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June 30, 2009JAMA news releases are made available to the public after 3 pm US Central time on the first 4 Tuesdays of each month. The Archives of Journals news releases are made available to the public after 3 pm Central time on Mondays. We also provide a list of previous news releases. THIS WEEK'S CONTENTS
JAMA NEWS RELEASES
(Embargoed for Release: 3 p.m. CT Tuesday, June 30, 2009) JAMA REPORT (VIDEO SCRIPT)
INFORMATION CONTAINED IN THESE NEWS RELEASES IS PROTECTED BY COPYRIGHT. JOURNAL ATTRIBUTION IS REQUIRED. JOURNALISTS CAN NOW ACCESS EMBARGOED JAMA/ARCHIVES STUDIES ON-LINE. Go to www.jamamedia.org for more information and to apply for access. TV Note: This week's JAMA Report video is on participating in biomedical research. The report will be fed Tuesday, June 30, from 9:00 - 9:30 a.m. ET and 2:00 - 2:30 p.m. ET, on Galaxy 28 (C-Band), Transponder 19, downlink frequency: 4080 vertical, audio 6.2/6.8. For more information, call 312/464-JAMA. Please Note: The FOR THE MEDIA website now has a search feature to enable media to find previous JAMA/Archives news releases on specific medical topics. This search feature link is located on the home page at www.jamamedia.org EMBARGOED FOR RELEASE UNTIL 3 P.M. (CT), Tuesday, June 30, 2009
Findings of Genetics Study Does Not Support Causal Association of C-Reactive Protein With Coronary Heart Disease
CHICAGO—An analysis of the association between genetic variations of the inflammation biomarker C-reactive protein (CRP) with coronary heart disease failed to support a causal association, according to a study in the July 1 issue of JAMA. Coronary heart disease (CHD) is the leading cause of death worldwide. Inflammation plays a key role in the development of CHD at every stage, from initiation to progression and rupture of plaque. CRP is currently the most widely used biomarker of inflammation, according to background information in the article. "There is considerable interest in establishing whether CRP has a causal role in CHD or whether CRP is merely a marker of underlying atherosclerosis," the authors write. Paul Elliott, F.R.C.P., of Imperial College London, and colleagues conducted a genetic association study to identify common genetic loci (the specific site of a particular gene on its chromosome) that influence CRP levels and used the concept of mendelian randomization (the randomized allocation of alleles—an alternative form of a gene at a locus—at conception) to examine the possible causal relationship of CRP levels with CHD. First a genome-wide association (n = 17,967) and replication study (n = 13,615) were conducted to identify genetic loci associated with plasma CRP concentrations. Data collection took place between 1989 and 2008 and genotyping between 2003 and 2008. The researchers then carried out a mendelian randomization study of the most closely associated single-nucleotide polymorphism (SNP) in the CRP locus and published data on other CRP variants involving a total of 28,112 cases and 100,823 controls, to investigate the association of CRP variants with coronary heart disease. These findings were compared with findings predicted from meta-analysis of observational studies of CRP levels and risk of coronary heart disease. The researchers found: "The present genome-wide association study confirms the associations of common genetic variants in the LEPR, IL6R, CRP, and HNF1A loci and APOE-CI-CII cluster with CRP levels. However, the minor allele of SNP rs7553007 and other variants in the CRP locus included in our mendelian randomization study were not associated with CHD risk." The authors write that the variants included in their mendelian randomization study are associated with approximately 20 percent lower CRP levels, corresponding to a 6 percent reduction in CHD risk predicted by the meta-analysis of observational studies of CHD risk. "The lack of association with CHD of genetic variants in the CRP locus suggests that the observational data linking CRP levels and CHD may be confounded [factors that can influence outcomes] by association with other CHD risk factors, or reflect a secondary inflammatory response associated with atherosclerosis (reverse causation), rather than indicate a causal relationship."
"In summary, our mendelian randomization study of more than 28,000 cases and 100,000 controls found no association of variants in the CRP locus and CHD, arguing against a causal role for CRP in atherosclerosis. Moreover, this study suggests that development of therapeutic strategies targeting specific reductions in plasma levels of CRP are unlikely to be fruitful," the researchers conclude.
