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New Approaches to Molecular Diagnosis

“Advances in understanding the molecular basis of rare and common disorders, as well as in the technology of DNA analysis, are rapidly changing the landscape of molecular genetic and genomic testing,” writes Bruce R. Korf, M.D., Ph.D., of the University of Alabama at Birmingham, and Heidi L. Rehm, Ph.D., of the Partners Healthcare Center for Personalized Genetic Medicine, Cambridge, Mass., in a Special Communication.

“Genomic testing may be used to identify risk factors for common disorders, although the clinical utility of such testing is unclear. Genetic and genomic tests may raise new ethical, legal, and social issues, some of which may be addressed by existing genetic non-discrimination legislation, but which also must be addressed in the course of genetic counseling.”

In this article, the authors provide information “to assist physicians in recognizing where new approaches to genetic and genomic testing may be applied clinically and in being aware of the principles of interpretation of test results.”

(JAMA. 2013;309[14]:1511-1521. Available pre-embargo to the media at https://media.jamanetwork.com)

Viewpoints in This Issue of JAMA

Realizing the Opportunities of Genomics in Health Care

April 14, 2013, marks the 10th anniversary of the completion of the Human Genome Project. In this Viewpoint, Geoffrey S. Ginsburg, M.D., Ph.D., of the Institute for Genome Sciences & Policy, Duke University, Durham, N.C., examines the question of how sequencing the human genome has contributed to achieving the health care aims of reducing costs, increasing access, and improving outcomes.

“Pioneering scientists chose to sequence the human genome because it was a bold challenge and because success would substantially advance the understanding of humankind, biology, and of the science of medicine. Ten years later the benefits of genomics in clinical medicine are just beginning to be realized. In the next decade, there is little doubt that genomics and genomic medicine will continue to inform patients, researchers, health care professionals, and society in ways currently unimaginable.”

(JAMA. 2013;309[14]:1463-1464. Available pre-embargo to the media at https://media.jamanetwork.com)

The Indispensable Role of Professional Judgment in Genomic Medicine

Amy L. McGuire, J.D., Ph.D., of the Baylor College of Medicine, Houston, and colleagues discuss the appropriate role for genetic professionals in test ordering, interpretation, and delivery of whole-genome sequencing and whole-exome sequencing results and the decisions that will require professional judgment.

“Both physician-ordered and self-directed genome sequencing have the potential to create preventable risks to patients and downstream negative impacts on the health care system as a whole. As in any other realm of medicine, patients must be included in decisions about genomic testing. Moreover, participants in genomic research should be informed of the potential discovery of clinically relevant findings and consumers should be able to access reliably interpreted, clinically applicable information about their genomic heritage. However, provision of inadequately interpreted results does not empower informed decision making. Individuals who are not sufficiently knowledgeable or adequately trained in genomics do not know how to query the genome or interpret results, and nonclinicians have insufficient expertise to make treatment plans based on the results of sequencing. Thus, to fully realize the promise of genomics in health care, professional judgment must play an indispensable role.”

(JAMA. 2013;309[14]:1465-1466. Available pre-embargo to the media at https://media.jamanetwork.com)

Genomic Medicine, Health Information Technology, and Patient Care

In this Viewpoint, Christopher G. Chute, M.D., Dr.P.H., of the Mayo Clinic, Rochester, Minn., and Isaac S. Kohane, M.D., Ph.D., of Harvard Medical School, Boston, examine how health information technology will contribute to or hamper the promise of genomic medicine.

The authors write that “three criteria must be met to enable health care to address the scope and complexity of the genomic medicine challenge with clinical process automation linked to authoritative genome-scale annotation knowledge bases: (1) the emergence of a coherent, consistent, and uniform naming convention for genomic variants; (2) an authenticated, well-annotated, curated, and freely accessible knowledge base of genomic associations, risks, and warnings in machine-readable form; and (3) modular, standards-based decision-support rules that can be integrated into any electronic health records environment with associated, easily readable documentation and guidance.”

(JAMA. 2013;309[14]:1467-1468. Available pre-embargo to the media at https://media.jamanetwork.com)

Accessing Genomic Medicine – Affordability, Diffusion, and Disparities

Reed V. Tuckson, M.D., of UnitedHealth Group, Minnetonka, Minn., and colleagues describe health care system characteristics that will shape the accessibility, management, and financing for new technologies involving genomic medicine. “In addition, questions of value, clinical management, and patient engagement will influence the emergence of personalized medicine.”

