecasts following FDA approval of the stent in July. The company's market share includes sales under the Xience V brand as well as distribution of the stent under the Promus brand by Boston Scientific, which earned the right to sell the stent as part of its acquisition of Guidant. Boston Scientific reportedly pays Abbott a 40% royalty on every Promus stent it sells.

Boston Scientific's Taxus stent, formerly the market leader, now has a 19% market share. Cordis's Cypher stent has an estimated 15% share, while Medtronic's Endeavor has fallen to 13% in the most recent quarter.

The TCT conference celebrated its 20th anniversary this year. The event drew more than 11,000 cardiologists, radiologists, surgeons, cardiac catheterization lab technicians, and other hospital personnel from around the world. The exhibit hall featured product displays and equipment demonstrations from nearly 150 companies.

Next year, for the first time since its launch, TCT will leave its base in Washington, DC, and hold its 2009 meeting in San Francisco's Moscone Center on September 21–26.

© 2008 Canon Communications LLC

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