Editor's Note: Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc. Editorial: Biomarkers and Cardiovascular Disease
In an accompanying editorial, Svati H. Shah, M.D., M.H.S., of Duke University Medical Center, Durham, N.C., and James A. de Lemos, M.D., of the University of Texas Southwestern Medical Center, Dallas, comment on the two studies in this week's JAMA that examine the use of biomarkers for predicting cardiovascular disease.
"What are the implications of these 2 important studies? Ideally, biomarkers would also be risk factors and could be used for both risk assessment and to individualize specific therapies. Large collaborative investigations incorporating genome-wide association study and mendelian randomization as highlighted by Elliott et al offer a blueprint for definitive evaluation of the causal role of intermediate traits such as biomarkers. Similarly, studies such as that by Melander et al exemplify the necessity of comprehensive appraisal of the value of novel biomarkers, including CRP, beyond standard risk factors in specific populations. Studies such as these will help determine which biomarkers are likely to be useful as specific drug targets but also whether they have a potential role in risk assessment or even therapeutic selection. In the future, better biomarkers and more creative strategies for combining them will be needed, along with comprehensive statistical and functional evaluation of causality, to fulfill the promise of biomarkers for personalized medicine."
Editor's Note: Please see the article for additional information, including financial disclosures, funding and support, etc. For more information, contact JAMA/Archives media relations at 312/464-JAMA (5262) or e-mail mediarelations{at}jama-archives.org. EMBARGOED FOR RELEASE UNTIL 3 P.M. (CT), Tuesday, June 30, 2009
Compared to Conventional Risk Factors, Certain Biomarkers May Have Limited Added Benefit For Predicting Cardiovascular Events
CHICAGO—Use of several older and newer biomarkers appears to offer minimal added benefit in the prediction of cardiovascular events compared to conventional risk factors such as high cholesterol and high blood pressure, according to a study in the July 1 issue of JAMA. "Cost-effective cardiovascular prevention relies on the accurate identification of individuals at risk. However, a large proportion of individuals with cardiovascular events have 1 or fewer of the conventional risk factors, including smoking, diabetes, hypertension, or hyperlipidemia," the authors write. As a result, the use of recently identified biomarkers to supplement standard risk algorithms has attracted increasing attention in recent years. However, prior studies have reached differing conclusions regarding the usefulness of biomarkers for cardiovascular risk prediction, according to background information in the article. Olle Melander, M.D., Ph.D., of Lund University, Malmö, Sweden, and colleagues assessed several cardiovascular biomarkers, individually and in combination, regarding their usefulness in predicting future cardiovascular events, compared with conventional risk factors. The study included 5,067 participants (average age, 58 years; 60 percent women) without cardiovascular disease from Malmö, Sweden, who were examined at the beginning of the study, between 1991 and 1994. Participants underwent measurement of older biomarkers (C-reactive protein [CRP] and N-terminal pro-B-type natriuretic peptide [N-BNP]) and newer biomarkers (cystatin C, lipoprotein-associated phospholipase-2 [Lp-PLA2], midregional proadrenomedullin [MR-proADM], and midregional proatrial natriuretic peptide [MR-proANP]. There was follow-up until 2006, using the Swedish national hospital discharge and cause-of-death registers and the Stroke in Malmö register for first cardiovascular events (heart attack, stroke, coronary death). During median (midpoint) follow-up of 12.8 years, there were 418 cardiovascular events and 230 coronary events. When considered individually, 5 of 6 biomarkers predicted future cardiovascular events and 3 (cystatin C, MR-proADM, and N-BNP) predicted future coronary events in models adjusting for conventional risk factors. "The best combinations of biomarkers were CRP and N-BNP for predicting cardiovascular events and MR-proADM and N-BNP for predicting coronary events. The use of multiple biomarkers minimally improved the accuracy of risk prediction models over and above conventional cardiovascular risk factors and did not reclassify a substantial proportion of individuals to higher or lower risk categories," the authors write. The researchers add that what may be relevant to clinical care, however, is not whether changes in predicted probabilities are statistically significant but whether they result in reclassification of individuals to new, clinically meaningful risk categories. "Our data indicate that a relatively small proportion of individuals are moved to new risk categories by the addition of biomarkers—8 percent or fewer when both upward and downward risk category movement are included and fewer than 1 percent when only the movements likely to lead to changes in therapy according to the Adult Treatment Panel III [cholesterol] guidelines are included. Furthermore, these reclassifications result in only modest improvements in the overall concordance between risk categories and actual event rates, as measured by the net reclassification improvement."
