April 2004 Clinical and Industry News

New Study Links Aspirin Resistance to Heart Muscle Death During Interventional Procedures Patients who do not respond adequately to aspirin therapy are more likely to experience heart muscle damage when undergoing coronary interventions. Aspirin resistance is one of the most provocative pieces of the aspirin saga, and this study helps brings aspirin resistance to the forefront of clinical practice, Deepak L. Bhatt, MD, director, interventional cardiology fellowship at the Cleveland Clinic Foundation, notes. In the study, researchers at Queen Mary Hospital in Hong Kong found that patients who did not show an adequate response to aspirin lost significantly more muscle, as measured by a common enzymatic indicator of cell death, compared to patients who showed a good response to aspirin. The greater extent of muscle death occurred even though patients were simultaneously treated with clopidogrel (Plavix®). Other studies have found that patients who suffer heart muscle damage during a coronary intervention have a higher rate of death, heart attack or the need for repeat procedures. These are intriguing findings that could have direct implications for patient care, said Steven Steinhubl, MD, an interventional cardiologist and cardiovascular researcher at the University of North Carolina Medical Center in Chapel Hill, who was not involved in the study. For example, if we know that a patient is aspirin resistant, we might increase the dose of clopidogrel or add another class of antiplatelet agent to provide the patient with a greater degree of protection. To measure aspirin response, the researchers used a new blood test called VerifyNow Aspirin. The VerifyNow Aspirin test, launched commercially in March by Accumetrics, provides a convenient, reliable method to determine if a patient is resistant or unresponsive to aspirin therapy. The simple blood test gives a quick office or bedside result in about 30 minutes. In the current study, approximately 20 percent of patients were found to be aspirin resistant. This is consistent with other studies suggesting that as many as one-third of the nearly 20 million Americans on chronic aspirin therapy do not achieve sufficient anti-platelet effects, the mechanism by which aspirin confers its protective benefit. Recent research indicates that these so-called nonresponders have a 40 percent greater risk of suffering a potentially life-threatening cardiovascular event than aspirin responders. Aspirin resistance is a serious concern in patients with chronic cardiovascular disease but it has not received sufficient attention, in part because there has been no reliable, validated method for measuring aspirin response, Dr. Bhatt added. This study helps bridge that gap by linking aspirin response as determined by the VerifyNow test to relevant clinical findings. New Homocysteine CME/CEU Educational Program Accredited Program to Assist Physicians and other Healthcare Professionals with Understanding Homocysteine Cardiologists attending the American College of Cardiology meeting in New Orleans were the first to gain access to a new CME/CEU course on homocysteine. Understanding Homocysteine: An Emerging Cardiovascular Risk Factor was unveiled March 7, 2004 by HMP Communications. Divided into seven areas of interest, the program details the clinical implications of homocysteine and its relationship with conventional risk factors. It also describes clinical effects of homocysteine lowering along with strategies and therapeutic goals for high-risk patients. The program is the first accredited course offering two hours of CME/CEU credit hours focusing on homocysteine. Eric J. Topol, M.D., Provost, Cleveland Clinic Lerner College of Medicine; Chief Academic Officer, Cleveland Clinic Foundation; Professor of Medicine and Genetics, Case Western Reserve University, serves as Faculty Chairperson for the project. Homocysteine is still one of the key risk factors of benign neglect. Our hope is that more awareness and education on this key topic will lead to appropriate testing and intervention in patients with hyperhomocysteinemia, said Dr. Topol. Designed for physicians, pharmacists, registered dietitians, nurse practitioners, physician assistants, nurses and cardiovascular technologists, the program is easily accessible via CD-ROM and online at hmpcommunications.com or pamlab.com. The homocysteine CME program allows convenience and flexibility for healthcare professionals. Users may work from beginning to end or alternate between modules. They may also work at their own pace before entering the testing phase of the program. Another unique feature of the program is the availability of the information in digital and printed formats. Users may download educational information, charts and slides for their own practical use. The educational activity is supported by educational grants from Pamlab, LLC and Axis-Shield. The program expires March 7, 2005. New Approach Limits Damage After Heart Attack and Improves Survival, Say Scripps Research Scientists A team led by scientists at The Scripps Research Institute has developed a potential new treatment for heart attacks. The therapy inhibits fluid leakage from cardiac blood vessels following a heart attack and thereby significantly prevents long-term heart damage and improves survival. Immunology Professor David A. Cheresh, PhD led the research with postdoctoral fellow Sara Weis, Ph.D at The Scripps Research Institute. Using laboratory models that are designed to mimic the pathology of heart attacks in humans, Cheresh, Weis, and their colleagues found that a single dose of a compound designed to block edema can, even if given as late as six hours after the event, drastically reduce tissue injury and increase long-term survival following a heart attack. A biopharmaceutical company, TargeGen Inc. in San Diego, is finalizing