Clinical and Industry News II

Study Reports Increased Cardiovascular Risk from Mercury in Fish A study directed by a team of researchers at Johns Hopkins University weighed the cardiovascular benefit of docosahexaenoic acid (DHA) derived from fish consumption, as compared to the cardiovascular health risk posed by the mercury content in certain fish. Researchers found that, while high DHA levels were directly correlated with a lower risk for cardiovascular disease, high mercury levels were directly correlated with the risk of heart attack. Based on these findings, researchers concluded that, High mercury content may diminish the cardioprotective effect of fish intake. These findings follow a scientific statement issued by the American Heart Association (AHA) regarding the cardiovascular health benefit of omega-3 fatty acids, specifically DHA. The statement cautioned, however, that fish intake must be balanced with concerns about environmental pollutants because some species of fish may contain significant levels of methyl mercury, polychlorinated biphenyls (PCBs), dioxins, and other contaminants. Both the FDA and the Environmental Protection Agency have advised that children, pregnant women, women who may become pregnant and nursing mothers limit their intake of certain fish. In consideration of the health risks posed by such contaminants, the authors of the AHA statement concluded by stating, The availability of high-quality omega-3 fatty acid supplements, free of contaminants, is an important prerequisite to their extensive use. Major Clinical Studies Using Arixtra® (fondaparinux) Show Promise for Patients With Deep Vein Thrombosis The first evidence that outpatient treatment with the synthetic antithrombotic Arixtra* (fondaparinux) is at least as safe and effective as hospital-administered heparin to treat symptomatic venous thromboembolism (VTE) was presented on December 9 at the American Society of Hematology Annual Meeting. The treatment of VTE represents an annual cost of approximately $1.5 billion to the U.S. healthcare system. With more than 4,500 patients enrolled, the MATISSE trials comprise the broadest evaluation of VTE treatment ever designed to examine the efficacy and safety of outpatient treatment for patients with PE. In the MATISSE PE study, 2,213 patients presenting with a symptomatic PE were randomized in more than 200 centers in 20 countries. In this open label trial, patients were randomly assigned to receive either Arixtra 7.5 mg or a continuous dose- adjusted infusion of unfractionated heparin (UFH) for at least five days. The incidence of symptomatic recurrent VTE at day 90 was 3.8 percent (42 of 1,103 patients) in the Arixtra group and five percent (56 of 1,110 patients) in the unfractionated heparin group. The incidence of major bleeding (1.3 percent for Arixtra versus 1.1 percent for UFH) was low and comparable in both groups. There was no significant difference in total death at day 90. In the MATISSE DVT study, 2,205 patients with asymptomatic DVT and free of symptomatic PE were randomly assigned to receive either Arixtra 7.5 mg1 once daily or body-weight-adjusted low-molecular-weight heparin (LMWH-enoxaparin, 1mg/kg twice daily) for at least five days. The incidence of symptomatic recurrent VTE was 3.9 percent (43 of 1098 patients) in the Arixtra group and 4.1 percent (45 of 1107 patients) in the enoxaparin group. The incidence of major bleeding (1.1 percent for Arixtra versus 1.2 percent for enoxaparin) was low and comparable in both groups. There was no significant difference in total death at day 90. The double-blind study involved patients from 23 countries and 154 centers worldwide. Arixtra has recently been approved in both U.S. and Europe for the prevention of VTE in patients undergoing major orthopedic surgery of the lower limb such as hip fracture and major knee or hip replacement surgery. Caritas St. Elizabeth's Medical Center to Begin NIH Funded Gene Transfer Trial for Diabetic Neuropathy Caritas St. Elizabeth's Medical Center has begun enrolling patients in a trial to evaluate the safety and impact of VEGF (Vascular Endothelial Growth Factor) gene transfer on patients with diabetic neuropathy. The trial is being funded as part of a $10.2 million dollar grant awarded to Caritas St. Elizabeth's by the National Institutes of Health (NIH) to establish a Center of Excellence in Gene Therapy. Allan Ropper, MD, chief of Neurology and recipient of the Remondi chair in Neurology at Caritas St. Elizabeth's, is the principal investigator of the trial, and Douglas Losordo, MD, chief of Cardiovascular Research, is the principal investigator