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Clinical and Industry News II

Long-Term: Abciximab & Tirofiban Similar A recent study clarifies the differences between tirofiban and abciximab. This study looked at outcomes for 4,809 people six months after they had coronary-artery angioplasty with stent placement. They found that 14.8 percent of the people who took tirofiban died, had a heart attack or had repeat surgery within those six months, compared to 14.3 percent of the people who took abciximab. The study concludes that both drugs are similar in terms of preventing these long-term events. An earlier study by the same researchers showed that abciximab was significantly better than tirofiban at preventing death, heart attacks and repeat surgery within 30 days after people had angioplasty for narrowed coronary arteries. As studied, abciximab was more protective against a heart attack occurring during, or immediately following angioplasty. Yet the two drugs were associated with similarly low rates of death and renarrowing of the heart's arteries at six months. Our conclusion is that, while the more expensive drug (abciximab) is better 'up front', it provides little long-term advantage compared with tirofiban, says the study's lead author, Dr. David Moliterno of the Cleveland Clinic Foundation. Genzyme Biosurgery Forges Cardiac Cell Therapy Collaboration Genzyme Biosurgery, a division of Genzyme Corp., will collaborate with the French biotechnology company Myosix SA to further develop a clinical program in the use of cell therapy to treat heart disease. The program is focused on blocking the progression from a heart attack to heart failure. The companies plan to launch a global multi-center Phase 2 clinical trial later this year examining the effectiveness of autologous cell therapy to restore function in areas of the heart damaged by a heart attack. As currently proposed, the Phase 2 clinical trial will involve multiple sites and hundreds of patients in Europe, and will be partly funded by Assistance Publique Hopitaux de Paris. It follows the completion last year of a nine-patient Phase 1 safety trial led by Principal Investigator Philippe Menasche, MD, PhD, of Hopital Bichat in Paris, the largest such trial ever completed. Dr. Menasche, who will be the principal investigator for the upcoming trial, presented positive data from the Phase 1 study at the 2001 American Heart Association annual meeting. The cell therapy program developed by Myosix and Dr. Menasche is based on the principle that by stopping or reversing the damage done to heart muscle during a heart attack, doctors may be able to halt the patient's likely progression to congestive heart failure. The planned Phase 2 clinical trial will involve harvesting a patient’s own skeletal muscle cells through a small biopsy in the leg, multiplying the cells many-fold using proprietary cell-culture techniques in the laboratory, and injecting them into the heart during a coronary artery bypass operation. This approach has shown promise in Phase 1 and pre-clinical studies in restoring muscle mass and function in tissue damaged during a heart attack. Our Phase 1 trial showed that cell therapy has the potential to heal damaged heart muscle, a result that could have a tremendous impact on patient care if it is borne out by well-controlled clinical studies, said Dr. Menasche. Dr. Menasche has already received approval for a Phase II clinical trial protocol from French regulatory authorities. Company officials and Assistance Publique have agreed to enlarge the scope of the trial to include hundreds of patients and multiple clinical trial sites, and they are in discussions with French regulatory authorities about these changes. Genzyme Biosurgery is also in discussions with the U.S. FDA regarding implementation of this study in the United States. Acunav® Diagnostic Ultrasound Catheter from Siemens Eliminates Radiation During Closure of Pregnant Women’s ASD For the first time, use of the AcuNav® diagnostic ultrasound catheter from Acuson, a Siemens Company, eliminated the need of fluoroscopy during a minimally invasive surgical procedure on a 21-year-old pregnant woman. The AcuNav catheter, a tool that brings the full performance of diagnostic ultrasound into the heart, was the only visualization device used during closure of the patient’s Atrial Septal Defect (ASD). At the Ochsner Clinic Foundation in New Orleans, J. Stephen Jenkins, MD, FACC, FSCAI, performed the potentially life-saving ASD closure procedure on the pregnant patient at six months gestation. The need for fluoroscopy has potentially been reduced because of the AcuNav catheter’s ability to provide detailed information about target cardiac structures and other devices located within the heart. Our patient was 21 years old, 24 weeks gestation and had been experiencing symptoms of heart failure, Dr. Jenkins said. We needed to close her large ASD, as she had had a previous miscarriage which may have resulted from this defect and her symptoms were progressing. We also had to consider the safety concerns with respect to the fetus. Our option to use fluoroscopy was not good considering the possibility of birth defects, so we opted to perform closure of the ASD using the AcuNav catheter as our sole visualization tool without turning on the fluoroscopy unit. This catheter is a significant step forward in the transcatheter closure of ASD and Patent Foraemen Ovale (PFO) due to the potential to eliminate fluoroscopy, Transesophageal Imaging (TEE), and the use of general anesthesia, Dr. Jenkins added. The AcuNav catheter may aid in the diagnosis and treatment management of the tens of millions of American suffering from heart disease and irregular heart rhythms. Electrophysiologists who use the catheter have reported that the breakthrough technology allows them the ability to conduct procedures they were previously unable to do, by enabling them to image the heart from within. Additionally, a University of Chicago study reported that the AcuNav catheter successfully guided minimally invasive surgical closure of holes in the heart, like the ASD closure procedure performed at the Ochsner Clinic Foundation, and PFO, a possible cause of embolic strokes. The results of the study demonstrated how the diagnostic ultrasound catheter could eliminate TEE, general anesthesia and intubation during ASD/PFO closure procedures in children and adults. The company also announced that New York Presbyterian Hospital Cornell University Medical Center is the 100th customer to receive shipment of the AcuNav catheters for use on its Sequoia® echocardiography platform. According to Bruce Lerman, MD, FACC, Chief, Division of Cardiology and director, Cardiac Electrophysiology Laboratory at the New York Hospital Cornell University Medical Center, The AcuNav has changed the way we identify anatomy and physiology within the heart by enabling us to accurately deploy catheters in the proximal pulmonary veins for the purpose of ablating the triggering sites of atrial fibrillation. Furthermore, with the AcuNav catheter, we can determine flow in the pulmonary veins before, during and after ablations, and thereby, obtain pertinent information regarding the potential development of pulmonary vein stenosis. The AcuNav catheter is available on the Sequoia echocardiography system, the Aspen echocardiography system and the Cypress® echocardiography system. Inceptio Medical Receives FDA Approval for PunctSURE® Vascular Access Imaging System Inceptio Medical Technologies, LC, specializing in the development of ultrasonic vascular access imaging products and technologies, has received approval from the Food and Drug Administration (FDA) to market PunctSURE, the company's new ultrasonic vascular imaging system. Designed to help anesthesiologists and cardiologists visually locate and identify veins and arteries for precise needle placement, the PunctSURE system provides real-time procedure monitoring and visualization combined with hands-free operation. That is, once the setup is complete, the clinician can use both hands to perform vessel cannulations with clear views of the blood vessels on the PunctSURE dual-view imaging monitor. With PunctSURE, the setup and imaging process normally requires no more than 60 to 90 seconds. Components of the system secure the imaging transducer to the patient’s skin, allowing the clinician to perform vessel cannulation procedures with both hands. For inquiries and further information, contact Inceptio Medical Technologies at (801) 593-6300 or CVT-3146 Phase II Trial Results Support CV Therapeutics’ Advance Into Phase III Program CV Therapeutics, Inc. plans to advance CVT-3146 into a pivotal Phase III clinical trial, which the company intends to commence in 2003. CVT-3146 is a selective A2A adenosine receptor agonist being jointly developed with Fujisawa Healthcare, Inc. (FHI) for potential use as a pharmacologic stress agent in cardiac perfusion imaging studies. Data from an open label Phase II trial of CVT-3146 demonstrated that an intravenous bolus of CVT-3146 produced a dose-dependent increase in coronary blood flow velocity. The magnitude and duration of the increase in coronary blood flow velocity seen following administration of CVT-3146 in this trial achieved CV Therapeutics' target profile for potential use as a pharmacologic stress agent in cardiac perfusion imaging studies. The most common adverse events which may be drug-related were flushing and dyspnea. More detailed results of this study will be presented at upcoming scientific meetings. In 1999, approximately 6.5 million cardiac perfusion imaging studies were performed in the U.S. Many patients exercise on a treadmill to generate the increase in coronary blood flow necessary to perform a cardiac perfusion imaging test. However, more than a third of patients undergoing a cardiac perfusion imaging test are unable to exercise adequately because of medical conditions such as peripheral vascular disease or arthritis. For these patients, a pharmacologic agent that temporarily increases coronary blood flow is used to mimic the increase in blood flow caused by exercise. CVT-3146 is being studied for potential use as a pharmacologic agent under these circumstances. CVT-3146 has not been approved for marketing by the U.S. FDA or other foreign agencies. CVT-3146 presently is being investigated in clinical trials subject to a United States IND and applicable foreign authority submissions. CV Therapeutics has not yet submitted a new drug application to the FDA or equivalent application to any other foreign regulatory authorities for CVT-3146 and has not yet been determined CVT-3146 to be safe or effective in humans for its intended use. Update on the Sitaxsentan Phase IIb/III Pulmonary Arterial Hypertension Trial ICOS-Texas Biotechnology LP, a partnership between ICOS Corporation and Texas