EP Lab Digest - January 2008 - (Page 42) NEWS JANUARY Simple Two-in-One Test Signals High Risk After a Heart Attack Problems in Both the Nervous System and the Heart’s Electrical System Spell Trouble Continued from page 1 he research, which appears in the December 11 issue of the Journal of the American College of Cardiology (JACC), found that by examining both the nervous system and the heart’s electrical system, cardiologists could better identify which patients were at highest risk of cardiac arrest or death, even years after a heart attack. “This is important because past studies, focusing on a single test, failed to identify most people at risk,” said Derek V. Exner, MD, MPH, a heart rhythm specialist and an associate professor at the University of Calgary’s Libin Cardiovascular Institute of Alberta, in Canada. “We developed a simple method of identifying approximately twice as many people at risk.That means we can potentially save more lives.” The REFINE study* — formally named the Risk Estimation Following Infarction, Noninvasive Evaluation — assessed two factors critical to the development of serious cardiac arrhythmias. An electrical system that has been damaged by a heart attack sets the stage for serious disturbances in the heart’s rhythm. At the same time, a nervous system that’s on high alert, even without a patient realizing it, makes it more likely that a serious arrhythmia will take hold and progress to cardiac arrest and death. For the study, Dr. Exner and his colleagues enrolled 322 patients who had suffered a heart attack and had at least a mild abnormality in the heart’s pumping ability.Within 2 to 4 weeks of the heart attack, and again at 10 to 14 weeks, they performed a variety of tests to measure the status of both the nervous system and the heart’s electrical system. They then tracked patients for an average of nearly four years. Having patients wear a heart monitor for 18 to 24 hours as they went about their daily activities turned out to be both a simple and effective way to identify high-risk patients. Using the all-day electrocardiogram, researchers analyzed the heart’s electrical system by looking for T-wave alternans (TWA). Researchers also analyzed the electrocardiogram for evidence that the nervous system was on high alert by looking for abnormalities in “heart rate turbulence” (HRT), a measure of the heart’s ability to adapt to change. Early after a heart attack, TWA and impaired HRT were not accurate warning signs of future risk.At the 10- to 14-week mark, however,TWA and impaired HRT clearly identified patients at increased risk — and they were particularly powerful when used in combination. The 20 percent of patients who had both TWA and impaired HRT on the all-day heart monitor and, in addition, had a persistent abnormality in the heart’s pumping ability, faced more than six times the risk of cardiac arrest or death during follow-up when compared to other patients in the study. Using an exercise test to detect TWA was also effective, but not as simple and efficient as using the all-day heart monitor to look for both impaired HRT and TWA at the same time. Studies that are expected to begin in 2008 will evaluate whether an implantable cardioverter-defibrillator (ICD) can save the lives of patients with abnormalities in both the nervous system and the heart’s electrical system. Until then, those at highest risk should receive intensive follow-up, Dr. Exner said. “The outlook is good for most heart attack survivors. However, the one in five patients in our study who had abnormal tests were at high risk of serious problems,” he said.“Close follow-up with a physician and the use of medications known to be beneficial after a heart attack — aspirin, beta blockers,ACE inhibitors, and statins — are very strongly recommended.” ThromboGenics Presents Results of the Phase I Trial of TB-402 TB-402 Shows Clear Promise as a Stable Long-acting Anticoagulant for the Prevention of Thromboembolic Disorders hromboGenics NV, a biotechnology company, announced that the results of the first Phase I trial of TB-402 were presented at the prestigious American Society of Hematology (ASH) 49th Annual Meeting in Atlanta, Georgia.TB-402 is being co-developed in collaboration with BioInvent International. TB-402 is a recombinant human monoclonal antibody that has shown a beneficial partial inhibition of the blood coagulation Factor VIII. Its long half-life of approximately three weeks enables it to produce a stable and long-acting inhibition. This indicates well-controlled inhibition of Factor VIII activity with low risk of spontaneous bleeding, thus avoiding the possibility of overdose and the need for patient monitoring. These unique features may be of major clinical significance, as it suggests that a product with an excellent safety profile, with ease of administration and compliance superior to alternative anticoagulants, can be developed. The Phase I trial presented at ASH was a randomized, single-dose, placebocontrolled, dose escalation trial in healthy male volunteers. A total of 56 subjects were enrolled into the trial, including both younger age (18-45) and older age (55-76) volunteers. Results of the trial show that TB-402 is both safe and welltolerated. No serious adverse events related to TB-402 were reported. In addition, there were no major bleeding complications, with the overall incidence being similar in both the TB-402 treated group and the patients who received placebo. The pharmacokinetic analysis undertaken as part of the study confirms a prolonged half-life of approximately three weeks, which will allow for longterm stroke prevention in atrial fibrillation (AF). The pharmacodynamic analysis also shows stable and long-acting anticoagulant activity. The Joint Steering Committee of ThromboGenics and BioInvent confirm their previous decision to move TB-402 into Phase II clinical development. As part of the development T T * The REFINE study was supported by the Alberta Heritage Foundation for Medical Research, the Canadian Institutes of Health Research, and the Heart and Stroke Foundation of Alberta. Cambridge Heart Inc. and GE Healthcare Technologies provided unrestricted donations of equipment and testing materials for the study. Dr. Exner reports having received honoraria and conducted research with GE Healthcare and Cambridge Heart. program, drug interaction studies will be performed in H1 2008 in parallel with the preparatory work needed to start the Phase II trial. Professor Peter Verhamme, Department of Vascular Diseases, University of Leuven, who presented the results at the ASH meeting, commented "The results from the first Phase I study with TB-402 show that this novel human monoclonal antibody is safe and well-tolerated, an important first step in the development of this new anticoagulant drug. Of equal importance, the results clearly indicate that TB-402 has the long half-life we predicted and a stable longacting anticoagulant effect based on partial factor VIII inhibition.We are looking forward to starting the Phase II clinical trials, which will investigate the potential of TB-402 in the prevention of thromboembolic disorders." Thromboembolic diseases represent a major unmet medical need. The annual sales of anticoagulants worldwide are over $5 billion. Nevertheless, available anticoagulants are still inconvenient and associated with a high risk of bleeding. Improved anticoagulants are therefore required. In particular, agents that allow for improved ease of administration (without requirement for daily dosing and frequent dose adjustment) would fill a significant unmet need. Atrial fibrillation, which is a strong risk factor for ischemic stroke, is the most common sustained arrhythmia observed in clinical practice.The prevalence of AF is estimated at 0.4% of the general population and increases with age, rising to 8.8% in the group aged 80-89 years. Given the aging population in the U.S. and other developed countries, the overall prevalence of AF is expected to continue to grow over the next several decades. ThromboGenics is a biotechnology company focused on discovery and development of biopharmaceuticals for the treatment of a range of vascular and eye diseases. ThromboGenics is headquartered in Leuven, Belgium and has subsidiaries in Dublin, Ireland and New York.
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