Clinical and Industry News

Recent Clinical Trials Funded by For-Profit Organizations More Likely to Report Positive Findings Than Trials Funded by Not-For-Profits Cardiovascular clinical trials published between 2000 and 2005 were significantly more likely to report positive findings if they were funded by for-profit organizations than those funded by not-for-profit organizations, according to a study in the May 17 issue of Journal of the American Medical Association. Surveys of randomized trials published between 1990 and 2000 raised awareness in the medical community that trials funded by for-profit (FP) organizations were more likely to report positive findings than those funded by not-for-profit (NFP) organizations. These surveys raised questions regarding the design and conduct of industry-funded clinical trials as well as certain ethical concerns. Whether recognition of these concerns has affected contemporary clinical trials was unknown. Paul M. Ridker, MD, of Brigham and Women’s Hospital, and Jose Torres, BA, of Harvard Medical School, Boston, analyzed outcomes of 324 cardiovascular clinical trials published between 2000 and 2005 in JAMA, The Lancet, and the New England Journal of Medicine, stratifying the results on whether the trial was funded by for-profit or not-for-profit organizations and if the trial outcome favored newer treatments over the standard of care. Of the 324 trials, 21 cited no funding source. Overall, 58.6 percent of the 324 trials reported evidence significantly favoring newer treatments, while 34.6 percent reported no significant difference between therapies, and 6.8 percent reported evidence significantly favoring standard of care. Among not-for-profit trials, 49 percent of 104 reported evidence significantly favoring newer treatments, whereas 51 percent either significantly favored standard of care or showed no difference. Among for-profit trials, 67.2 percent of 137 reported evidence significantly favoring newer treatments with 32.8 percent reporting data favoring standard of care or no difference. The proportion of trials significantly favoring new treatments for studies jointly funded by for-profit and not-for-profit organizations was approximately midway between these 2 values (56.5 percent). For 202 randomized trials evaluating drugs, the proportions favoring newer agents were 39.5 percent for not-for-profit, 54.4 percent for jointly sponsored, and 65.5 percent for for-profit trials. For the 38 randomized trials evaluating cardiovascular devices, the proportions favoring newer treatments were 50.0 percent, not-for-profit; 69.2 percent, jointly funded; and 82.4 percent, for-profit trials. Regardless of funding source, clinical trials using surrogate end points, such as intravascular ultrasound, quantitative angiography, plasma biomarkers, and functional measures were more likely to report positive findings (67.0 percent) than were clinical trials using clinical end points (54.1 percent). As suggested in surveys of randomized trials published prior to 2000, these contemporary data appear to show that incentives surrounding for-profit organizations have the potential to influence clinical trial outcomes. Previous attempts to explain this phenomenon have focused largely on design bias, interpretation bias, data suppression, and differential data quality.. We believe there are additional issues that help to explain, in part, the observed results. For example, when the first trial report of a truly novel therapy is null or negative, it becomes less likely that any funding source will support subsequent studies. On the other hand, when the first trial of a truly novel therapy is positive, the likelihood of further trials is increased. These subsequent trials understandably and perhaps appropriately are more likely to be funded by for-profit organizations, the researchers write. Source: JAMA 2006;295:2270-2274. Technique Eases Patient Allergy to Clopidogrel A new method developed by U.S. researchers can help patients overcome an allergy to clopidogrel (brand name Plavix). About two out of every 100 patients who receive clopidogrel develop an allergic reaction marked by rash, itching, hives, or swelling of the tongue and airway. Some patients develop an anaphylactic reaction and go into shock. Allergic reactions can be quite frightening to patients and physicians, and can lead to discontinuation of the medication. We showed we could successfully and safely desensitize patients who had just recently had a drug-eluting stent placed. That's a critical population to manage, Dr. Nicolas E. Walker, a cardiology fellow at the University of Iowa in Iowa City, said in a prepared statement. The desensitization protocol was used on eight patients. While being monitored in the cardiac ICU, the patients were first given a small dose of clopidogrel mixed into a drinkable solution. Every 15 minutes over the next few hours, the patients received an additional, higher dose of the drug. This continued until they were able to tolerate the target dose of 75 milligrams of clopidogrel. In total, the patients received nine doses totaling 150 milligrams of the drug. Antihistamines and other anti-allergy medicines were used to treat patients who developed allergy symptoms during the desensitization process. All eight patients completed the process and were able to safely take a daily 75 milligram dose of clopidogrel at home without suffering allergic reactions. Patients who suffer the most severe reaction anaphylactic shock to clopidogrel were not included in this study. The findings were presented at a meeting of the Society for Cardiovascular Angiography and Interventions in Chicago. Scientists Discover Two Genes Linked to Early Heart Attack Risk Scientists at UCSF, Celera Genomics and The Cleveland Clinic have discovered two gene