preclinical studies to translate these initial research findings into practical human therapies. Using extensive preclinical models that mirror human heart attacks, TargeGen scientists report that 40 to 60 percent reductions in infarct size with a small molecule drug that inhibits vascular leak and edema. Based on the encouraging preclinical efficacy and safety studies, TargeGen plans to initiate a combined Phase I/II human clinical trial in the second half of 2004 for patients undergoing an acute heart attack. The team also included scientists from St. Elizabeth’s Medical Center at Tufts University School of Medicine in Boston, MA; the Department of Radiology at Beth Israel Deaconess Medical Center in Boston; and the private company TargeGen, Inc. of San Diego, CA. The team reports a dramatic effect of using Src kinase inhibitors to stop the edema-induced damage following a heart attack, thereby reducing heart tissue injury and increasing survival. Through the work of Cheresh and other basic science researchers over the past decades, a number of the adhesion molecules that hold endothelial cells together and the signaling molecules that induce them to let go of one another during events like edema have been identified. Cheresh and his colleagues wanted to develop a strategy to block blood vessel leak without blocking the beneficial vascular growth-promoting effects of vascular endothelial cell growth factor (VEGF). This was accomplished with a Src kinase inhibitor. Cheresh, Weis, and colleagues found that VEGF stimulates Src kinase to cause junctional adhesion proteins (cadherins) to disengage from each other, thereby causing endothelial cells lining the blood vessels to permit fluid leak into the surrounding tissue. Normally cadherins form mortar-like junctions between the endothelial cell bricks and maintain the integrity of blood vessel walls. But cadherins come apart rapidly when they are given the right stimulus such as VEGF. Just as removing mortar between bricks in a subterranean tunnel might cause the tunnel to become permeable to groundwater, blood vessels become leaky when the mortar that holds these endothelial cells together crumbles. A few years ago, Cheresh and his colleagues discovered that mice born without the ability to make certain proteins belonging to the Src family have a deficiency in vascular permeability. These animals showed a high degree of resistance to the damaging effects of a heart attack. Src, it turns out, is necessary for breaking the cadherin junctions in response to VEGF. In fact, these mice lacking Src were protected against the edema that followed a heart attack. This led Cheresh and his colleagues to speculate that treating normal mice with Src inhibitors might do the same thing. In their latest study, they demonstrate exactly that result. The cadherin junctions between cells lining the blood vessels in animals treated with Src inhibitors following a heart attack do not break down. New Computer-aided Approach Tailors Drug Dose to Patient Needs A computer-aided approach based on software-that-learns may provide a new tool that helps doctors tailor the dosage of abciximab. Dr. Mirna Urquidi-Macdonald, professor of engineering science and mechanics at Penn State University, says, While we tried our approach first with abciximab, it may be applicable to other medicines that have a narrow therapeutical range between under dosing and overdosing. The new approach is based on neural network software that can learn when given a large body of data on which to train. Using data from 8 patients undergoing coronary angioplasty and 30 healthy patients, the researchers trained the software to predict the best dose strategy for an individual patient based on 17 characteristics. These include, race, sex, age, weight, stable angina, previous myocardial infarction, diabetes, hypertension, hypercholesterolemia, smoking, prior coronary angioplasty, coronary artery bypass graft, statins, beta blocker, nitrates, calcium antagonists and diuretics. Urquidi-Macdonald and additional members of the research team trained the software to predict the individual patient doses versus the time necessary to achieve 20 percent of the baseline platelet aggregation over 15 days. The researchers also identified key patient characteristics that contribute significantly to establishing the abciximab dose-effect relationship. These characteristics include, among others, whether the patient smokes or not, ethnicity and the patient’s weight. By comparing the dosages predicted by the new system with dose-effect data from 39 patients who had undergone standard abciximab therapy, the researchers found that the new software offered potential for dose prescription improvement. For example, the software predictions suggest that the targeted degree of platelet inhibition may be achieved in some patients with lower doses, which could translate into a reduced risk for adverse side effects. The Penn State researcher says, The software also predicts that administering a smaller initial dose, followed by one or two infusions to keep the platelet concentration at 20 percent of baseline, achieves the same effect as giving the patient a larger initial dose. In addition, the software predicted that two of the patients tested would not achieve the target response within the tested range of doses. The researchers note, The utility of this approach and whether it may provide an improvement in therapeutic outcomes clearly remain to be determined in a randomized, double-blind, prospective clinical trial. Should the utility of the new approach be borne out in clinical trials, they predict that by using personal computers, laptops or personal digital assistants, clinicians could simply to enter the necessary input parameters to obtain a network-predicted regimen to aid in their decisions. Medicare Weighs Defibrillator Coverage Medicare is