“Medical innovation that enhances human survival and relieves disease burden has been a capstone of the healing sciences and continues to drive advances in genetics and genomics. World realities, however, demand focus on the appropriate use of genomic medicine if all are to experience affordable, safe, and equitable access to their benefits. Health care stakeholders from the ‘bench to the bedside’ have critical roles to play. While the challenges are significant, the opportunities are even greater.”

(JAMA. 2013;309[14]:1469-1470. Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: Please see the article for additional information, financial disclosures, funding and support, etc.

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Media Advisory: To contact Mingzhao Xing, M.D., Ph.D., call Vanessa Wasta at 410-614-2916 or email wasta@jhmi.edu. To contact editorial co-author Anne R. Cappola, M.D., Sc.M., call Kim Menard at 215-662-6183 or email kim.menard@uphs.upenn.edu.

CHICAGO – Presence of the genetic mutation BRAF V600E was significantly associated with increased cancer-related death among patients with papillary thyroid cancer (PTC); however, because overall mortality in PTC is low and the association was not independent of tumor characteristics, how to use this information to manage mortality risk in patients with PTC is unclear, according to a study in the April 10 issue of JAMA, a Genomics theme issue.

“Papillary thyroid cancer is the most common endocrine malignancy and accounts for 85 percent to 90 percent of all thyroid cancers,” according to background information in the article. “The overall 5-year patient survival rate for PTC is 95 percent to 97 percent. A major clinical challenge is how to reliably distinguish patients who need aggressive treatments to reduce mortality from those who do not. This represents a widely controversial issue in thyroid cancer medicine, particularly because of the low overall mortality of this cancer. The issue has become even more challenging given the high annual incidence of PTC.” BRAF V600E is a prominent oncogene [ a gene, one or more forms of which is associated with cancer] in PTC and “has drawn considerable attention as a potential prognostic factor for PTC. However, the clinical significance of this mutation in PTC-related mortality has not been established.”

Mingzhao Xing, M.D., Ph.D., of the Johns Hopkins University School of Medicine, Baltimore, and colleagues conducted a study to examine and define the association between the BRAF V600E mutation and PTC-related mortality. The study included 1,849 patients (1,411 women and 438 men) with a median (midpoint) age of 46 years and an overall median follow-up time of 33 months after initial treatment at 13 centers in 7 countries between 1978 and 2011.

The overall prevalence of BRAF V600E was 45.7 percent (845/1,849). There were 56 PTC-related deaths among the 1,849 patients, representing an overall mortality of 3.0 percent. Among these deaths, 45 cases (80.4 percent) were positive for BRAF V600E. The overall mortality of all PTC cases was 5.3 percent (45/845) in BRAF V600E-positive patients vs. 1.1 percent (11/1,004) in mutation-negative patients.

When the aggressive tumor features of lymph node metastasis, extrathyroidal invasion, and distant metastasis were also included in the model, the association of BRAF V600E with mortality for all PTC was no longer significant, the authors write. “A higher BRAF V600E-associated patient mortality was also observed in several clinicopathological subcategories, but statistical significance was lost with adjustment for patient age, sex, and medical center.”

“In summary, in this multicenter study, the presence of the BRAF V600E mutation was significantly associated with increased cancer-related mortality among patients with PTC. However, overall mortality in PTC is low, and the association was not independent of tumor behaviors. Therefore, how to use BRAF V600E for the management of mortality risk among patients with PTC is not clear. These findings support further investigation of the prognostic and therapeutic implications of BRAF V600E status in PTC.”

(JAMA. 2013;309(14):1493-1501; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc.

Editorial: Molecular Testing in Thyroid Cancer – BRAF Mutation Status and Mortality

In an accompanying editorial, Anne R. Cappola, M.D., Sc.M., and Susan J. Mandel, M.D., M.P.H., of the University of Pennsylvania, Philadelphia (Dr. Cappola is also Contributing Editor, JAMA), write that “these analyses provide 2 important insights.”

