News from the Transcatheter Cardiovascular Therapeutics Meeting (TCT)

Abbott Reports Initial Results from World’s First Clinical Trial Featuring a Fully Bioabsorbable Drug-Eluting Coronary Stent Early Data on First 30 Patients Enrolled in Ongoing Study Presented at TCT Early clinical results from Abbott's ongoing ABSORB clinical trial, the world's first study to evaluate the safety and performance of a fully bioabsorbable drug-eluting stent platform for the treatment of coronary artery disease in humans, were presented during the 18th annual Transcatheter Cardiovascular Therapeutics (TCT) scientific symposium in Washington, D.C. Initial results for the first 30 patients in the trial demonstrated no MACE (Major Adverse Cardiac Events, such as heart attack) and no stent thrombosis at 30 days for patients who received a bioabsorbable everolimus-eluting stent. Abbott's bioabsorbable drug-eluting stent is made of polylactic acid, which is designed to be fully absorbed and slowly metabolized by the coronary artery. The everolimus-coated stent will release the drug into the artery and then slowly absorb over time. The goal is to leave a healed natural vessel behind. The ABSORB trial is designed to assess safety and performance of Abbott's bioabsorbable everolimus-eluting stent in the treatment of patients with single de novo, native coronary artery disease or untreated lesions. Everolimus has been shown to reduce tissue growth in the coronary vessels following stent implantation. The ABSORB trial is a prospective, non-randomized (open label) study and has been designed to enroll up to 60 patients in Belgium, Denmark, France, New Zealand, Poland and The Netherlands. The key endpoints of the study include an assessment of the safety (MACE and stent thrombosis rate) at 30, 180, and 270 days, with an annual follow-up for up to five years, and successful deployment of the bioabsorbable drug-eluting stent. Additional endpoints of the study include angiography and intravascular ultrasound (IVUS) follow-up at 180 days and two years. Abbott's drug-eluting stent is the Xience V Everolimus Eluting Coronary Stent System, launched in Europe in early October 2006. In April 2006, Abbott acquired the vascular intervention and endovascular solutions businesses of Guidant Corporation. Safety and Efficacy Benefits of Next-Generation TAXUS® Liberte Stent Sustained at Twelve Months Positive results also reported for TAXUS Liberte stent direct stenting Boston Scientific Corporation announced 12-month follow-up data from TAXUS ATLAS, the pivotal clinical trial evaluating the Taxus® Liberte paclitaxel-eluting stent system. The data demonstrated that the safety and efficacy benefits associated with the Taxus Liberte Stent System at nine months were maintained at 12 months in workhorse lesions. The results were presented by Mark Turco, MD, Director of the Center for Cardiac and Vascular Research, Washington Adventist Hospital, and co-principal investigator of the trial, at the Cardiovascular Research Foundation's (CRF) eighteenth annual Transcatheter Cardiovascular Therapeutics (TCT) scientific symposium in Washington, D.C. "The TAXUS ATLAS Workhorse trial results are extremely compelling and the data from the Taxus Liberte stent in this study suggest safety and efficacy comparable to the TAXUS® Express stent in the treatment of coronary artery disease," said Dr. Turco. "We are also seeing significant advantages in the deliverability and conformability of the more flexible Taxus Liberte stent as compared to the Taxus Express stent." While identical inclusion and exclusion criteria were used for both the Taxus Liberte stent and the Taxus Express stent historical control group, more complex lesions were treated with the Taxus Liberte stent than with the Taxus Express stent. Despite this difference, the study reported comparable results in clinical outcomes between both groups. The study reported a low 12-month overall cardiac death rate of 0.8 percent for the Taxus Liberte stent, as compared to 1.0 percent for the control group (P=0.62). The study also reported an overall myocardial infarction (MI) rate of 4.0 percent for the Taxus Liberte stent group, as compared to 3.9 percent for the control group (P=0.89). The overall rate of stent thrombosis at 12 months for the Taxus Liberte stent group was 0.9 percent, as compared to 0.7 percent for the control group (P=0.63). The TAXUS ATLAS trial reported an overall target vessel revascularization (TVR) rate of 9.2 percent for the Taxus Liberte stent group, as compared to 8.9 percent for the control group (P=0.83) at 12 months. TAXUS ATLAS, a global, multi-center, single-arm