News from the American College of Cardiology meeting (Part II)March 7-10, 2004 New Orleans, Louisiana

Miravant’s PhotoPoint PDT May Stabilize Atherosclerotic Vulnerable Plaque and Prevent Disease Progression Miravant Medical Technologies, a pharmaceutical development company specializing in PhotoPoint® photodynamic therapy (PDT), announced preclinical data that may support the future treatment of patients with atherosclerosis and atherosclerotic vulnerable plaque. The following results were demonstrated in atherosclerosis models at 28 days after PDT treatment: Plaque reduction: Intravascular PhotoPoint PDT promotes plaque stabilization by removing the inflammatory cells responsible for disease progression. This was determined to be a sustained event that also yielded up to 40% reduction in plaque volume. Plaque stabilization: Following PhotoPoint treatment, the plaque matrix is replaced with stable, non-proliferating smooth muscle cells, suggesting that the tendency for plaque re-growth is limited. These results are indicative of appropriate healing and repair of the artery walls. These experimental studies were conducted under the direction of Ron Waksman, MD, Professor of Medicine (Cardiology), Georgetown University and Associate Chief of Cardiology at the Washington Hospital Center; and analyzed under the direction of Renu Virmani, MD, Chair, Cardiovascular Pathology, Armed Forces Institute of Pathology, Washington, D.C. Additional studies in target vessel coronary arteries, also presented at the ACC meeting, analyzed arterial healing responses at acute (3 days post-PDT) and long time points (14-90 days). The studies, conducted at the Washington Hospital Center, measured the effects of Intracoronary PDT on vascular cellular populations (smooth muscle cells and endothelial cells). The coronary artery wall displayed positive healing responses and normalization at 30-90 days post-treatment. These results provide further evidence of a potentially beneficial aspect of the treatment for atherosclerotic plaque and/or restenosis, suggesting stabilization of the artery wall over time. Cardiovascular disorders, including acute coronary syndrome and vulnerable plaque, are the leading cause of morbidity and mortality in the developed world. Miravant is currently developing PhotoPoint PDT as a minimally invasive interventional procedure for the treatment of such at-risk patients. The catheter-based treatment uses a systemic light-reactive drug in combination with low power light to selectively treat the lesion site. Recent studies have indicated that vulnerable plaque causes 60-80% of fatal heart attacks. PhotoPoint PDT uses photoreactive (light-activated) drugs to selectively target diseased cells and blood vessels. Miravant’s cardiovascular program focuses on life-threatening diseases, with PhotoPoint MV0633 in advanced preclinical testing for vulnerable plaque, atherosclerosis and restenosis. PROCAM Calculator Plus CT Examination Support Treatment of Coronary Events In collaboration with the International Task Force for Prevention of Coronary Heart Disease, Siemens Medical Solutions introduces a refined method for the assessment of a patient’s risk for coronary heart disease (CHD) at the 53rd Annual Scientific Session of the American College of Cardiology (ACC). It consists of the combined use of the Prospective Cardiovascular Muenster (PROCAM) Calculator and a multi-slice computed tomography (CT) examination of the heart to identify individuals at high risk for a future coronary event according to their PROCAM Score. Scientists led by Gerd Assmann, MD at the Institute of Arteriosclerosis Research in Muenster, Germany, have developed a simple point-scoring scheme that virtually any doctor can use to accurately assess his or her patient's risk of suffering a coronary event in a simple calculation. The PROCAM Calculator looks at the various factors that contribute to heart attack risk, including age, gender, blood lipids, high blood pressure, family history, smoking and diabetes. The PROCAM score then helps to quantify risk reduction via life-style adjustments and LDL cholesterol targeted treatment. Assmann now combines the simple calculator with multi-slice CT technology from Siemens Medical Solutions to create a tool for identifying high-risk patients. Using multi-slice cardiac CT examinations can help to visualize harmful constrictions and plaque lesions inside the coronary vessels non-invasively at an early stage and thus might allow for early and more targeted treatment of high risk individuals. Using the PROCAM score, the population can be divided into three risk groups based on the risk in percent of myocardial infarction or sudden coronary death in 10 years. More than 2 % is considered high-risk, 10 to 20% is considered intermediate risk and less than 10 percent is considered low to moderate risk, respectively. It is currently suggested that low and moderate risk individuals undergo follow-up investigations using the PROCAM score system within two to five year intervals. For persons at