of the Program Project Grant. Caritas St. Elizabeth's expects to enroll 200 patients for this Phase I/II trial over the next four years. Last year, a preliminary study conducted at Caritas St. Elizabeth's indicated that a related problem called ischemic neuropathy is reversed using the gene transfer of VEGF. Some of the patients in the trial had diabetic neuropathy and they too were improved. Work in the laboratory in an experimental type of pure diabetic neuropathy treated with gene therapy also showed a great deal of improvement in nerve function and in blood flow to the nerves. In the preliminary study, VEGF was injected into a patient's critically ischemic limb. Seventeen patients, (19 limbs two patients had both legs treated) completed the study. Six months following treatment, an improvement in neurological symptoms was seen in more than 50 percent of the patients. Sixty-three percent of treated limbs showed improvement in neurologic symptoms such as severe pain and loss of sensation, and 53 percent of treated limbs showed improved nerve responsiveness. The $10.2 million dollar grant awarded to Caritas St. Elizabeth's by the NIH will also include a trial that will examine VEGF gene transfer to prevent coronary artery restenosis. The application of the gene is done in conjunction with angioplasty and the delivery of a stent for patients with narrowed coronary arteries. Caritas St. Elizabeth's pioneered the use of gene transfer in 1994 when the world's first clinical trials were conducted by Jeffrey Isner, MD, to treat patients with severe peripheral vascular disease. History was made again in 1998 when the procedure was used to treat patients who had low blood flow to certain areas of the heart due to coronary artery disease. Cooling Body Helps Cut Heart Attack Damage Catheter devices can quickly cool the bodies of heart attack victims from the inside out while they receive angioplasty, and this cooling may help reduce heart attack damage. The study is the first to report the use of cooling in people with heart attacks. Researchers at nine centers in the United States, Germany and Australia cooled 20 heart attack patients by inserting heat-exchange balloon catheter devices into the patients' inferior vena cava. Once a patient's body temperature was cooled to 33 degrees C (91.4 F) from the normal 37 degrees C (98.6 degrees F), doctors performed angioplasty, stenting or other conventional treatments. The patients who received the cooling treatment were compared to a control group of 21 heart attack patients who didn't receive the cooling treatment. Scans indicated heart muscle scar tissue seemed smaller on average in the cooled patients than in the control group. The trial design and small number of patients make it impossible to draw any definite conclusions about the effectiveness of this cooling. A larger trial is currently underway. Periodontal Disease Linked to Stroke Why should people who have periodontal disease and lose a lot of teeth be more likely to have a stroke? Kaumudi J. Joshipura, lead author of a new study finding the link, says she can't explain the relationship. It is still a mystery, says Joshipura, who is an associate professor of epidemiology at the Harvard School of Public Health and the Harvard School of Dental Medicine. We need more studies. It's true that the report, which used data on 41,380 men in the Health Professionals' Follow-Up Study, did find that participants with fewer teeth generally were older, drank more alcohol, were less physically active, and were more likely to smoke, all of which are risk factors for stroke. But those common risk factors aren't enough to explain the relationship, Joshipura says. Indeed, the analysis came up with one counterintuitive finding: The association between tooth loss and stroke was higher among nonsmokers than among smokers. Other studies have tended to find a similar association, but they have been controversial, Joshipura says. One strength of her study, Joshipura says, is that its population consisted largely of professionals (dentists, veterinarians, pharmacists, optometrists, and the like, most white, mostly male) who generally behave properly as far as health habits are concerned. All of them filled out health questionnaires that were mailed to them every two years. Over 12 years, there were 349 ischemic strokes, the kind that happen when a clot blocks an artery leading to the brain. Men who had fewer than 25 teeth when they entered the study were 57 percent more likely to have an ischemic stroke than those with more than 25 teeth. Breaking it down by numbers, the risk was 50 percent