Thus far, the two drug-eluting stent (DES) products commercialized in the U.S. utilize a polymer as a method of incorporating drug and device. But the first-generation use of polymers may not be a model for future DES technologies, according to Martin Leon, MD, chairman of the Cardiovascular Research Institute (New York), in a presentation on the future of DES technologies during this year's annual meeting of the American Heart Association (Dallas) in New Orleans. And in one of the late reports from the annual meeting of the AHA, interventional cardiologist Alexandre Abizaid, MD, PhD, presented what he described as "promising" data concerning such a stent – the BioMatrix from Biosensors International (Singapore).
As compared to current DES devices that employ polymer coatings that remain permanently inside the patient's coronary artery, Abizaid said that the BioMatrix stent "uses a bioabsorbable coating that dissolves during drug release into all-natural products. The natural product is then metabolized and excreted by the body as carbon dioxide and water." He added: "This may offer potential advantages over permanent stent coatings by eliminating concerns over long-term structural failure or chronic inflammatory effects of the polymer."
The data he reported were derived from six-month results of the Stent Eluting A9 BioLimus Trial in Humans (STEALTH) trial. Abizaid, a contributing investigator from the Instituto Dante Pazzanese of Cardiology (S o Paulo, Brazil), said that the BioMatrix, which elutes the rapamycin derivative Biolimus A9 from a bioabsorbable polylactic acid (PLA) polymer coating, "demonstrates significantly reduced neointimal hyperplasia when compared to bare-metal control stents in this first-in-man experience." He added: "The low adverse event rate and the absence of cardiac deaths suggest that this new stent is safe."
The 120-patient, double-blinded, randomized first-in-man trial of the new stent was conducted at two German heart centers, the Siegburg Heart Center (Siegburg) and Br derkrankenhaus Trier (Trier) and at Instituto Dante Pazzanese of Cardiology, a medical research hospital. The objective of the STEALTH trial was to investigate the safety and efficacy for the new DES device, which releases Biolimus A9, a rapamycin derivative pharmaceutical, eluted from the PLA polymer-coated stent, in de novo coronary lesions. Abizaid said, "New rapamycin derivatives such as Biolimus A9 are being developed to improve upon the pharmacokinetic properties of anti-restenosis drugs, known as 'limuses,' for implantable 'on-stent' medical device coating applications." He added, however, that it is unknown "whether structural changes to the rapamycin molecule will lead to improved efficacy, particularly in high-risk sub-groups."
Among the trial results reported by Abizaid:
- A low restenosis rate (3.9% vs. 7.7%) and decreased late loss inside the stent (0.26 vs. 0.74) in the Biolimus A9 stent group compared with the bare-metal stent control group.
- No restenosis at the proximal or distal edges of the stent in either group.
- The same low incidence (3%) of late-acquired incomplete stent apposition in both groups, comparing favorably with currently marketed DES devices.
"The BioMatrix stent, eluting the rapamycin derivative Biolimus A9 from a bioabsorbable PLA polymer coating, demonstrates significantly reduced neointimal hyperplasia when compared to bare-metal control stents in this first-in-man experience," and that the low adverse event rate and the absence of cardiac deaths "suggests that this new stent is safe."
In a breakfast meeting preliminary to release of the final results, Uwe Christians, a pharmacologist at the University of Colorado Health Science Center (Denver) described the rapamycin drug formulation used for the stent as having "fast release into the target tissue" and "equal patency to sirolimus," from which rapamycin is derived.
The device uses Biosensor's S-sent as its "bare-metal backbone." John Shulz, chief technology officer for Biosensors, described the S-stent as having "tremendous efficacy as a bare-metal device" and featuring a construction of "rings" to provide high flexibility. Flexibility, rather than thin, "translates to low restenosis rate," he said.
Company executives at the meeting said that Biosensors will be submitting a technical dossier for seeking European approval for the BioMatrix DES in the first half of 2005, and that it expects to launch a U.S. pivotal trial in the second half of 2005 for FDA approval. Shulz declined, however, to project a timeline for achieving U.S. commercializaton. At the preliminary meeting, Yoh Chie Luh, CEO of Biosensors, said that the company is currently ramping up manufacturing of the device and that it has first developed a facility for doing the drug coating of the stent manually, after which it will transition to an automated system. "We are poised to become a leading company in the DES market," he said.
Eberhard Grube, MD, of Siegburg Heart Center, served as principal investigator for the study, while Dr. Hauptmann of Trier and Professor Sousa, chief of cardiology at Instituto Dante Pazzanese, are the co-investigators. The Harvard Cardiovascular Research Institute (Boston) and the Cardiovascular Research Foundation (New York) served as data and angiographic core laboratories for the study, and the Stanford Cardiovascular Research Institute (Stanford, California) served as the intravascular ultrasound core laboratory.
Study reports Corautus VEGF-2 progress
Corautus Genetics (Atlanta) in November unveiled the preclinical results of its gene transfer technology, administered in combination with cytokines (blood cell growth factors). In the preclinical study reported in the journal Circulation, a team of researchers under the direction of Douglas Losordo, MD, chief of cardiovascular research at Caritas St. Elizabeth's Medical Center (Boston), tested Vascular Endothelial Growth Factor-2 (VEGF-2) gene transfer in combination with cytokines in animal models of chronic and acute myocardial infarction. The results demonstrate that the combination approach led to improved oxygenation and increased growth of supplementary blood vessels. Losordo said that the primary goal of VEGF-2 therapy "is to increase angiogenesis, the growth of new blood vessels, in order to compensate for blocked or occluded coronary arteries which can no longer provide enough oxygen to the heart muscle. As demonstrated in previous preclinical studies, VEGF-2 provides the original signal to recruit early precursor cells to the site of low oxygen, where they form together to create new blood vessels. We believe that the addition of cytokines can induce further mobilization of these bone marrow-derived endothelial progenitor cells, potentially aiding their recruitment or retention."