considering expanding coverage for expensive cardiac defibrillators that are surgically implanted, following a government-funded study that showed the technology significantly reduced deaths in patients with even mild heart disease. The annual cost to the government would triple from just over $1 billion to more than $3 billion in five years if it decides to pay for more older and disabled Americans to get the device, according to Medtronic Inc., one of three companies that make most defibrillators in the United States. Guidant Corporation and St. Jude Medical Inc. are the other manufacturers. Private insurers also are closely watching Medicare. Currently, Medicare pays about $25,000 a person for defibrillators that are implanted in 40,000 patients who have congestive heart failure each year. Medicare is looking at expanding that number to cover people with less severe congestive heart failure. Dr. Sean Tunis, Medicare’s chief medical officer, said Wednesday he will meet this week with scientists who conducted the study to discuss its results in detail. We have to tease through what is spin and what's reality, Tunnis said. Only after we feel we have a clear and precise understanding of the science will we explore policy issues, including the cost. But Tunis said that if defibrillators cost only a few hundred dollars each, it wouldn’t be as critical to tease apart the data in exquisite detail. About 450,000 people die in the United States each year from sudden cardiac arrest. A Medicare advisory committee recommended a year ago that the government widen coverage. But the Centers for Medicare and Medicaid Services decided on a modest expansion, saying it would await the results of the new study. Earlier trials showed a benefit in the severest cases of heart disease, but the new one extended that to more moderate disease, a category that includes between 1 million and 2 million Americans. After almost four years of follow-up, there was a 23 percent reduction in death in those getting defibrillators. The study, conducted on 2,521 patients, was directed by Dr. Gust Bardy of the University of Washington and financed by the National Institutes of Health. While expensive, defibrillators are more effective than drugs used to stave off sudden cardiac arrest, the study said. Dr. Bruce Wilkoff, director of cardiac pacing at the Cleveland Clinic, said Medicare has been slow to make decisions about defibrillators. Tunis said a decision should come within nine months. Until then, Dr. Marc Silver, a Raleigh, NC, cardiologist, said he will have to tell Medicare patients that they are good candidates for defibrillators, but can get them only if they have the money. Exercise As Good As Angioplasty For Some Heart Patients Twenty minutes a day on an exercise bike is better and cheaper than angioplasty in easing angina for people with narrowed heart arteries if they have the discipline to choose that alternative, a German study finds. Cardiologists at the University of Leipzig gave men 70 years and older with stable coronary artery disease a choice between lifestyle changes, including the daily exercise program, or angioplasty. If you ask such patients, about 30 percent are willing to make full lifestyle changes, says Dr. Rainer Hambrecht, a professor of medicine at Leipzig and leader of the group reporting the finding. Hambrecht and his colleagues got 101 men who accepted the offer. All had at least a 75 percent narrowing of one artery. To test the effectiveness of the two approaches, 51 of the men had stents implanted, and the other 50 started an exercise program, spending 20 minutes a day on an exercise bike. The two groups were matched for major heart risk factors including blood cholesterol, blood pressure, smoking history and diabetes. At the end of a year, 88 percent of the men who completed the exercise program had no heart attacks or other adverse events, while the event-free survival rate for the stented men was 70 percent. Chest pain in the participants was graded on a three-class scale. The medical cost of a one-class improvement for men who got stents averaged $6,956, compared to $3,429 for those who exercised. The benefits have persisted long since the official end of the study, Hambrecht says. Over two years, and now five years, there has been a very high compliance rate, and the event rate is still significantly different, he says. As a result, the exercise option is being offered to all patients who meet the study criteria at Lepizig, and the program has been expanded to five centers in Germany and other European centers, with further expansion planned, Hambrecht says. It's a program that makes excellent biological sense for the kind of patients enrolled in the Leipzig program, those with narrowed coronary arteries but no major symptoms other than angina, says Dr. Richard A. Stein, chief of medicine at Beth Israel Medical Center Singer division in New York and a spokesman for the American Heart Association. For people with an unstable syndrome, angioplasty is beneficial, Stein says. But it does not reduce the incidence of heart attacks; it changes them from fatal to nonfatal. Several programs using noninvasive tactics combining exercise with cholesterol-lowering drugs, for example have gotten good results in patients with stable angina, Stein says. But the major challenge is compliance, he says. Generally, within six months of starting a program, half of the patients are no longer with you. By a year, you settle down to a third. The Leipzig approach of asking patients to volunteer led to better numbers, Stein says, since the more you screen people for an initial level of enthusiasm, the more you predict compliance. New Device Offers Way to Stitch Up Arterial Punctures After Coronary Procedures A new device that enables cardiologists to stitch together an arterial puncture wound is making the final steps of angioplasty, stenting, and