Biotechnology Corporation announced that patient enrollment has been completed in the Sitaxsentan To Relieve ImpaireD Exercise in Pulmonary Arterial Hypertension (STRIDE) Phase IIb/III clinical trial. Sitaxsentan is a small molecule that antagonizes the action of endothelin, which is a potent mediator of blood vessel constriction and of the growth of smooth muscle in vascular walls. Endothelin receptor antagonists are believed to be effective in the treatment of a variety of diseases where the regulation of vascular constriction and muscle tone is important. Sitaxsentan is selective in the targeting of the endothelin A receptor. Initial safety and efficacy results for this 12-week double-blind, placebo controlled trial, comparing two once a day dose levels, 100 mg and 300 mg, of sitaxsentan with placebo, are expected to be available in the second half of 2002. Patients completing the 12-week safety and efficacy trial have been eligible to enroll in an extension trial for the purpose of obtaining long-term safety data. Because the 12-week safety and efficacy trial is still ongoing and the results are blinded, ICOS and Texas Biotechnology do not know the risk/benefit profile of sitaxsentan at this time. As seen previously with sitaxsentan and other endothelin receptor antagonists, liver function abnormalities have been observed in both the pivotal 12-week safety and efficacy trial (STRIDE) and the long-term extension trial. All liver injury in the current trials has been reversible. Until ICOS and Texas Biotechnology LP have established the efficacy and safety profile of sitaxsentan from the ongoing pivotal trial, in order to be cautious, the Partnership has decided to conclude the extension trial. This decision does not impact the ongoing Phase IIb/III STRIDE trial conduct or results. Once the safety and efficacy results of that study are unblinded, additional consideration can be given to the appropriate doses for the purpose of assessing long-term safety. Heart Attack Culprit May Spell Further Trouble A look inside the arteries of people who have had heart attacks shows that many of them are highly vulnerable to more of the same kind of trouble. French researchers report the new finding, which presents both an opportunity and a challenge to cardiologists. American experts explain that the door could be opened to new ways of preventing further trouble, but the technology that would make such treatment possible doesn't exist and it's not clear what treatments would help. Intravascular ultrasound was used by physicians at the Hospices Civils de Lyon to get three-dimensional views of the three major coronary arteries of 24 patients in the month after they had heart attacks. They found that 80 percent of them had a number of the same sort of lesions that first caused the heart attacks scattered throughout those arteries. The report adds to a growing body of evidence that inflammation plays an important role in heart disease. A heart attack is not just a problem in itself, but also a sign of overall coronary instability, which the French call pancoronarteritis and Americans call acute coronary syndrome, says Dr. Gilles Rioufol, an associate professor in the hemodynamics department at the hospital who led the study. The fact that we discovered multiple ruptured plaques means that probably the pancoronarteritis process exists, and so to treat only the simple lesion is not enough, he says. It is an argument to treat and check inflammation in patients. The diagnosis of vulnerable lesions before rupture would have tremendous potential for even prevention, say cardiologists at the Cleveland Clinic. However, a more usable test than the intravascular ultrasound used in the French study is needed. What this study demonstrates is what we have been thinking for a long time, says Dr. E. Murat Tuzcu, director of intravascular ultrasound at the Cleveland Clinic. When a heart attack patient comes to the hospital, generally you find that one site in a blood vessel suffers severe narrowing created by a plaque that has ruptured. For many years we have been convinced that there are a number of similar sites in the arteries. The implication is that acute coronary syndrome is a systemic disease of the arteries. The ideal would be to find and treat the other unstable plaques before they rupture. That would require easy detection of those plaques. It would be nice if we had a relatively simple tool that we could put into a coronary artery or, better yet, some way to look into the coronary arteries, find the other plaques and treat them accordingly, Tuzcu says. Unfortunately, what we have not is not ready for prime time. But as different methodologies improve, then maybe we will be able to identify and treat the unstable plaques. Treatment of unstable plaque is equally or more challenging, they say. Maybe existing drugs, such as beta blockers, calcium channel blockers or cholesterol-lowering statins might help, Rioufol says. Drugs designed to stabilize plaque could also be used, the Cleveland cardiologists say, but they can have damaging side effects. Using stents to seal off the unstable plaques might be possible, but there is no clinical experience in favor of such a treatment. At the moment, it's best to stick with the drugs that are known to be effective against heart disease, they say. There are also difficulties in putting the findings of this small study to use on a large scale. There is