high and intermediate risk of a coronary event, however, the combined use of the PROCAM score and multi-slice CT of the coronary arteries provide potential for more accurately targeted preventive measures. Recent studies at the University of Muenster have shown that CT examinations of persons at high risk of a coronary event according to the PROCAM score demonstrate calcified and non-calcified lesions in the coronary arteries in more than 80 percent of cases. Non-invasive measurement of the atherosclerotic plaque burden and assessment of cardiac and coronary anatomy by multi-slice CT may be particularly useful in improving the stratification of individuals at intermediate PROCAM risk. The use of multi-slice CT coronary calcium quantification and non-invasive multi-slice CT angiography for the identification of the so called vulnerable patient in the intermediate risk group has also been proposed by a leading international expert panel and the American Association of Eradication of Heart Attack. The finding of advanced calcified atherosclerotic lesions in the coronary arteries is associated with high calcium. Scores above 75 percentile values (age and gender adjusted) may justify more aggressive treatment of patients in the intermediate risk category. Follow-up examinations after invasive or drug therapy can also be performed with multi-slice CT scanners without risk of complications and at low cost. GE Healthcare and American College of Cardiology Partner to Create Cardiovascular Career Development Award GE Makes Three-year Commitment of More Than a Half Million Dollars to Support Emerging Cardiology Researchers GE Healthcare announced a commitment of more than a half million dollars to the American College of Cardiology (ACC) through the ACC Foundation to fund and support a new ACC Fellowship research awards program. The goal of the three-year, $530,000 contribution will be to offer financial support through research grants to cardiologists who have recently completed their training. GE is the first medical technology provider to partner with the ACC on an award program of this kind. The ACC Fellowship award program, while funded by GE, will be administered entirely by the ACC. Procedures for applying for the research Fellowships and specific criteria will be posted on the ACC website at www.acc.org. The first class of Fellows will be named in the first quarter of 2005. Outcomes Indicate SimSuite® System Differentiates Physicians’ Skills during Simulated Training of Cardiovascular Procedure A validation study called Medical Simulation: New Tools for Educating Physicians was presented at the American College of Cardiology’s (ACC) 53rd Annual Scientific Session symposium. The study indicates that the use of medical simulation by physicians performing a minimally invasive procedure differentiates skill levels during a cardiovascular procedure. The validation study is the first of its kind for an endovascular simulation system. There are more than two million right heart catheterization procedures performed annually in the United States. This procedure was chosen for the study in order to help to address federal recommendations for standardized education programs that help increase the overall skill level of health care professionals, and help to maximize the safety of the pulmonary artery catheterization (PAC) procedure. Forty physicians from a broad range of training and experience levels used the SimSuite® System to perform simulated right-heart catheterization procedures. The physicians experienced the entire clinical scenario, often referred to as the process of care. The simulation system, developed by Medical Simulation Corp., Denver, CO, highlights patient history, imagery and labs, cognitive thinking and procedural skills, a follow-up care plan, a metric self-assessment of physician performance, and more. The validation study was led by Dr. John Messenger, interventional cardiologist and assistant professor of medicine at the University of Colorado Health Sciences Center and supported in part by the National Board of Medical Examiners® (NBME®) Stemmler Medical Education Research Fund. Preliminary results show that the endovascular simulator, the SimSuite System, can be used to objectively discriminate skill level for PAC procedural performance in realistic, standardized simulated cases, and is acceptable to physicians for both training and testing. The results of this study indicate that an endovascular simulator can differentiate skill level and has the potential to be used for testing. Overwhelmingly, the majority of physicians felt this simulation system could be used for both training and testing of procedural skills, concludes Dr. Messenger. Highlighting the need for increasing skill levels, one report on participants in a National Heart, Lung, and Blood Institute and FDA workshop on pulmonary artery catheterization and clinical outcomes, recommended that an educational program was urgently needed. A program could include the development of standardized education information and