study enrolling 871 patients at 61 sites, was designed to demonstrate that the Taxus Liberte stent is non-inferior in safety and efficacy to the Taxus Express stent. This trial compares patients with de novo coronary lesions treated with the Taxus Liberte stent to a historical case-matched Taxus Express stent control group derived from TAXUS IV and TAXUS V de novo. The TAXUS ATLAS trial met its primary endpoint of nine-month TVR non-inferiority, in spite of more complex patients treated with the Taxus Liberte stent. Similar rates of TVR were maintained at 12 months. Clinical follow-up at 12 months in the Taxus Liberte stent arm of the TAXUS ATLAS trial included 98.7 percent of patients receiving the study stent (856/867). Positive results also reported for TAXUS ATLAS DIRECT STENT. Boston Scientific also announced nine-month data from its TAXUS ATLAS DIRECT STENT clinical trial. The TAXUS ATLAS DIRECT STENT trial is a 247-patient, global, multi-center, single-arm study of the Taxus Liberte paclitaxel-eluting coronary stent system for the treatment of patients with de novo coronary artery lesions using the direct stenting deployment technique. The study assessed the safety of direct stenting compared to placement of a stent using balloon pre-dilatation. The control arm for the trial is the angiographic cohort of the TAXUS ATLAS WORKHORSE clinical trial, which mandated pre-dilatation. Although the TAXUS ATLAS and TAXUS ATLAS DIRECT trial had the same inclusion and exclusion criteria, simpler lesions were selected for the direct stent group. "We saw significantly less target lesion revascularization (TLR), target vessel revascularization (TVR) and major adverse cardiac events (MACE) rates for the direct stent group as compared to the pre-dilatation control group," said John Ormiston, MD, co-principal investigator of both the TAXUS ATLAS DIRECT STENT trial and the TAXUS ATLAS WORKHORSE study, and Interventional Cardiologist, Mercy Hospital and Green Lane Cardiovascular Unit, Auckland, New Zealand. "Overall, the trial suggests that the direct stenting method using the Taxus Liberte stent is as safe and effective as stenting with pre-dilatation." The study reported a success rate of 97.6 percent for delivery of the Taxus Liberte stent by direct stenting, and a shorter procedure time for patients assigned to receive intravascular ultrasound during the index procedure. The study reported a low nine-month overall cardiac death rate of 0.8 percent for the direct stent group, as compared to 1.3 percent for the control group (P=0.73). The study also reported an overall myocardial infarction (MI) rate of 4.5 percent for the direct stent group, as compared to 4.3 percent for the control group (P=0.87). The rate of stent thrombosis for the direct stent group was 0 percent, as compared to 0.9 percent for the control group (P=0.33). The rate of target vessel revascularization was 5.0 percent for the direct stent group, as compared to 11.2 percent for the control group (P=0.0056). The rate of MACE was 9.1 for the direct stent group, as compared to 14.7 for the control group (P=0.0307). The rate of target lesion revascularization was 2.9 percent for the direct stent group, as compared to 7.8 percent for the control (P=0.0087). The study met its primary endpoint of non-inferiority of in-segment percent diameter stenosis (by QCA) at nine months. The Company received the CE Mark for the Taxus Liberte stent in Europe and other international markets in September 2005 (the Taxus Liberte stent is not available for sale in Japan). The Taxus Liberte stent is not indicated for direct stenting in the European Union. The Taxus Liberte stent is currently pending approval by the U.S. Food and Drug Administration and is not available for sale in the United States. The Company plans to launch the Taxus Liberte stent in the United States in 2007. The Company received the CE Mark for its everolimus-eluting Promus stent in October 2006 and plans to launch the Promus stent in Europe in early 2007. The Promus stent, a private-label Xience V Everolimus Eluting Coronary Stent System, is manufactured by Abbott and distributed by Boston Scientific. The Promus stent is not available for sale in the United States. Cordis to Study Impact of Contributing Factors to Stent Thrombosis in Expansion of 30,000-Stent Patient Registry Independent Analysis of Long-term Clinical Data for Cypher® Sirolimus-Eluting Coronary Stent Confirms Safety Profile and Treatment Benefits;Drug-eluting Stent Compares Favorably to Bare-Metal Stents in Analysis of Thrombosis Incidence In order to further advance understanding of stent thrombosis, Cordis