“First, they suggest that the BRAF V600E mutation mediates features of the clinically aggressive tumors that account for the vast majority of PTC mortality. This provides a strong biological rationale for current trials of targeted tyrosine kinase inhibitor therapy for BRAF V600E-positive PTC patients with advanced disease. At the same time, these study results suggest that BRAF V600E testing does not add predictive value for PTC-related mortality beyond the information collected in the process of PTC tumor staging, including postoperative histopathology reporting and clinical evaluation. This is particularly relevant when considering that 45 percent of all PTC tumors are BRAF V600E-positive, and implies that additional tumor or host genomic factors may influence tumor aggressiveness.”

“Although these findings do not support widespread BRAF V600E testing, they do support the need for additional study of how BRAF testing can be used to improve the already excellent prognosis of patients with PTC.”

(JAMA. 2013;309(14):1529-1530; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr. Mandel reported membership on the scientific advisory board of Asuragen. No other disclosures were reported.

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, APRIL 9, 2013

Media Advisory: To contact corresponding author Michael J. Ackerman, M.D., Ph.D., call Traci Klein at 507-284-5005 or email klein.traci@mayo.edu. To contact editorial co-author Alan E. Guttmacher, M.D., call Robert Bock at 301-496-5133 or email bockr@mail.nih.gov.

CHICAGO – In a molecular genetic evaluation involving 91 cases of intrauterine fetal death, mutations associated with susceptibility to long QT syndrome (LQTS; a heart disorder that increases the risk for an irregular heartbeat and other adverse events) were discovered in a small number of these cases, preliminary evidence that may provide insights into the mechanism of some intrauterine fetal deaths, according to a study in the April 10 issue of JAMA, a Genomics theme issue.

“Intrauterine fetal death is a major public health problem. About 1 million fetal deaths occur in the United States annually, with the vast majority occurring prior to 20 weeks’ estimated gestational age,” according to background information in the article. Fetal death occurring after 20 weeks is defined as stillbirth, and in 2009, an estimated 2.64 million stillbirths occurred worldwide. Postmortem evaluations fail to identify a cause of death in approximately 25 percent to 40 percent of fetal deaths. “However, LQTS has been shown to be a major determinant in young sudden death individuals for which an autopsy was performed but had remained inconclusive and a determinant for as much as 10 percent of sudden infant death syndrome (SIDS). Long QT syndrome may also contribute to sudden unexpected fetal mortality.”

Lia Crotti, M.D., Ph.D., of the University of Pavia, Italy, and Michael J. Ackerman, M.D., Ph.D., of Mayo Clinic, Rochester, Minn., and colleagues conducted a study to determine the spectrum and prevalence of mutations in the 3 most common LQTS-susceptible genes (KCNQ1, KCNH2, and SCN5A) for a group of unexplained fetal death cases. In this case series, retrospective postmortem genetic testing was conducted on a sample of 91 unexplained intrauterine fetal deaths that were collected from 2006-2012 (average estimated gestational age at fetal death, 26.3 weeks; 51 females, 40 males). More than 1,300 ostensibly healthy individuals served as controls. In addition, publicly available exome (the entire portion of the genome consisting of protein-coding sequences) databases were assessed for the general population frequency of identified genetic variants.

Excluding 2 very common genetic variants, the researchers identified 14 genetic variants in 18 intrauterine fetal deaths (19.8 percent) of 91 including 3 of 30 late abortion or miscarriages (10 percent) and 15 of 61 stillbirths  (24.6 percent). “Three variants found in 3 intrauterine fetal death cases (3.3 percent) of 91 were considered putative [supposed] pathogenic mutations based on their absence in more than 1,000 ethnically similar controls, a heterozygote [a person possessing two different forms of a particular gene] frequency below the prevalence of LQTS in the general population (0.05 percent) as determined by analysis of more than 10,000 publicly available exomes, and an abnormal functional electrophysiological profile.”

In addition, 5 intrauterine fetal deaths hosted SCN5A rare nonsynonymous genetic variants (a polymorphism that results in a change in the amino acid sequence of a protein [and therefore may affect the function of the protein]) that conferred in vitro electrophysiological characteristics consistent with potentially pro-arrhythmic phenotypes.

