Clinical and Industry News

High-dose Statin Therapy Outperforms Typical Care Study compares aggressive cholesterol-lowering to usual treatment in real-world settings Patients treated with high doses of atorvastatin had about a one percent lower annual rate of heart attacks than similar patients receiving usual care, according to a new study. The real world concept is the unique feature of the study, said Michael J. Koren, MD, FACC, at the Jacksonville Center for Clinical Research in Jacksonville, Fla. Most of the work in the study was not done at the research centers; it occurred in managed care organizations, so we got a true reflection of what's happening in the community, rather than a reflection of what clinical trial centers are capable of doing for patients. At the end of the day, we found that when doctors use the aggressive cholesterol-lowering approach in a real-world setting, there is a significant reduction of cardiovascular events compared to when doctors follow less aggressive practices, Dr. Koren said. A total of 2,442 coronary heart disease patients with high cholesterol were randomized to either an aggressive treatment arm using atorvastatin (Lipitor) or usual care. They were followed for 51.5 months on average. Patients in the atorvastatin group were treated with increasing doses of the drug until their LDL cholesterol levels dropped below 80 milligrams per deciliter or until they reached the maximum dose of 80 milligrams per day of atorvastatin. Common starting doses of atorvastatin range from 10 milligrams to 40 milligrams a day. During the study period averaging just over four years, 4.3 percent of patients in the atorvastatin group suffered a nonfatal heart attack compared to 7.7 percent of the patients in the usual care group. This difference in heart attacks accounted for most of the 4 percent difference in primary outcomes between the two groups (23.7 percent of atorvastatin patients vs. 27.7 percent of those receiving usual care). Dr. Koren said a larger group or a longer study period would have been needed to detect mortality differences. There was a strong trend toward fewer cardiac deaths in the aggressively treated patients though this component of the improvement in overall outcomes, 43 deaths in the aggressively treated group versus 61 cardiac deaths in the usual care group, fell slightly outside of a statistically significant range, Dr. Koren said. Dr. Koren highlighted the point that this study was not a comparison of drug treatment to placebo. He noted that the advantage observed in the atorvastatin group was on top of any benefits achieved through usual care, including medications, diet and other lifestyle changes. Indeed about two-thirds of the participants were already taking some cholesterol-lowering medication at the time they entered this study. There was no statistically significant difference in reported side effects. We saw a big benefit overall for people who were treated aggressively. If you look at all the parameters, there was a 17 percent improvement, but more significantly, if you look at the worst events, there was a 47 percent reduction in those events in patients who were treated aggressively, Dr. Koren said. And there was no difference between the two groups in severe myalgias, hospitalizations for side effects or other safety parameters we evaluated. We are not saying that no one gets side effects with these drugs. What we are saying is that when you use these drugs aggressively, the average person in a real-world setting is going to do better overall. Dr. Koren said the biggest problem the study encountered was the turmoil in the health care market. As managed care companies failed or merged, the researchers were unable to access some details of participants’ medical records. Nevertheless, he said the study has profound implications for treating cholesterol levels in these patients. Doctors need to approach all of their atherosclerosis patients with a plan, meaning that when they come to you, you should have a very specific goal, and you should have a complete commitment to reaching that goal for that patient, Dr. Koren said. Funding for this study was provided by Parke-Davis and then Pfizer Pharmaceuticals, the manufacturers of atorvastatin. Dr. Koren said he was involved in all aspects of the study design and execution and that the authors had the final word in the preparation of their article. David T. Nash, MD, at the State University of New York Health Science Center in Syracuse, NY, who also was not part of this research team, said that while the study shows the benefits of statin treatment, it does not highlight other non-drug approaches that may produce similar