variants associated with a significantly increased risk for early heart attack, or myocardial infarction (MI). One of the genes, known as VAMP8, normally expresses a protein essential for early stages of clotting. Knowing gene mutations that increase heart attack risk can help identify people at risk and clarify molecular changes involved in heart disease. This knowledge can lead to new potential drug targets to treat the disease. The research will be reported in the July 2006 edition of Arteriosclerosis, Thrombosis, and Vascular Biology and is being made available online on https://atvb.ahajournals.org/ . A person with either of the two gene variants has about twice the risk of early heart attack as someone with neither, the research showed. The retrospective study analyzed clinical records and gene variations in more than 2,000 patients and controls in three independent investigations. All study participants were Caucasian, and the average age of heart attack among the cardiac patients was under 60. Neither of the two genetic variants, known as single nucleotide polymorphisms or (SNPs), has previously been associated with heart attack. VAMP8 is involved in platelet aggregation. The other gene, HNRPUL1, encodes a protein involved in RNA activity. This research and other large, carefully controlled studies can provide valuable insights into genetic contributions to early-onset heart attack, said John P. Kane, MD, PhD, professor of medicine at UCSF and associate director of UCSF’s Cardiovascular Research Institute. A number of studies have identified genes linked to increased heart attack risk, but many of the studies have been made with a single cohort of patients and have not been replicated. The new study involved three sequential cohorts, and applied a statistical analysis that increases the likelihood that these are indeed true associations. He suspects that the newly discovered variant of VAMP8 either speeds the clotting process, triggers it too early or allows clotting to continue too long. We are now eager to screen the population for people with two copies of this gene and study its action at the molecular level, Kane said. VAMP 8 could be a target for a new drug. Large-scale studies like this one, with well-characterized samples from carefully selected patients, hold significant promise to enable the development of new diagnostics and targeted therapeutics, the scientists say. In order for genetic marker studies to translate into diagnostic tests with significant medical impact, discovery study results must be reproducible and applicable to a wide group of people, said Tom White, PhD, chief scientific officer at Celera Genomics. Too often, when new markers are reported, the disease association cannot be confirmed because the study used a small sample set. In addition, a spurious disease association could be found due to chance alone if a large number of SNPs are not tested. The size of this study and the identification of VAMP8, coupled with other prospective studies of the general population underway at Celera, are providing valuable insight toward the development of a Genetic Risk Score that is expected to identify individuals at elevated risk for heart disease, White said. Celera evaluated DNA samples from more than 2,000 individuals in three studies to compare patterns of genetic variation in people with a history of early-onset MI to those with no history of heart disease. The results were significant in all three studies. The key finding of the study was that variants of the VAMP 8 and HNRPUL1 genes were associated with early-onset MI, and the same variants were associated with risk in all three studies. Each of these gene variants individually confers an increased risk for MI that is comparable to conventional risk factors such as smoking, high blood pressure and elevated cholesterol levels. These genetic markers were identified through a genome-wide study of 11,647 single SNPs in 7,136 genes. The study focused on SNPs that could influence gene function in order to increase the likelihood of identifying disease-causing gene variants. These were tested for association with early-onset MI in three case-control studies with a total of 821 cases and 1,200 controls. Two of the samples drew on the very large and complete collection of clinical records, blood samples, DNA analysis and other records of more than 27,000 heart disease patients stored and studied as part of the Genomics Resource in Arteriosclerosis at UCSF’s Cardiovascular Research Institute (CVRI). The third sample comes from a collection at The Cleveland Clinic. The study is a collaboration of UCSF, Celera, The Cleveland Clinic Foundation, Case Western Reserve University and Brigham Young University. New Study Finds that Seeing Plaque Buildup Prompts More Patients to Comply with Potentially Life-Saving Medications A new study has found that seeing the build-up of plaque in their own arteries is the incentive patients need to comply with doctor’s orders. The study, conducted at the Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center (LA BioMed) and published in the journal Atherosclerosis, found that patients who see more plaque in their arteries (coronary artery calcium) tend to be more likely to stay on statin therapy than those who do not get visual proof of their risk of heart attack. Cholesterol agents such as statins have been used to reduce cardiac morbidity and mortality, but patients are not inclined to stay on the medication. In most studies, compliance is less than 50 percent after one year. Authors of the new study found that over a period of 3.6 years, patients who saw visual proof of more plaque after undergoing an electron beam tomography (EBT) scan of their heart were much more likely to comply with prescribed statin therapy. In fact, compliance