presently no diagnostic tool that could guide the operator to those lesions that are at high risk to cause acute coronary events, researchers note. Even if such a targeted approach would be safe and effective, it would leave many other sites unprotected and the benefit from treating an individual lesion may be small. The big point, Rioufol says, is that a heart attack now can be seen as just one aspect of a condition that affects the entire arterial system. It is important to diagnose it, and understanding it helps to treat it, he says. Clot-Busting Protein May Lead to Clogged Arteries A protein that is commonly used as a clot-busting drug may worsen atherosclerosis if it is supplied in large quantities through gene therapy, the results of a new study suggest. Because the protein, urokinase-type plasminogen activator, works by thinning blood, a potential side effect is excessive bleeding in other areas of the body. Researchers have previously discovered that they could use gene therapy to induce the body to produce excess amounts of the protein only at the location of the thickened arteries. This targets the blood-thinning effects without the risk of bleeding elsewhere. In the current study, researchers sought to discover if there were any adverse effects of this gene therapy approach. Using rabbits as subjects, the investigators found that high levels of urokinase can actually lead to thickened blood vessels, according to researcher Dr. David Dichek, a professor of medicine and associate director for research in the division of cardiology at the University of Washington School of Medicine in Seattle. We were interested in engineering blood vessels so they wouldn't form blood clots inside them, Dichek said. Our approach was to get the blood vessels to express larger quantities of a molecule that would prevent or dissolve blood clots. Dichek and his colleagues started by cloning the gene for urokinase in rabbits and then used a virus to carry the gene into rabbit arteries. The rabbits were fed a special high-cholesterol diet, which presumably would make them more likely to develop clogged arteries. A second group of rabbits received an inactive placebo injection and were also fed an artery-clogging diet. The researchers then checked the rabbits' arteries every week for 4 weeks after the gene was injected. Even after one week the results were surprising, Dichek said, noting that rabbits in the genetically-engineered group had narrowed arteries. Scientists have noticed that arteries tend to narrow in the early stages of atherosclerosis, Dichek said. During the second week of the study, there were no major differences between the normal rabbits and those with higher levels of urokinase. But between the third and fourth weeks, the researchers noticed that inner linings of the arteries of the genetically-engineered rabbits were starting to thicken. Ultimately, the study showed that gene therapy with urokinase would be a poor choice for patients with clogged arteries, Dichek said. Still, the results may help researchers better understand the processes that lead to atherosclerosis, he added. Other studies have shown that patients with clogged arteries have higher levels of urokinase in their blood vessels, Dichek said. This study shows that the protein may be part of the cause of atherosclerosis rather than the result of the disease. I think gene therapy has gotten a bit of bad press, Dichek said. This is an example of where, if you proceed slowly and carefully, you can gain useful information even if the results are negative. They may help you better understand the disease you are treating. Finnish Study Links Pollution with Heart Disease Air pollution worsens heart disease by cutting off circulation to the heart, Finnish researchers reported in a study that helps explain why polluted environments aggravate not only asthma but heart conditions. The U.S. Environmental Protection Agency estimates that 60,000 people a year die in the United States alone from particulate air pollution the kind caused when small particles of smoke pervade the air. Dr. Juha Pekkanen of the National Public Health Institute in Kuopio, Finland, and colleagues looked specifically at pollution coming from factory smokestacks and the tailpipes of some diesel-powered buses and trucks. The researchers said they could measure clear changes in oxygen supply to the heart using electrocardiograms (ECG). They studied 45 heart disease patients, nearly half of them women, all living within an area in Helsinki where air pollution could be easily measured. The pollution may either be helping clumps of plaque break off or it could be causing dangerous heart rhythms, or both, the researchers said. Heart rate also increased after exposure to pollution from an average of 61 beats per minute to 90. Dr. Murray Mittleman, director of cardiovascular epidemiology at Harvard University and Beth Israel Deaconess Medical Center in Boston, and colleagues cited studies that showed health risks from particle-containing air pollution were notable not only in the expected cities, such as Los Angeles and Houston, but in cities that are considered to have relatively clean air, such as Boston, Seattle and Minneapolis. Mittleman also noted a number of holes in the study. The original study was supposed to include volunteers in Germany and the Netherlands, but not enough of those patients had enough measurable ischemia to be used in the study.