the monitoring of critical care practice improvement as it relates to PAC. The participants gave this recommendation their highest priority, saying that increasing the overall skill level of health care professionals would maximize the safety of PAC. The participants also had the objective to develop a process to measure stated outcomes of training. It has been four years since the NIH and the FDA published their findings and recommendations regarding PAC use, and two years since this simulated clinical skills assessment study was designed. Anticoagulant Shows Promise An experimental anticoagulant shows promise in treating people with coronary artery disease. The results, from two Phase II clinical studies, were presented at the American College of Cardiology’s annual scientific sessions in New Orleans. The anticoagulant, called DX-9065a, prevents the formation of blood clots earlier in the coagulation process than other anticoagulants. It does this by inhibiting the action of Factor Xa, an important player in the formation of a blood clot. In the first Phase II study, Duke University Medical Center cardiologists demonstrated the safety and effectiveness of DX-9065a in stable heart patients undergoing angioplasty. The second and larger Phase II trial was conducted on high-risk heart patients. Patients who received high-dose DX-9065a tended to have a reduction in death, heart attack or the need for urgent revascularization procedure, says Duke cardiologist Dr. John Alexander. Both low and high does of DX-9065a also tended to result in fewer bleeding episodes than the standard therapy of unfractionated heparin. We believe that the DX-9065a results to date set the stage for larger Phase III trials for patients with acute coronary syndrome or undergoing angioplasty, Alexander says. Preliminary Data Illustrates Success in Deploying Stem Cells into Damaged Heart Tissue via a Catheter-Based System Data from the POZNAN Trial, a human feasibility study evaluating the safety of stem cell delivery via a catheter-based system in heart attack patients, was released at the American College of Cardiology Annual Scientific Session. Dr. Tomasz Siminiak, principal investigator of the POZNAN Trial and Professor of Cardiology at the University School of Medical Sciences, District Hospital, Poznan, Poland, presented the results of the preliminary 10 patient study one of the first human studies of its kind. The study is sponsored by the University School of Medical Sciences and the Institute of Human Genetics, Polish Academy of Sciences, Poznan, Poland. The objective of the trial was to evaluate the safety of delivering autologous skeletal myoblast stem cells into heart attack patients via a catheter-based system. Once implanted, stem cells may serve to regenerate and restore damaged heart tissue caused by heart attacks and could help reduce the potential of future heart failure. The procedures in the trial were performed using Medtronic’s TransAccess® Delivery System, a catheter system that incorporates a proprietary needle-based delivery system with on-board IVUS (Intravascular ultrasound) imaging technology. This combination is designed to allow physicians to precisely deploy therapeutic agents, such as stem cells, via a needle with real time imaging capability through the vascular system into the muscle of the heart. Medtronic acquired the TransAccess catheter technology through its acquisition of TransVascular, Inc. in August 2003. Results from the trial indicate that the stem cell delivery procedure was performed safely in nine of 10 patients, with one procedure suspended due to an inability to place a guide wire. In addition, Dr. Siminiak presented six-month follow up results on six of the nine cases which indicated two major findings: 1) Improvement in New York Heart Association (NYHA) heart failure classification in all six cases and 2) Ejection fraction improvement in four of the six cases. Post-procedure follow up on the remaining three patients continues. Though this trial included a very limited patient population, I am particularly pleased with the results to date, which support our belief that a catheter-based delivery system can be used safely to deploy stem cells to heart attack patients, said Dr. Siminiak. The trial data to date suggests that we can take this method of stem cell delivery to the next phase of human trials to assess the efficacy of this approach. Post-infarction heart failure is a major clinical problem, and thousands of patients could benefit from myocardial regeneration. Caution: The TransAccess® Delivery System Catheter is currently under development and is not available for sale. Beta Blockers Usage Low Despite Insurance A Duke University Medical Center analysis of a Council for Affordable Quality Healthcare study of more than 15,000 insured patients has shown that during the year after suffering a heart attack, less than half of the patients had been taking beta-blockers regularly. This is a disturbing finding, the researchers said, since numerous clinical trials have proven