higher for men with 17 to 24 teeth, 74 percent higher for men with 11 to 16 teeth, and 66 percent higher for men with 10 or fewer teeth. The number of teeth lost during the 12-year study didn't have much of an effect on the risk of stroke perhaps because tooth loss tended to be minor, perhaps because it takes many years for the effect of tooth loss to impact stroke risk, Joshipura says. One hypothesis gaining attention is that the infection related to periodontal disease and tooth loss causes inflammation that injures the arteries, says Dr. Ralph L. Sacco, professor of neurology and epidemiology at Columbia Presbyterian Medical Center in New York City and a spokesman for the American Stroke Association. We have our own studies showing that tooth loss is related to carotid artery disease, Sacco says. Could chronic infection, periodontal disease being one of its manifestations, possibly be related to hardening of the arteries? That concept has led to growing attention to C-reactive protein, a marker of inflammation that studies have associated with heart disease, he says. At any rate, Sacco says, the relationship is another good reason to brush your teeth. Study Confirms Benefits of Lower Blood Pressure Lowering your blood pressure can pay off in significant reductions in your risk of strokes and heart attacks, regardless of your age and even if your readings are already in the normal range. So say British researchers who analyzed the link between blood pressure and cardiovascular death in a million adults. They found that during middle age every drop in systolic pressure (the top number) of 20 millimeters of mercury, and every 10 point decline in diastolic pressure (the lower figure) reduced the risk of deadly strokes, coronary artery disease, and other vascular problems by more than 50 percent. Somewhat surprisingly, lower blood pressure also helped the very elderly avoid cardiovascular deaths, though not by quite as much as in younger people. And the benefits weren't limited to people who brought their blood pressure down from unhealthy levels, according to the researchers. If the general population could all reduce their blood pressure by just a few millimeters of mercury, you could prevent about 10 percent of [fatal] strokes and 7 percent of deadly coronary artery disease, said Sarah Lewington, an Oxford University epidemiologist and a co-author of the study. An estimated one in four Americans has hypertension though a third don't know it, according to the American Heart Association. The condition, called the silent killer, is the leading changeable cause of stroke in the United States, raising the risk sevenfold compared with people with normal blood pressure. High blood pressure is also a main source of kidney problems, which affect 8 million people in this country. Lewington and her colleagues analyzed 61 previous studies of blood pressure and cardiovascular disease, which together included 1 million people. Of the 120,000 who died during the nearly 13 years of follow-up, 56,000 suffered fatal strokes, cases of deadly coronary artery disease, and other vascular mortality. Another 66,000 died of causes unrelated to the heart or vessels. The researchers saw a protective effect of lower blood pressure until it hit about 115/75 mmHg, a low but fairly common reading. This study confirms what prior studies have been telling us for a long time, but in a much more powerful way, said Dr. Donald Lloyd-Jones, a researcher on the Framingham Heart Study and a cardiologist at Massachusetts General Hospital in Boston. It is always better as long as it's not too low to have a lower blood pressure than a higher blood pressure in terms of your risk for cardiovascular disease. Esperion Initiates Multiple-Dose LUV (ETC-588) Phase II Clinical Trial in Patients with Acute Coronary Syndromes Esperion Therapeutics, Inc., a biopharmaceutical company focused on discovering and developing HDL-targeted therapies, announced the initiation of a multiple-dose, multi-center Phase II clinical trial of its LUV (large unilamellar vesicles) product candidate (ETC-588). ETC-588 is one of the Company's investigational therapies in development for the treatment of patients with Acute Coronary Syndromes (ACS). The randomized, double-blind, placebo-controlled study will evaluate ETC-588 at two dose levels. ETC-588 will be administered to patients in intravenous infusions once-weekly over an eight-week period. The primary objective of this Phase II trial is to determine the safety and tolerability of ETC-588 in patients with ACS. In addition, as part of adverse event monitoring, cardiovascular event data