benefits. This is a good study. Nevertheless, we await the results of the Treating to New Targets (TNT) trial for confirmation that lower is better. In addition, it is important to note that the study revealed that there was no mortality benefit for those in the aggressive treatment group. Also, the researchers could have spent some of the money giving people a lower dose of atorvastatin and having everyone see a fitness trainer every three months and a dietician four times a year, Dr. Nash said. So we have here roughly one patient in 25 over four years, or one percent per year, that gets a benefit. In other words you have to treat 100 people to see one benefit. I'm not against that, and given the choice I would take the pill, but I think you have to understand that you don't have to take the pill the way the authors describe, Dr. Nash added. If you just drank orange juice and ate almonds, not tough to comply with, you would get the same difference. Medtronic Launches 3rd Phase of Carotid Stenting Trial Medtronic, Inc. announced that the first patient was enrolled in the MAVErIC III Clinical Trial the third in a series of studies. The first patient implant in the trial was conducted by Robert Molnar, MD, at McLaren Regional Medical Center in Flint, Michigan. Dr. Molnar is a member of the Michigan Vascular Center. The MAVErIC III study will gather data for submission to U.S. regulatory authorities to evaluate the safety and efficacy of the Medtronic Interceptor® Plus Carotid Filter System with the Medtronic Exponent® Self-Expanding Carotid Stent System for the treatment of carotid stenosis. MAVErIC III will include 413 high-risk patients at 35 investigational sites in North America. Principal investigators for the trial are Randall T. Higashida, MD of the University of California, San Francisco, and Stephen R. Ramee, MD, Ochsner Foundation Hospital, New Orleans, LA. The MAVErIC III trial will primarily test the combination of the Exponent Self-Expanding Carotid Stent with the Interceptor Plus Carotid Filter System. The cone-shaped Interceptor Plus carotid filter is manufactured from braided strands of nitinol designed to fit and conform snugly against vessel walls, then collapse and hold particulate debris while the filter system is withdrawn from the body. The MAVErIC (Evaluation of the Medtronic AVE Self-Expanding Carotid Stent System in the Treatment of Carotid Stenosis) Clinical Trials are a series of trials designed to gather data to support worldwide product approvals for Medtronic's Exponent Self-Expanding Carotid Stent System, the GuardWire® Balloon Occlusion and Aspiration System and the Interceptor Plus Carotid Filter Occlusion System. The MAVErIC I Clinical Trial was a 99-patient feasibility study designed to demonstrate the safety of the Exponent Self-Expanding Carotid Stent with the GuardWire Balloon Occlusion and Aspiration System for the treatment of carotid stenosis. At one year, the study found a Major Adverse Event (MAE) rate of 5.1 percent. MAE includes any stroke, myocardial infarction (MI) and/or death. The MAVErIC I study completed enrollment in December 2002 and was performed at 16 centers in the United States. The MAVErIC II Clinical Trial was a 399-patient pivotal trial designed to study the safety and efficacy of the Self-Expanding Exponent Carotid Stent with the GuardWire Balloon Occlusion and Aspiration System for the treatment of carotid stenosis. The preliminary 30-day results showed a Major Adverse Event (MAE) rate of 5.3 percent. The MAVErIC II Clinical Trial completed enrollment at 34 centers in the United States in August 2003. The Medtronic Exponent Self-Expanding (Over-the-Wire) Carotid Stent System and the Medtronic Interceptor PLUS Carotid Filter System are investigational devices and are not available for commercial distribution in the United States. The GuardWire Balloon Occlusion and Aspiration System for use in carotid stenting procedures is an investigational device in the U.S. The GuardWire Balloon Occlusion and Aspiration System is available in the U.S. for use with diseased saphenous vein graphs. The Exponent Self-Expanding (Rapid Exchange) Carotid Stent System, the Interceptor PLUS Carotid Filter System, and the GuardWire Balloon Occlusion and Aspiration System have received CE Mark and are approved for use outside the United States. MedClose Arterial Closure Device Passes GLP Testing Simpler single-user design confirms excellent hemostasis/healing Biomed Research, Inc. reported successful completion of Good Laboratory Practices (GLP) animal testing of the refined MedClose Internal Puncture Closure Device. The MedClose is a proprietary catheter-based system that uses Tissee® VH