announced a study of the multiple factors that may lead to the condition and potential benefits of medical regimens. The 30,000 patient registry, currently underway in Europe and Asia/Pacific, will now extend to the U.S. and will include a prospective randomized subset of patients. This expanded registry will evaluate a variety of safety and efficacy measures, including the need for target lesion revascularization, major adverse cardiac events such as heart attack and death, stent thrombosis, as well as detailed information about the use of dual anti-platelet therapy. Additionally, the company announced that it would extend out to eight years the SIRIUS, E-SIRIUS and C-SIRIUS clinical trials, which were each originally designed to end after five years. Together, the new registry and expanded clinical trials will provide ongoing information about the safety and efficacy of the Cypher Stent, especially in terms of stent thrombosis. Cordis also announced that although an independent clinical research organization has confirmed that the safety and clinical benefits of the Cypher Stent, based on data from four randomized controlled clinical trials, extend out to four years with no significant difference in the incidence of thrombosis between the Cypher Stent and bare-metal stents, its studies will attempt to understand phenomena related to timing of the events. Data are being presented for the first time at the Transcatheter Cardiovascular Therapeutics (TCT) Conference. The independent, intent-to-treat analysis, which applied a new, broad consensus definitions developed by academic investigators, industry and regulators known as the Academic Research Consortium (ARC), demonstrated that the rate of any thrombosis from 0-4 years was 3.5 percent (29 patients from a pool of 832) for the Cypher Stent arm and 3.4 percent (28 patients from a pool of 825) for bare-metal stents. The analysis was performed on the complete four-year data of 1,748 patients, the longest of any drug-eluting stent, from the randomized clinical trials SIRIUS, E-SIRIUS, C-SIRIUS and RAVEL, all of which compared the Cypher Stent to bare-metal stents in the treatment of de novo coronary artery lesions. The data did demonstrate differences in the timing of the incidence of such events between bare-metal and drug-eluting stents. At no point throughout the four-year period were the differences significant. Analyses of sub-populations are ongoing. The ARC definitions for thrombosis included definite, which required confirmation of a clot by angiogram at follow up; probable, which included a heart attack in the treated vessel in patients who did not have an angiographic confirmation of a thrombosis; and possible, which included sudden unexplained death that could not be attributed to another cause, such as a car accident or cancer. These definitions were used to capture all possible adverse events that might be attributable to stent thrombosis and to thoroughly evaluate the long-term safety of potential treatments for coronary artery disease. Thrombosis that was considered "definite or probable," a more specific assessment of the rates of thrombosis in the two treatment arms according to the ARC definitions, was 1.6 percent (13 out of 832 patients) in the Cypher Stent group and 1.7 percent (15 out of 870 patients) in the bare-stent arm from 0-4 years. "Our analysis shows that the Cypher Stent is not associated with an increased overall risk of thrombosis, also known as blood clots, when compared to the same bare-metal stents out to four years," said Donald Cutlip, MD, Executive Director and Chief Medical Officer, Harvard Clinical Research Institute (HCRI), Cambridge, Mass., which conducted the independent analysis based on the new ARC definitions. Dr. Cutlip is also Associate Professor of Medicine, Harvard Medical School and an interventional cardiologist at Beth Israel Deaconess Medical Center in Boston. "The independent analysis by HCRI per the ARC definitions evaluated the data using two definitions of thrombosis any and definite/probable thrombosis and there is no difference versus bare-metal stents in the rate of thromboses at four years by either version of this standardized definition," said Dr. Donohoe. "We recognize that data are subject to interpretation by a number of methodologies, some of which may yield significant differences at certain time points, but we are confident that the complete analyses conducted by HCRI provide the most appropriate information about the safety of the Cypher Stent." The HCRI analysis of data based on the ARC definitions is also the first- ever comprehensive evaluation of thrombosis in