among those whose scans found the most plaque exceeded 90 percent. The study followed more than 1,000 patients, each of whom were scanned and then shown their coronary arteries and the plaque that was present. Being able to see the buildup of plaque is one of the best and easiest methods to improve patient’s compliance, not only with cholesterol medications, but with diet and exercise as well, said Dr. Budoff, a principal investigator at LA BioMed and senior author of the study. Patients seeing the plaque in their own coronary arteries was a powerful motivator of good behavior persisting over three years. Electron beam tomography screening is one of the methods of assessing an individual’s heart attack risk endorsed by the SHAPE (Screening for Heart Attack Prevention and Education) Task Force, of which Dr. Budoff is a member. This summer, the SHAPE Task Force will publish a new practice guideline for cardiovascular screening in the asymptomatic at-risk population in the American Journal of Cardiology, calling for non-invasive screening of all asymptomatic men 45-75 years and women 55-75 years to assess their coronary plaque volume or carotid wall thickness. The SHAPE Task Force estimates that screening the asymptomatic population will effectively prevent more than 90,000 deaths each year. Electron beam tomography identifies heart disease early, which gives us the ability to aggressively care for the disease with treatments that work, said John Duncan, PhD, founder and CEO of ViaScan of Las Colinas. We can alter the pathway from disease to death. By aggressively intervening, we can save lives. According to the American Heart Association’s 2005 Heart Disease and Stroke Statistics Update, cardiovascular diseases (CVD) accounted for 38 percent of all deaths in the U.S in 2002. Patient Registry to Evaluate Long-Term Safety and Efficacy of Cordis Next Generation Drug-Eluting Coronary Stents in Clinical Practice e-SELECT Registry Designated to Provide Longest Follow Up of Any DES Registry A new global patient registry called e-SELECT designed to evaluate the real-world safety and efficacy of the Cypher Select Sirolimus-eluting Coronary Stent and later generations of Cordis drug-eluting stents was initiated today by Cordis Corporation. Slated to be the only drug-eluting stent registry in the world with three-year follow-up, the multi-center, prospective, observational e-SELECT Registry enrolled its first patient on May 10th. Ultimately, the registry will include 30,000 patients in up to 500 centers outside the United States. The Cypher Select Stent is only available in Europe, Asia Pacific, Latin America and Canada. Philip Urban, MD, FESC, is the coordinating investigator for the Registry and Director of Invasive Cardiology, La Tour Hospital, Geneva, Switzerland. The e-SELECT Registry will evaluate a variety of safety and efficacy measures including the need for target lesion revascularization, major adverse cardiac events (MACE) such as heart attack and death and stent thrombosis. Additionally, the registry population will also allow investigators to perform sub-analyses on such complex patient groups as diabetics and those with multi-vessel disease, restenosis or a prior history of myocardial infarction. With three-years of clinical follow, the e-SELECT Registry will provide some of the most comprehensive long-term data on the safety and efficacy of a drug-eluting stent device within the field of interventional cardiology. Data collected for the registry will be uniformly reported through an Internet electronic data capture system, and an independent Clinical Event Committee made up of interventional cardiologists will meet regularly to review and adjudicate all major clinical events. Site monitoring for a selected group of participating centers is also being planned to ensure data accuracy. Enrollment in the e-SELECT Registry will include patients treated with the Cypher Select Stent in countries where the stent has been approved for commercial use. Patients treated with later generations of Cordis drug-eluting stents will also be enrolled as stents become commercially available. Tryton Announces First Clinical Use of its Side-Branch Stent to Treat Coronary Bifurcation Lesions Tryton Medical, Inc. announced today the first clinical use of its Tryton Side-Branch Stent. The initial cases were performed at the Heart Center/Siegburg under the direction of Professor Eberhard Grube, MD. These cases demonstrate that a Tryton stent strategy provides a simple and easy way to treat complex bifurcation lesions with beautiful results, according to Professor Grube. The Tryton First-In-Man Study is a multi-center clinical trial evaluating the utility of the Tryton Side-Branch Stent to treat coronary artery arterial lesions involving a bifurcation. The study is being performed at the Institute Cardiovascular Paris Sud, France (Marie-Claude Morice, Principal Investigator) and Heart Center/Siegburg, Germany (E. Grube, Principal Investigator). Coronary artery disease located at the branch of arteries occurs in up to 25% of patients currently undergoing coronary stenting. The designs of available drug-eluting stents do not adequately address this group of patients, said Dr. Aaron Kaplan, Founder of Tryton and Associate Professor, Dartmouth Medical School. Stents placed at bifurcations are currently associated with higher acute complications as well as late restenosis. According to Tryton's Chief Technology Officer, Richard Davis, The Tryton Side-Branch Stent is a balloon-expandable, 5-French compatible system that is delivered with a single wire. When used in conjunction with any existing standard stent for the main vessel, it provides superior coverage and hoop strength to the origin of the side branch.

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