Fibrin Sealant to rapidly seal arterial puncture sites following angiography and angioplasty. MedClose is not presently available for human use. The Company previously reported completion of engineering refinements that were identified during testing of an earlier MedClose design. While the earlier design demonstrated that the MedClose system resulted in rapid hemostasis and excellent healing, the ergonomics of the device did not meet the expectations of a cardiologist focus group. The refined device addresses the user interface issues of the focus group, resulting in a product that is easily administered by a single operator, and provides excellent tactile feedback, re: vessel wall capture. The simplified, re-designed MedClose also improves efficiency of the tissue factor / biological glue mixing feature, and adds a fixed guidewire to ensure centering of the intra-lumenal balloon within the femoral artery. The GLP animal testing demonstrated that MedClose results in hemostasis 78% faster (Avg. 24 sec) than manual compression, and rapid ambulation without re-bleeding or oozing. Angiography showed widely patent arteries in all animals with no embolization in the toes. Histopathology confirmed earlier findings of excellent healing associated with Tisseel. Gross examination revealed no nodes or bumps on the artery to indicate where it had been catheterized, while exam under dissecting microscope showed healing so complete in some cases that it was not possible to identify the access site on the adventitia or within the lumen. This finding suggests that the same vessel location may be re-accessed after closure with MedClose. With the successful completion of GLP testing, the Company intends to produce approximately 800 MedClose units for use in human studies, and to submit an application (IDE) to the Food and Drug Administration to begin a clinical trial. Study Questions Safety of Heart Procedures at Hospitals Without Cardiac Surgery Programs Rekindling a debate on the safety of performing angioplasty in hospitals that do not have onsite cardiac surgery programs, a study led by Dartmouth Medical School (DMS) concluded that patients who undergo the procedure in hospitals without cardiac surgeons have a higher rate of mortality than those in hospitals with a cardiac surgery program. The study investigates the outcomes of over 600,000 Medicare enrollees who underwent a percutaneous coronary intervention (PCI) at a US acute care facility between 1999 and 2001. It concluded that patients who underwent PCI at a hospital without a cardiac surgeon onsite had a 29% overall increased risk of mortality compared to those who had the procedure in a hospital with surgical backup. In the U.S., hospitals with cath labs but without cardiac surgery on location are rapidly developing PCI programs in hopes of improving patient care and remaining competitive. Our findings suggest that the current ‘wave’ to move PCIs into hospitals that don't have coronary artery bypass surgery programs should be questioned, said Dr. David Wennberg, adjunct associate professor of community and family medicine and of medicine at DMS. Headed by Dr. David Malenka, associate professor of medicine and a cardiologist at Dartmouth-Hitchcock Medical Center, the study used data from a total of 178 hospitals that performed PCIs without onsite cardiac surgery and 943 hospitals that performed PCIs with onsite cardiac surgery. Patients undergoing PCIs in hospitals without cardiac surgery were more likely to die, authors wrote in the article, which appeared in the Journal of the American Medical Association. PCIs in hospitals without cardiac surgery backup are often performed for reasons other than immediate treatment of a myocardial infarction and are associated with a higher risk of adverse outcomes, the study found. Most of the current clinical and policy debate about where PCIs should be performed surrounds treatment of acute myocardial infarction (AMI) so we were surprised that the majority of cases performed in centers without coronary artery bypass surgical programs were performed for indications other than acute treatment of an acute myocardial infarction, said Wennberg, a member of the Center for the Evaluative Clinical Sciences (CECS) at DMS. The findings that these non-AMI populations are at higher risk of death 36% higher when they have their procedures in hospitals without onsite surgery programs is concerning. In an editorial accompanying the study, Dr. W. Douglas Weaver noted, Clearly, if these findings are true and representative, it is necessary to reconsider and perhaps curtail expanding the availability of PCI.

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