bare-metal stents out to four years. "Our study also shows an early hazard for stent thrombosis among the bare-metal stent patients," Dr. Cutlip said. "Additional analyses are needed to evaluate the possible association with restenosis and subsequent revascularization procedures. This phenomenon may have been missed by previous studies, which excluded patients with repeat revascularization procedures who sustained later thrombosis events." The ARC group, led by Professor Patrick Serruys, MD, The Thoraxcenter, Erasmus Medical Center, Rotterdam, The Netherlands and Dr. Cutlip, created the standardized definitions to ensure that safety data for drug-eluting stents were comparable. The Consortium represented participants in the "Scientific Working Sessions on Study Endpoints in PCI Trials" earlier this year in Washington and Dublin, including HCRI, the Cardiovascular Research Foundation and Duke Clinical Research Institute from academia; the FDA, several academic medical centers and hospitals, and, from industry, Abbott Vascular, Boston Scientific, Cordis Corporation, Conor Medsystems and Medtronic. "The definitions developed by ARC are important because they seek to standardize how we view an event like thrombosis across all clinical studies," said Dr. Serruys. "Without a common language, ambiguity arises and that is not helpful for physicians or the patients they treat. With these standardized definitions, we succeed in creating a foundation for clinical advancement of interventional cardiology." The FDA has requested that Cordis review the readjudicated data based on the ARC definitions at the upcoming panel meeting (December 7-8, 2006). Medtronic Announces Positive Results for Endeavor RESOLUTE Drug-Eluting Coronary Stent System Professor Ian Meredith, MD, Monash Medical Centre, Melbourne, Australia, presented positive preliminary results from the Medtronic RESOLUTE clinical trial, a first-in-man study evaluating the new Endeavor Resolute zotarolimus-eluting stent system. Four-month angiographic and clinical results reinforce that zotarolimus continues to be a very potent drug in preventing restenosis, even in challenging patient populations. The presentation was made at the Cardiovascular Research Foundation’s eighteenth annual Transcatheter Cardiovascular Therapeutics (TCT) scientific symposium in Washington, D.C. Current drug-eluting stents (DES) do not meet all the requirements of physicians who deal with the most challenging clinical cases, such as patients with diabetes. The newest DES from Medtronic introduces a proprietary, new biocompatible polymer called BioLinx. This new polymer is designed to help match the duration of drug delivery with the longer healing duration often experienced by patients with complex medical conditions. BioLinx is different than other polymers in that its outer surface is hydrophilic (water-friendly), which leads to high biocompatibility with the body, while the interior of the polymer is hydrophobic, which helps to precisely control the drug release. The RESOLUTE trial enrolled 130 patients at 12 clinical centers in Australia and New Zealand, with a primary endpoint of late lumen loss (in-stent) at nine months and customary angiographic, intravascular ultrasound (IVUS) and clinical secondary endpoints. Thirty-day clinical results for 130 patients showed a Major Adverse Cardiac Event (MACE) rate of 3.8 percent, with zero target lesion revascularization (TLR) and no stent thrombosis. In 30 patients with four-month angiographic follow-up, in-stent late loss was 0.12 mm and in-segment late loss was 0.05 mm. Both in-stent and in-segment binary restenosis were zero, and intravascular ultrasound (IVUS) results showed neointimal volume obstruction of 2.2 percent at four months. Stent device and lesion success was 100 percent. This trial enrolled patients who required smaller, longer stents and Endeavor Resolute produced initial clinical and angiographic results that show great promise, said Prof. Meredith, principal investigator of the RESOLUTE trial. By extending the drug delivery to address the delayed healing often seen in difficult patient populations, zotarolimus exhibits strong potency with low in-stent and in-segment late loss at four months. Also, acute device and procedural success was very high, particularly when the long lesion lengths were considered. The polymers on some drug-eluting stents can produce an inflammatory response within the blood vessel, which can lead to thrombosis and occlusion of the artery. This is more pronounced in patients with complex medical conditions. BioLinx is a non-inflammatory polymer blend that mimics the make-up