will be collected. Previous clinical studies indicate ETC-588 rapidly mobilizes cholesterol. Another Phase II study of ETC-588 is continuing to enroll patients with established vascular disease to measure changes in carotid plaque volume. Results are expected in 2003. ETC-588 is made of naturally occurring lipids that circulate through arteries to facilitate the role of high-density lipoprotein (HDL) in removing accumulated cholesterol and other lipids from cells including those in the arterial wall. LUV are believed to be capable of transporting excess cholesterol from the vasculature to the liver for eventual elimination as part of the reverse lipid transport (RLT) pathway. Third party preclinical studies with LUV have demonstrated regression of atherosclerosis. Esperion is currently developing ETC-588 as a treatment for patients with high risk atherosclerosis, including acute coronary syndromes. White Wine Lovers Get Taste of Health If you're a confirmed white wine drinker but want all the health benefits that red has to offer, French scientists may have just the tipple. They have developed a wine called Paradoxe Blanc that is rich in polyphenols which may help to prevent heart disease. Polyphenols are concentrated in the skin of grapes, and it's mostly the way red wine is made that gives it a higher polyphenol content. Pierre-Louis Teissedre and a team of scientists at the University of Montpellier in France used white grapes containing plenty of polyphenols and altered the wine making process to produce a white with all the reported benefits of red wine. Polyphenols are antioxidants which destroy harmful substances called free radicals that can cause cancer. They may also help to keep arteries clear and reduce heart disease. Paradoxe Blanc, a pun on the so-called French paradox of low heart disease in a country whose people enjoy a rich diet, was originally developed for people with Type 1 diabetes whose bodies cannot destroy free radicals efficiently. Tests of the wine suggest a glass or two a day restores antioxidant levels in diabetics, but the team has yet to show that their wine keeps arteries clear of fat deposits and thus reduces the chances of heart attack or strokes. Although the benefits of a glass or two of red wine a day have been well documented, medical experts now say that equal amounts of other alcoholic drinks are just as good. Statins Improve Heart Transplant Survival Giving heart transplant recipients a cholesterol-lowering statin drug greatly improves their chances of long-term survival, German cardiologists report. The eight-year survival rate for transplant patients who were given simvastatin, marketed in the United States as Zocor, was 88.6 percent, or 31 of 35 patients, compared to 59.5 percent, or 22 of 37 patients who got standard medical treatment, says a report by the heart transplant team at the Munich-Bogenhausen hospital. The study was originally planned to run eight years, but the difference in survival, and in the condition of the patients' arteries, was so clear that they all were given simvastatin after four years, the report says. In particular, the statin treatment prevented transplant vasculopathy. It also reduced the incidence of transplant rejection episodes that were severe enough to be life-threatening or fatal. The transplant arteriopathies that a lot of people develop is recognized as a different disease than standard coronary artery disease, says Dr. Daniel J. Rader, director of preventive cardiology at the University of Pennsylvania School of Medicine. We know that reducing blood cholesterol reduces the risk of heart disease, but we have not had the same reason to believe it reduces the risk of transplant arteriopathy. This is one of the first studies to suggest that it does. The German study provides convincing evidence for a practice that has become common in most American heart transplant centers, says Dr. Sean Pinney, an attending cardiologist in the Columbia-Presbyterian Medical Center in New York City and a member of the center's heart transplant team. All the patients in our center and in other centers are treated with statins, Pinney says. The interesting thing is that this study started eight years ago, before a consensus emerged on the use of statins. What it does is provide more supportive information about the use of statins in heart transplant patients, reinforcing their role in preventing artery disease. The consistent and effective lowering of cholesterol levels played a decisive role, the report says. However, Dr. Edward M. Geltman, professor of medicine at Washington University in St. Louis and director