"The challenge will be to find new cardiovascular biomarkers that alone or in combination with existing biomarkers can bring about improvements in risk assessment that are not just statistically significant but clinically significant as well," the authors conclude.
Editor's Note: Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc. For more information, contact JAMA/Archives media relations at 312/464-JAMA (5262) or e-mail mediarelations{at}jama-archives.org. EMBARGOED FOR RELEASE UNTIL 3 P.M. (CT), Tuesday, June 30, 2009
Agent Often Used in Spinal Fusion Surgery Associated With Higher Rate of Complications, Greater Inpatient Charges
CHICAGO—A new study indicates that bone-morphogenetic protein (BMP; a biological agent used to promote bone creation) is used in 25 percent of spinal fusion procedures and is associated with a higher rate of complications than in fusions that did not use BMP, and greater hospital charges for all categories of spinal fusions, according to a report in the July 1 issue of JAMA. Back pain continues to be a leading cause of disability in the United States and is one of the most common reasons for seeking evaluation by a physician, second only to the common cold. "Nonsurgical interventions remain the first-line of therapy; however, many patients eventually progress to surgical treatments with 1 option including fusion. Spinal arthrodesis (fusion) as a treatment for back pain has rapidly evolved with the development of advanced spinal instrumentation and biologics to promote bony fusion," the authors write. According to background information in the article, BMPs promote bone creation and remodeling and clinical use of recombinant BMP protein was approved by the U.S. Food and Drug Administration (FDA) in 2002 for surgery of the anterior lumbar spine to promote bone fusion. The current rates and patterns of BMP use since the clinical introduction more than 5 years ago are not known at the national level and no population-based data are available. Likewise, the complication rates and financial impact associated with national BMP usage have not been evaluated. Kevin S. Cahill, M.D., Ph.D., M.P.H., of Brigham and Women's Hospital, Boston, and colleagues examined the national trends in the adaptation of BMP into clinical practice since 2002 and the association between BMP use and postoperative complications, length of stay and hospital charges. The analysis included data on 328,468 patients who underwent spinal fusion procedures from 2002-2006, identified from the Nationwide Inpatient Sample database, a 20 percent sample of U.S. community hospitals. The researchers found that when comparing immediate postoperative, in-hospital rates of complications for the year 2006 among patients undergoing spinal fusion by BMP use status, no differences were seen for lumbar, thoracic, or posterior cervical procedures. After additional analysis, the use of BMP in anterior cervical fusion procedures was associated with a higher rate of complication occurrence (7.09 percent with BMP vs. 4.68 percent without BMP) with the primary increases seen in wound-related complications (1.22 percent with BMP vs. 0.65 percent without BMP) and dysphagia (difficulty in swallowing) or hoarseness (4.35 percent with BMP vs. 2.45 percent without BMP). BMP use was associated with greater inpatient hospital charges across all categories of fusion. Increases between 11 percent and 41 percent of total hospital charges were reported, with the greatest percentage increase seen for anterior cervical fusion. Results from the study also indicated that nationwide usage of BMP has increased from 0.69 percent of all fusions in 2002 to 24.89 percent of all fusions in 2006. Use of BMP varied by patient sex, race, and primary payer with increased use seen in women, Medicare patients and decreased use in nonwhite patients.
"In conclusion, this report highlights the robust nationwide application of BMP in spinal fusion procedures in the first 5 years of clinical usage since FDA approval. The effects on complication occurrence in anterior cervical fusion, as well as the increases in length of stay and hospital charges illustrate the need to continue to develop refined guidelines for usage and to further study the long-term risks and benefits of usage," the authors conclude.
Editor's Note: Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc. For more information, contact JAMA/Archives media relations at 312/464-JAMA (5262) or e-mail mediarelations{at}jama-archives.org.
JAMA REPORTS
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