In a separate project, Corautus' technology is being tested in the Phase IIb Genetic Angiogenic Stimulation Investigational Study (GENASIS) trial, which is enrolling up to 404 patients with Class III or IV angina in roughly 20 cardiac medical centers in the U.S., with Losordo has the national principal investigator. In GENASIS, defined doses of VEGF-2 in the form of naked DNA plasmid, a non- viral vector, are delivered to diseased heart muscle tissue via the Stiletto endocardial direct injection catheter system from Boston Scientific (Natick, Massachusetts). Corautus in 2003 entered into an alliance with Boston Scientific to commercialize and distribute the VEGF-2 gene therapy products.
"VEGF-2 gene transfer is an approach that has already shown encouraging results in early-stage clinical tests of patients with severe coronary artery disease," said Richard Otto, president and CEO of Corautus. "Based on these clinical findings, we initiated in September the largest trial of its kind in gene transfer therapy in the U.S."
Study targets astronaut arrhythmias in-flight
As the National Aeronautics and Space Administration (NASA) looks to launch extended missions, the NASA John H. Glenn Research Center (Cleveland) has partnered with MetroHealth Medical Center (also Cleveland) to develop a method of measuring whether astronauts are more susceptible to serious cardiac episodes as they spend these longer amounts of time space-side. Ultimately, NASA hopes the venture will enhance its ability to monitor astronauts' in-flight arrhythmic activity from earth. Assisting in the study will be the NASA turbojet – nicknamed the "Vomit Comet" for its gut-wrenching effects used to film the weightless scenes for the movie Apollo 13. Following last year's Columbia space shuttle disaster, astronaut health and well-being is a priority as NASA prepares for its first return-to-flight mission. NASA and MetroHealth will determine a method for assessing the heart's function during zero and partial gravity conditions, like those found on the moon and Mars.
"Since the heart is a very common source of problems, there obviously was concern that prolonged exposure to space could have deleterious effects on the heart," David Rosenbaum, MD, director of MetroHealth's Division of Cardiology and Heart & Vascular Center, told Cardiovascular Device Update. "There have been a number of reports in the past of arrhythmias occurring in astronauts and cosmonauts. And of course, if you're in space ... that's the last thing you want to deal with." Rosenbaum called cardiac arrhythmias, which often go undetected and can lead to sudden cardiac death, "the major public health problem in the U.S.," outnumbering deaths from cancer, lung disease and AIDS, combined. "It becomes critically important to have a way of identifying which individuals are likely to go on and suffer from this problem, because then you could go in with therapy and intervene." He said MetroHealth researchers have been at the forefront of this area, with a comprehensive program to understand the mechanism of arrhythmias and transform those discoveries into clinical practice.
MetroHealth recently completed a series of pilot studies with NASA, basing its research on an advanced electrocardiogram (ECG) test that uses technology pioneered at the medical center. The test looked for T-Wave Alternans (TWAs), or slight changes in the heart's rhythm, during a specialized exercise stress test. TWAs "are a high marker for susceptibility to the risk of cardiac arrhythmias, found in 70% to 80% of patients at risk," Rosenbaum explained. Much of the testing, involving ground and in-flight measures, was conducted on 15 NASA volunteers in the Vomit Comet. The KC-135 Low-G Flight Research aircraft allowed the team to gauge the effects of weightlessness in test subjects while the plane went through a series of severe climbs and descents, or parabolas. These parabolas are strung together in a wave-like configuration to create about 20 seconds of zero gravity.
During the tests, subjects pedaled a stationary bicycle for up to 15 minutes while attached to a 14-lead ECG to gauge their heart rate at various stages. Seven of the ECG electrodes, from Cambridge Heart (Bedford, Massachusetts), were specially designed to allow scientists to distinguish cardiac electrical activity from other electrical signals coming from the body. Data was acquired through a compact unit inside a holster worn by each test subject on the ground and in flight. "What we've discovered at this point is that we have established the feasibility of making these recordings under conditions of weightlessness," Rosenbaum said. "You can imagine the difficulty in trying to control heart rate on a stationary bicycle while someone is undergoing these trajectories in the Vomit Comet. This was not a trivial task."
NASA and MetroHealth are analyzing the data to determine whether microgravity in long-term flight does in fact impact the heart. "We're expecting that under various conditions of microgravity that there will be an effect on the electrical system of the heart and that it will be measurable on the electrocardiogram," Rosenbaum said, predicting that results should be determined in two to three months and will be submitted to cardiology journals for publication. NASA's ultimate goal is to couple TWA technology on the International Space Station with its embedded web technology to track astronaut heart activity remotely – in real time – with an Internet browser. By simply keying in the astronaut's name, their live heartbeat pattern could be monitored and tracked by another astronaut through the on-board central server or by multiple physicians once the data is transmitted to the ground.
Taxus DES continues to gain
The Taxus stent from Boston Scientific (Natick, Massachusetts) continued to gain market share with a 3% increase from September, according to the October utilization report of drug-eluting stent (DES) devices from Goodroe Healthcare Solutions (Atlanta). This represents the second-lowest utilization month (38.52%) for the Cypher stent from the Cordis (Miami Lakes, Florida) unit of Johnson & Johnson (New Brunswick, New Jersey) since the Taxus stent was released, according to Goodroe's data. The lowest utilization of the Cypher DES came in April at 34.22%. The new report comes in the seventh month of tracking by Goodroe.
Goodroe said that overall utilization of drug-eluting stents remained steady as a percentage of all patients receiving coronary stents. DES are now used in 84.13% of all coronary stent patients, it reported, just under September's use rate of 84.32%.