the effectiveness of beta-blockers in reducing the risk of future heart attacks and improving survival. Duke performed its independent analysis of study data collected by the Council for Affordable Quality Health Care (CAQH), Washington, D.C., a not-for-profit alliance of more than 20 health plans and networks, providing health care coverage to more 100 million Americans. While many studies have shown improvements in doctors’ frequency of prescribing beta-blockers at discharge after heart attacks, very few studies have looked at the long-term adherence to the drug, said Judith Kramer, MD, principal investigator of the Duke Center for Education and Research on Therapeutics (CERTS) at the Duke Clinical Research Institute. In the study, despite having prescription and commercial insurance coverage, less than 50 percent of this large population had been taking beta-blockers regularly over the first year after their heart attack. In order for the proven benefits of these drugs to be realized, we need to focus our efforts on increasing patient adherence to the therapy. Kramer presented the results of her analysis at the annual scientific sessions of the American College of Cardiology. Numerous studies have shown that approximately 90 percent of heart attack patients are receiving prescriptions for beta-blockers at discharge from the hospital, the researchers said. The researchers identified 15,070 patients in 44 states where CAQH had both administrative and prescription data. In terms of insurance type, 73 percent were covered by commercial insurance plans, while the remaining 27 percent were covered by the Medicare+Choice plan. The data used was for calendar year 2001. In the patients who survived one year after their heart attack, researchers measured the proportion of patients who had been taking beta-blockers for at least 75 percent of the time for periods of three, six, nine, and 12 months after their heart attack. We found a declining proportion of patients were adherent to beta-blockers over time from hospital discharge in all insurance products and all geographic regions, Kramer said. Specifically, 55 percent of patients had been taking beta-blockers regularly over the first 3 months. However, looking over the full year after heart attack, only 46 percent of patients had been taking beta-blockers at least 75 percent of the time. The researches believe that reasons for the declining adherence are probably many and complex. Many patients do not realize, or were not told, that these drugs need to be taken for years, Kramer said. For others, it could be an economic issue, since many of these patients tend to be older and take many other prescription medications. We obviously need to conduct further research to better understand the reasons why patients stop taking the drugs. The researchers are now adding data for calendar year 2002, which they hope will provide additional insights in beta-blocker use in the U.S., particularly how the usage differs by age and gender. Kramer’s analysis was supported in part by a cooperative grant from the CERTS program and the Agency for Healthcare Research and Quality. Study Shows Cypher Sirolimus-eluting Coronary Stent Yields Strong Results Without Pre-dilatation The Cypher Sirolimus-eluting Coronary Stent yields the same patient outcomes with or without balloon pre-dilatation, according to results of the DIRECT trial presented at the American College of Cardiology 53rd Scientific Session. The 225-patient, non-randomized study, funded by Cordis Corp., a Johnson & Johnson company, compared the results of direct stenting to those obtained using conventional balloon pre-dilatation in the previously reported SIRIUS trial. The DIRECT trial is being conducted under an Investigational Device Exemption in the United States. The Cypher Stent is currently labeled for use with balloon pre-dilatation. Principal investigator Jeffrey Moses, MD, Lenox Hill Hospital and the Cardiovascular Research Foundation, New York, NY, said, Our findings indicate that in patients who meet the criteria for direct stenting, it’s possible to omit pre-dilatation and obtain outcomes equivalent to, and in some instances better than those documented in earlier Cypher Stent studies. Dr. Moses said DIRECT trial findings for in-stent late lumen loss compared favorably with those documented in the SIRIUS trial, which used balloon pre-dilatation (0.18 mm for DIRECT patients versus 0.17 mm for SIRIUS patients). In-lesion late loss in patients who underwent direct stenting was very low (0.21 mm) and similar to that seen in the SIRIUS trial. In-stent and in-lesion restenosis rates (3.6 percent and 6.0 percent, respectively) in the DIRECT trial also compared favorably to in-stent and in-lesion restenosis rates in the SIRIUS trial (3.2% and 9.1%, respectively). Dr. Moses described an overall 47 percent reduction in stent-margin restenosis (peri-stent restenosis) below that observed in the SIRIUS trial, which he attributed to improved stent implantation technique and the avoidance of vessel injury