of the heart failure program at Barnes Jewish Hospital there, says the reduction in severe rejection episodes could also be important. By themselves, statins are not known to have any effect on the immune system. That might change in the presence of cyclosporine A, which is given to transplant patients to prevent the immune system from reacting against the transplanted tissue, Geltman says. Our assumption is that the way it works is not entirely by lowering cholesterol but by reducing the number of inflammatory episodes, he says. It could be due to the way the liver detoxifies cyclosporine, a metabolic pathway in which there is an interaction with the statin. That has been shown for two different statins, simvastatin and pravastatin. Whatever the reason, the high survival rate in the German study is outstanding, way beyond the U.S. national average, Geltman says. And statin treatment is remarkably safe, with no significant side effects, he adds. Bacchus Vascular's Trellis Reserve Isolated Thrombolysis System Receives FDA 510k Clearance Bacchus Vascular announced that it has been granted 510(k) clearance from the U.S. Food and Drug Administration (FDA) to market its Trellis Reserve System with Integral Aspiration (IA) Technology. The Trellis Infusion Catheter is a minimally invasive system designed to facilitate the delivery of physician-specified agents, including thrombolytics (clot-dissolving drugs), into the peripheral vasculature (the arteries and veins in upper and lower limbs) and evacuation of treated area. This technology is based upon the Company's percutaneous isolated accelerated lysis platform and does not require capital equipment. Arizona Heart Institute's Dr. Venkatesh Ramaiah stated that the Trellis Reserve with IA Technology is the only device with an integral embolic protection system and the ability to isolate thrombolytic infusion in combination with mechanical thrombus dissolution. Advantages of the Trellis system include isolation of the occluded segment, prevention of proximal or distal thrombus embolization, avoidance of systemic release of the thrombolytic agent, rapid revascularization of the treated limb, decreasing or completely eliminating the need for ICU stay, and early identification and treatment of the culprit lesion with PTA and stenting. Worldwide, over 200 patients have been treated with the Trellis Catheter with no major reported bleeding complications. The Trellis Reserve System allows a physician to aspirate within the 6 French Trellis catheter, thereby minimizing the need for a coaxial sheath. As Dr. Thomas J. Fogarty commented, The Trellis System works with any thrombolytic on the U.S. market and requires less than 20% of the standard catheter-directed thrombolysis (CDT) dosage. The minimal amount of thrombolytic that the Trellis system requires for its safe and efficacious clot removal, translates into a safer method of delivering thrombolytics into the vasculature. By administering significantly lower amounts of thrombolytics, isolating the treatment area, and aspirating the infused area, may allow physicians to use it in patients that are contra-indicated for systemic thrombolytic agents. This shows a major improvement over catheter-directed thrombolysis procedures that have a reported bleeding complication rate of 5-15%, which includes cerebral hemorrhage. The Trellis is an enabling technology that significantly increases the number of patients with limb ischemia and DVT that can be treated with thrombolytic drugs. The Trellis technology is based upon patented, isolated, accelerated lysis technology, which facilitates extremely efficient, localized mixing of infused fluids. Gebauer’s Ethyl Chloride® Pain-Ease® Topical Anesthetic Takes the Sting Out of Venipuncture and IV Procedures No matter what the pain tolerance level of your patient, you can make them more comfortable during venipuncture and IV procedures by spraying the affected area with a topical skin refrigerant such as Gebauer’s Ethyl Chloride® Pain-Ease®. Spray as directed to desensitize the affected area immediately prior to the procedure. Then quickly swab the target area with an antiseptic and perform the procedure. Cans come in either a mist or stream application, or in the familiar brown bottle. Pain-Ease can be used prior to minor surgical procedures and injections, as well as before venipuncture and IVs. For more information, including clinical evaluations, product and prescribing information, or to find a local distributor, visit the Gebauer Company web site at www.gebauerco.com or (800) 321-9348.

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