of a cell membrane to maintain biocompatibility. As a result, it offers uniform drug dispersion, sustained and controlled elution, and the opportunity for multiple drug platforms. Evalve Announces New Data Showing its First-in-Class Percutaneous MitraClip Device Reduces Mitral Regurgitation Without Surgery Evalve, Inc., a privately held medical device company, announced that investigators presented core laboratory data at the Transcatheter Cardiovascular Therapeutics (TCT) annual meeting in Washington, D.C. showing Evalve's MitraClip can significantly reduce mitral regurgitation (MR) and that the device is durable for up to three years. To date, 135 patients have been treated with a MitraClip in the EVEREST (Endovascular Valve Edge-to-Edge REpair STudy) Clinical Study. The EVEREST phase II pivotal study is ongoing to evaluate the safety and efficacy of treating mitral regurgitation in the cardiac catheterization laboratory without open heart surgery. All EVEREST patients had previously been referred for surgery to treat their MR. Investigators presented data on the first 92 non-randomized patients with completed 30 day follow-up and echocardiographic core lab analysis. The results show: Significant reduction of MR in patients with the two most common types of MR: degenerative and functional, o Reduction to Cardium Reports on Positive Effects of Hypothermia Following MI and Announces Clinical Study to Be Co-Sponsored By Swedish Cardiology Center Cardium Therapeutics and its subsidiary InnerCool Therapies reported on preclinical data demonstrating a new and expanded benefit of early rapid cooling for the potential treatment of acute myocardial infarction, as presented at the Transcatheter Cardiovascular Therapeutics (TCT) 2006 Annual Meeting in Washington, DC. The companies also announced their plans for a new clinical study to further assess the safety and potential usefulness of early cooling for heart attack patients, which is expected to be co-sponsored in Sweden and to begin within the next several months. The research reported at TCT was conducted by a team of interventional cardiologists led by Drs. Goran Olivecrona and David Erlinge at the Lund University Hospital, Sweden. In the recently completed study in a preclinical porcine heart attack model, researchers evaluated rapid cooling, induced by a combination of cold saline infusion along with InnerCool Therapies' endovascular Celsius Control System, prior to or coincident with percutaneous coronary intervention (PCI) procedures, which are used to restore blood flow in the heart. The data showed that cooling prior to PCI reduced overall infarct size (reflecting tissue damage) by an additional 40%. These findings strongly support the use of early rapid cooling in planned clinical studies, and suggest that InnerCool's endovascular cooling system may have the potential to enable interventional cardiologists to dramatically reduce tissue damage following a heart attack. Based on these findings, InnerCool plans to sponsor a study on the use of early rapid cooling following heart attack, which is expected to be co-sponsored and conducted by the interventional cardiology center at Lund University Hospital, Sweden. The planned study will be a randomized human clinical trial designed to evaluate the potential use of InnerCool's hypothermia system in the treatment of heart attack patients. This study will randomize approximately twenty patients who present within six hours of their heart attack for PCI alone or PCI plus the new early rapid cooling protocol. The hypothermia arm will include iced saline infusion plus use of the InnerCool Celsius Control System catheter prior to reperfusion in patients undergoing PCI. The trial will employ cardiac magnetic resonance imaging (MRI) to provide an accurate assessment of the damage to the heart within days of the injury. The trial is expected to begin this year and to complete enrollment and treatment within about six months. InnerCool's approach to therapeutic hypothermia is based on a single-use flexible metallic catheter and a fully-integrated endovascular cooling system, which allows for rapid and controlled cooling and re-warming. InnerCool's Celsius Control System integrates a number of features including a slim catheter profile, a flexible metallic heat transfer element, a built-in temperature monitoring sensor, and a programmable console capable of rapidly and controllably inducing, maintaining and reversing therapeutic cooling. InnerCool's endovascular catheter-based Celsius Control System has received FDA 510(k) clearance for use in inducing, maintaining and reversing mild hypothermia