Overall, genetic variants leading to dysfunctional LQTS-associated ion channels (a protein that acts as a pore in a cell membrane and permits the selective passage of ions by means of which electrical current passes in and out of the cell) in vitro were discovered in 8 cases (8.8 percent).

“To our knowledge, this represents the first demonstration of such findings. This preliminary evidence suggests LQTS is one plausible cause of intrauterine fetal death; supports the previously proposed mechanistic link between some cases of intrauterine fetal death, SIDS, and LQTS; and provides precedence for further large-scale investigations into the extent and role of cardiac channelopathies [a disease involving dysfunction of an ion channel] in stillbirth,” the authors write.

(JAMA. 2013;309(14):1473-1482; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc.

Editorial: Long QT Syndrome Susceptibility Mutations and Pregnancy Loss – Another Piece of a Still Unfinished Puzzle?

“Understanding the etiology of stillbirth is essential not just for crafting effective prevention strategies but also for providing families and clinicians with counseling information and the opportunity for a greater sense of closure,” writes Alan E. Guttmacher, M.D., of the National Institutes of Health, Bethesda, Md., and colleagues in an accompanying editorial.

“Recent efforts to fully characterize stillbirths have provided a foundation for identifying the causal factors and include novel technologies to evaluate the genomic alterations in stillbirth. The findings of Crotti and colleagues add another piece to solving this puzzle. If confirmed in well-characterized cohorts and amplified by broader genomic approaches, such work may provide an explanation for many cases of late miscarriage and stillbirth previously labeled as ‘unknown.’”

(JAMA. 2013;309(14):1525-1526; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, APRIL 9, 2013

Media Advisory: To contact corresponding author Richard Mayeux, M.D., M.Sc., call Elizabeth Streich at 212-305-3689 or email estreich@columbia.edu. To contact editorial author Robert L. Nussbaum, M.D., call Kristen Bole at 415-476-2743 or email kristen.bole@ucsf.edu.

CHICAGO – In a meta-analysis of data from nearly 6,000 African Americans, Alzheimer disease was significantly associated with a gene that have been weakly associated with Alzheimer disease in individuals of European ancestry, although additional studies are needed to determine risk estimates specific for African Americans, according to a study in the April 10 issue of JAMA, a Genomics theme issue.

“Late-onset Alzheimer disease (LOAD) is the most common cause of dementia, increasing in frequency from 1 percent at age 65 years to more than 30 percent for people older than 80 years,” according to background information in the article. The incidence of LOAD among African Americans is higher than among whites living in the same community. “Genetic variants associated with susceptibility to late-onset Alzheimer disease are known for individuals of European ancestry, but whether the same or different variants account for the genetic risk of Alzheimer disease in African American individuals is unknown. Identification of disease-associated variants helps identify targets for genetic testing, prevention, and treatment.”

Christiane Reitz, M.D., Ph.D., of Columbia University, New York, and colleagues conducted a study to identify genetic variants associated with LOAD in African Americans. The Alzheimer Disease Genetics Consortium (ADGC) assembled multiple data sets representing a total of 5,896 African Americans (1,968 case participants, 3,928 control participants) 60 years or older that were collected between 1989 and 2011 at multiple sites. The association of Alzheimer disease with genotyped and imputed single-nucleotide polymorphisms (SNPs; DNA sequence variations that occur when a single nucleotide in the genome sequence is altered) was assessed in case-control and in family-based data sets.

The researchers found that the genotypes with the strongest association with the risk of LOAD among African Americans were ABCA7 (odds ratio, 1.8) and APOE (odds ratio, 2.3), genotypes also associated with increased risk among individuals of European ancestry. However, the association with ABCA7 was 60 percent stronger that than observed among individuals of European ancestry.

“If validated by future replication and functional studies, identification of ABCA7 as a risk gene in LOAD among African Americans not only may help elucidate the disease etiology but also may have major implications for developing targets for genetic testing, prevention, and treatment,” the authors write.

“Identification of the genetic risk variants by resequencing and validation by functional studies would allow refinement of risk estimates and diagnostic and predictive testing protocols specific for African Americans.”

(JAMA. 2013;309(14):1483-1492; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc.

There will also be a digital news release available for this study, including the JAMA Report video, embedded and downloadable video, audio files, text, documents, and related links. This content will be available at 3 p.m. CT Tuesday, April 9 at this link.