that occurs with pre-dilatation. Eight-month angiographic in-stent and in-lesion restenosis rates were 0 percent for the 16 insulin-dependent patients in the DIRECT trial versus 10.5% (in-stent restenosis) and 35 percent (in-lesion restenosis) for the 25 insulin-dependent patients in the SIRIUS trial. The insulin-dependent subsets in the DIRECT and SIRIUS trials also showed differences in late lumen loss. In-stent and in-lesion late loss were 0.20 mm for the insulin-dependent DIRECT trial patients compared with 0.33 mm in-stent late loss and 0.58 mm in-lesion late loss for insulin-dependent SIRIUS trial patients. The target lesion revascularization rate (TLR) at 180 days was zero percent (0/16) for the insulin-dependent patients in the DIRECT trial compared to the 8.0 percent (2/25) for the insulin-dependent patients in the SIRIUS trial. Dr. Moses said findings for the overall diabetic patient group (insulin-dependent plus non-insulin-dependent) in the DIRECT trial compared very favorably to those for the overall diabetic patient subgroup in the SIRIUS trial (in-stent late loss: 0.25 mm versus 0.28 mm and in-lesion late loss: 0.26 mm versus 0.4 mm). The TLR rate at 180 days for the total diabetic population was 2.9 percent (2/70) in the DIRECT trial and 4.8 percent (5/105) in the SIRIUS trial. Dr. Moses described the results for the 70 diabetic patients 16 insulin-dependent and 54 non-insulin dependent included in the DIRECT trial as especially impressive. He said the excellent outcomes in these patients were attributable, at least in part, to increased vigilance to optimal stenting technique by the investigators. PAVE and DINAMIT: Clinical Trial Results Evaluate the Benefits of CRT and ICD Therapy in Additional Patient Populations St. Jude Medical, Inc. announced the results of the PAVE (Post AV Nodal Ablation Evaluation) and DINAMIT (Defibrillator IN Acute Myocardial Infarction Trial) clinical studies at the American College of Cardiology’s (ACC) Annual Scientific Session 2004. Both studies were sponsored by St. Jude Medical. The data from the PAVE study indicates potential benefits of cardiac resynchronization therapy (CRT) in non-heart failure patient populations, while the data from the DINAMIT study showed no overall mortality benefit of implantable cardioverter defibrillator (ICD) therapy in patients following a recent acute myocardial infarction. PAVE is the first large-scale, prospectively randomized study to evaluate Biventricular (BV) pacing vs. standard Right Ventricular (RV)-only pacing in patients undergoing ablate and pace therapy for atrial fibrillation (AF). The study found that: In patients with chronic AF treated with AV nodal ablation (targeted destruction of the AV node, the heart tissue that conducts the electrical impulse from the atria to the ventricles), biventricular pacing produced a statistically significant improvement in cardiac function over standard right-ventricular pacing as measured by the six minute walk test. In these same patients, biventricular pacing also produced a statistically significant improvement in functional capacity over standard right-ventricular pacing as measured by peak VO2 and exercise duration. BV-paced patients experienced fewer deaths during the trial than RV-paced patients. Based on these results, the PAVE study suggests that BV pacing should be the preferred mode of pacing therapy in patients with chronic AF undergoing AV nodal ablation. The objective of the PAVE trial was to prospectively compare the effect of BV pacing versus RV pacing in patients undergoing ablate and pace therapy, said Rahul Doshi, MD, Cardiovascular Consultants of Nevada, Las Vegas, Nevada, the leading enroller of patients in the study. Our results show a significant benefit of BV pacing over RV pacing in exercise and functional capacity for patients with chronic AF and AV nodal ablation. A previous St. Jude Medical-sponsored trial, DAVID (Dual Chamber And VVI Implantable Defibrillator), demonstrated the potential detrimental effects of active RV pacing in patients with low ejection fractions who received ICD therapy. The PAVE study looked at the potential benefits of pacemaker-based CRT therapy in a patient population required to receive ventricular pacing, and reinforces the conclusions from DAVID that RV pacing in patients with left-ventricular dysfunction may be detrimental. Data from the PAVE study have been submitted to the U.S. Food and Drug Administration (FDA) in support of a pre-market approval (PMA) application for the St. Jude Medical Frontier CRT system in post-AV nodal ablation cases. St. Jude Medical reaffirms its previous guidance that it expects FDA approval of this system by the May 2004 NASPE/Heart Rhythm Society meeting. There were about 37,000 ablate and pace procedures for AF in the United States in 2003. Health Research International predicts an annual growth rate of 18%, with an estimated 63,000 procedures annually by 2006. DINAMIT was a prospective randomized trial to assess ICD therapy for prevention of death in high-risk patients early