other catheter-based cardiac procedures simpler, safer, and more comfortable for patients. That is the finding of a study from eight U.S. medical centers where researchers evaluated the suturing device. We’re actually seeing a reduction in complications, said the study’s leader, Dr. Timothy Sanborn, at Evanston Northwestern Healthcare in Illinois. The Rapid Ambulation After Closure (RACE) study evaluated a novel stitching device known as the X-Press (X-Site Medical, Blue Bell, Pa). After being inserted into the puncture site, the X-Press guides the cardiologist in passing stitching needles through the skin and into the artery, both above and below the site. The X-Press captures the needles inside the artery and, as the device is removed from the body, pulls the leading end of each stitching thread out with it, creating a loop. The cardiologist then ties a knot in the threads and slides the knot into place, cinching together and closing the arterial hole. The RACE study involved nearly 400 patients who had either cardiac catheterization to diagnose heart disease or percutaneous coronary intervention (PCI). Two-thirds of the patients were randomly assigned to have the arterial puncture site stitched together using the X-Press device; the remaining one-third received manual pressure. Dr. Sanborn and his colleagues found that among patients who had only the diagnostic cardiac catheterization, those in the X-Press group were able to get out of bed and walk around after an average of 2.2 hours, as compared to 6.2 hours in the group treated with manual wound pressure. Among patients who had PCI, the difference was even greater, about 4 hours in the X-Press group, as compared to nearly 15 hours in the manual pressure group. Rates of major complications were about the same when the two groups were compared. When only patients who had PCI were considered, however, the X-Press significantly reduced complications. About half of patients who needed PCI were receiving medications that reduce the blood’s ability to clot. Nonetheless, no PCI patients in the X-Press group suffered major complications, as compared to 3.4 percent of PCI patients who received manual pressure to the wound. The X-Press device is not yet commercially available in the United States. Blood-Forming Stem Cells Fail to Repair Heart Muscle A new study adds a twist to the ongoing debate over using blood-forming stem cells to repair heart muscle. Researchers at the Stanford University School of Medicine report that the cells are unable to replace heart muscle after a heart attack, which refutes earlier findings. During the past three years, several groups had reported that stem cells found in bone marrow could lodge in the heart and repair muscle damaged by a heart attack. If the earlier findings were correct and the blood-forming stem cells switched their fates, that could reveal an exciting new path for treating heart attack patients. We started out attempting to validate and extend those findings, said Leora Balsam, MD, a research fellow working with Robert Robbins, MD, associate professor of cardiothoracic surgery. Instead of supporting previous findings, however, her experiments contradicted them. She found that in mice, blood-forming stem cells lodge in damaged hearts but retain the form of blood cells rather than transforming into muscle cells. Another research group supports Balsam’s findings using slightly different methods. If we are delivering bone marrow to patients with the expectation that it will regenerate the heart, that may not be realistic, Balsam said. One difference between Balsam’s study and previous experiments is the type of bone marrow cells she used. Amy Wagers, PhD, a postdoctoral scholar in the lab of Irving Weissman, MD, the Karel and Avice Beekhuis Professor of Cancer Biology, took whole bone marrow from mice, then isolated several purified groups of cells, including a highly purified subset of stem cells that can go on to form all blood cell types. Previous experiments had only used less purified cells. Balsam injected those cells directly into the heart muscle of 23 mice in which she had induced a heart attack. The injected cells produced a green protein that is easily visible under a microscope. She then examined the heart muscles of those mice 10 days and 30 days after the injection to search for signs of transplanted blood-forming stem cells. At 10 days she saw clusters of green cells, but none of them made proteins typical of heart muscle. The green cells did produce proteins commonly made by blood cells. By 30 days, very few green cells remained in the heart, and those that did still produced blood proteins rather than heart muscle proteins. Balsam found that 30 days after injecting the blood-forming stem cells, the mice died at the same rate as those in another group that received only water after their induced heart attacks. Even though the transplanted stem cells didn’t help the mice survive, the stem cell-injected group did have slight improvements in how well their hearts pumped blood. Robbins said even with these results, adult stem cells may offer potential for treating damaged hearts. Maybe these cells don’t need to differentiate, he said. Robbins said the transplanted blood-forming cells may recruit new blood vessels to the damaged tissues. These new blood vessels may keep heart muscle cells alive that would otherwise have died, thus indirectly rescuing the heart. By genetically engineering those cells to make additional factors to recruit blood vessels, they may become part of a successful therapy, Robbins said. Researchers are also examining embryonic stem cells and immature skeletal muscle cells as possible candidates for repairing heart muscle. Robbins and other members of his lab are looking into these alternative ways of repairing heart muscle.

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