in neurosurgical patients, both in surgery and in recovery or intensive care. The system has also received FDA clearance for use in cardiac patients in order to achieve or maintain normal body temperatures during surgery and in recovery/intensive care, and as an adjunctive treatment for fever control in patients with cerebral infarction and intracerebral hemorrhage. Potential future applications of the technology include endovascular cooling for cardiac arrest, acute ischemic stroke and myocardial infarction. Numerous articles have been published in scientific and medical journals describing the usefulness of therapeutic cooling, which is designed to protect endangered cells, prevent tissue death and preserve organ function following events associated with severe deprivation such as stroke or cardiac arrest. Therapeutic hypothermia is believed to work by protecting critical tissues and organs such as the brain, heart and kidneys following acute ischemic or inflammatory events, by lowering metabolism and preserving cellular energy stores, thereby potentially stabilizing cellular structure and preventing or reducing injuries at the cellular, tissue and organ level. The American Heart Association (AHA) recently revised its treatment guidelines to recommend the use of therapeutic cooling as part of the critical care procedures for patients with an out-of-hospital cardiac arrest following ventricular fibrillation. Studies for additional indications with InnerCool's system are expected to be conducted in collaboration with the AHA and with the National Institutes of Health (NIH). The Celsius Control System is now being used at a number of leading U.S. medical centers, including those at Stanford University, Cornell, Columbia, the University of Michigan, Harborview Medical Center, San Francisco General Hospital, the University of California Medical Centers at San Diego and San Francisco, and at medical centers in Australia and Sweden. Study Finds Injecting Patient's Own Stem Cells Into The Heart To Treat Severe Coronary Artery Disease Is Well Tolerated Encouraging 12-month results from a Phase I trial investigating the injection of adult, autologous CD34+ stem cells into the hearts of patients with severe coronary artery disease was presented for the first time at the Cardiovascular Research Foundation’s (CRF) eighteenth annual Transcatheter Cardiovascular Therapeutics (TCT) scientific symposium in Washington, D.C. The data provide evidence that this therapy is well tolerated at this stage and that larger, Phase II clinical trials can continue in humans. Douglas Losordo, MD, chief of cardiovascular research at Caritas St. Elizabeth’s Medical Center, a major academic medical center affiliated with Tufts University School of Medicine, is the principal investigator of the Phase I trial. The therapy involves injecting patients with severe coronary artery disease with a protein that helps to release stem cells from the patient’s own bone marrow into the blood stream. These autologous stem cells are gathered, selected and then injected into areas of the heart that have been damaged due to an insufficient supply of oxygen-rich blood. Data from this randomized, multi-center, placebo-controlled, double-blind trial indicate that the therapy appears to be well-tolerated as no serious adverse events directly related to the stem cell therapy were observed. Twenty-four patients were enrolled at three centers in the United States from December 2003 through March 2005. There were five females and 19 males with a mean age of 63. Through the duration of the study, there were no deaths or heart attacks. Fifteen of the 18 total Phase I study subjects who received the cells reported feeling better with reductions in chest pain and/or improved exercise capacity. Though not sufficiently powered to prove efficacy, these results did lead the way to the initiation of a randomized, multi-center, placebo-controlled, double-blind Phase II trial, sponsored by the Cellular Therapies business unit of Baxter Healthcare Corporation, in a larger (150 patient) study population. Heart disease is the number one killer of adults in this country, and yet, as clinicians, we are unable to adequately treat many patients with the severest forms of the disease, said Losordo. The Phase I results demonstrated that patients suffering from severe coronary artery disease who receive injections of their own stem cells can tolerate this treatment. By moving forward with the Phase II trial, we have reached a milestone in exploring further a much-needed therapy for this patient population.

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