after acute myocardial infarction (AMI). Inclusion criteria for the study included a heart attack within six to 40 days, a left ventricular ejection fraction (LVEF) of less than or equal to 35%, and signs of impaired cardiac autonomic modulation (i.e., depressed standard deviation of sinus RR intervals (less than or equal to 70 ms) or elevated heart rate (mean RR interval less than or equal to 750 ms)), and an age range of 18-80 years. The DINAMIT study found that, in this patient population: ICD therapy did not decrease all-cause mortality. ICD therapy did significantly decrease arrhythmic mortality. The study concluded, based on these findings, that ICD therapy is not beneficial in patients with a recent myocardial infarction, even if they have risk factors for arrhythmic death. Other therapeutic strategies need to be identified and investigated to reduce non-arrhythmic mortality in this patient cohort. The DINAMIT study showed that ICD therapy can significantly reduce the risk of sudden death in patients with a recent myocardial infarction who are at high risk of arrhythmic death due to extensive myocardial scarring and autonomic imbalance, but that this does not result in reduction in total mortality, said Stefan H. Hohnloser, MD, Professor of Medicine, J.W. Goethe University, Frankfurt, Germany, one of the study’s principal investigators. ICD therapy did not prove to be beneficial in patients early after acute myocardial infarction, said Stuart Connolly, MD, Professor of Medicine, McMaster University, Hamilton, Ontario, Canada, also a principal investigator in the study. This is most likely because their burden of myocardial ischemia puts them at risk of cardiac-related mortality from causes other than sudden cardiac death. Previous large-scale clinical trials of patients with ischemic heart disease, low ejection fractions and a history of AMI demonstrated that this patient group will experience decreased mortality when ICD therapy is utilized. These clinical trials have generally focused on patients whose AMI event occurred greater than 6 months prior to their ICD implant. The DINAMIT results demonstrate that the overall mortality benefits of ICD therapy in a post-AMI patient population do not extend to those who receive an ICD shortly after their AMI event, as other causes of death offset the observed decrease in arrhythmic mortality. Further analysis of the data from these studies will attempt to find evidence of other factors which lead to the differences in non-arrhythmic deaths. Rubicon Filter Featured in 3 Presentations at the American College of Cardiology Meeting Rubicon Medical’s Rubicon Filter was featured by three leading cardiologists in presentations delivered the American College of Cardiology (ACC) meeting. Dr. Eberhard Grube, at the Heart Center Siegburg in Germany, presented the Rubicon Filter in a session on Managing PCI Complications. Entitled Complications of Distal Protection Devices, Dr. Grube’s presentation compared the clinical performance of the Rubicon Filter to the performance of other distal protection devices and detailed its advantages. Dr. Grube is currently serving as the principal investigator for the CE Mark clinical study in Europe of the Rubicon Filter’s use in coronary arteries, but has no other formal relationship with Rubicon Medical. Simon Dixon, MD, interventional cardiologist at William Beaumont Hospital in Royal Oak, MI, also presented the Rubicon Filter in an Embolic Protection session. His presentation was entitled Saphenous Vein Graft Protection. Additionally, Dr. Jeffrey Popma, director of interventional cardiology at Brigham and Women’s Hospital and associate professor of medicine at Harvard University, presented the Rubicon Filter in the Distal Protection Devices session in a presentation entitled Device Overview and described the Rubicon Filter as the next generation in embolic protection. Neither Dr. Dixon or Dr. Popma has any formal relationship with Rubicon Medical. Rubicon believes the Rubicon Filter is the world’s smallest-profile embolic filtration device. It is deployed on a guide wire without a catheter, making it smaller and easier to navigate. Rubicon also believes the filter’s small profile should considerably decrease trauma to the body and the risk of dislodging particles during passage of the filter through a blockage in a blood vessel. Dr. Martin Leon will serve as the company’s lead investigator for its Rule-SVG U.S. randomized clinical trial of the Rubicon Filter to obtain FDA marketing clearance, expected to commence near the end of the second quarter of 2004. Rubicon Medical also has successfully used the Rubicon Filter in more than 30 coronary interventions as part of the initial patient enrollment for its RULE-SVG Europe study. The company will continue to conduct clinical testing on as many as 30 additional patients for this study. The Rubicon Filter is also currently undergoing CE Mark clinical studies in Europe for its use in carotid stenting procedures.

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