Editorial: Genome-Wide Association Studies, Alzheimer Disease, and Understudied Populations

In an accompanying editorial, Robert L. Nussbaum, M.D., of the University of California, San Francisco, writes about the significance of the findings in this study.

“First, of the many hundreds of genome-wide association studies (GWASs) reported in the National Human Genome Research Institute’s Catalog of Published Genome-Wide Association Studies, only a small fraction involve African American populations. Pursuing research in an understudied ethnic group is important for scientific and for ethical reasons. Second, replicating an association for the same alleles in different ethnic groups strengthens the case for these variants being important in increasing disease susceptibility. Third, the strong replication of the association between variants in 2 genes involved in lipid metabolism underscores how GWASs-can point to pathways that play a role in complex diseases. Proving the functional importance of these genes and variants, however, must await more direct functional studies.”

(JAMA. 2013;309(14):1527-1528; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: Please see the article for additional information, including financial disclosures, funding and support, etc.

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, APRIL 9, 2013

Media Advisory: To contact corresponding author Mark J. Pallen, M.A., M.D., Ph.D., email m.pallen@warwick.ac.uk. To contact editorial author David A. Relman, M.D., call Margarita Gallardo at 650-723-7897 or email mjgallardo@stanford.edu.

CHICAGO – Researchers have been able to reconstruct the genome sequence of an outbreak strain of Shiga-toxigenic Escherichia coli (STEC) using metagenomics (the direct sequencing of DNA extracted from microbiologically complex samples), according to a study in the April 10 issue of JAMA, a Genomics theme issue.  The findings highlight the potential of this approach to identify and characterize bacterial pathogens directly from clinical specimens without laboratory culture.

“The outbreak of Shiga-toxigenic Escherichia coli, which struck Germany in May-June 2011, illustrated the effects of a bacterial epidemic on a wealthy, modern, industrialized society, with more than 3,000 cases and more than 50 deaths. During an outbreak, rapid and accurate pathogen identification and characterization is essential for the management of individual cases and of an entire outbreak. Traditionally, clinical bacteriology has relied primarily on laboratory isolation of bacteria in pure culture as a prerequisite to identification and characterization of an outbreak strain. Often, however, in vitro culture proves slow, difficult, or even impossible, and recognition of an outbreak strain can be difficult if it does not belong to a known variety or species for which specific laboratory tests and diagnostic criteria already exist,” according to background information in the article. Metagenomics has been used in a clinical diagnostic setting to identify the cause of outbreaks of viral infection.

Nicholas J. Loman, M.B.B.S., Ph.D., of the University of Birmingham, England, and colleagues conducted a study to explore the potential of metagenomics to identify and characterize (by determining genome sequence data) bacterial strains from an outbreak without the need for laboratory culture. For this retrospective investigation, 45 samples were selected from fecal specimens obtained from patients with diarrhea during the 2011 outbreak of Shiga-toxigenic Escherichia coli (STEC) O104:H4 in Germany. Samples were subjected to sequencing (August-September 2012), followed by a 3-phase analysis (November 2012-February 2013).

In phase 1, a draft genome of the outbreak strain was constructed, using data obtained the HiSeq 2500 instrument in rapid-run mode. Outbreak-specific sequences were identified by subtracting sequences from the outbreak metagenome that were present in fecal samples from healthy individuals. In phase 2, the depth of coverage of the outbreak strain genome was determined in each sample. In phase 3, sequences from each sample were compared with sequences from known bacteria to identify pathogens other than the outbreak strain.

“During phase 2, the outbreak strain genome was recovered from 10 samples at greater than 10-fold coverage and from 26 samples at greater than 1-fold coverage. Sequences from the Shiga-toxin genes were detected in 27 of 40 STEC-positive samples (67 percent). In phase 3, sequences from Clostridium difficile, Campylobacter jejuni, Campylobacter concisus, and Salmonella enterica were recovered,” the authors write.

“Using metagenomics, we have been able to recover a draft genome sequence of the German STEC strain without the need for laboratory culture. We found that in most patients with STEC-positive samples, the outbreak strain of E coli accounted for a sizeable proportion of microbial sequences.”

“In conclusion, these results illustrate the potential of metagenomics as an open-ended, culture-independent approach for the identification and characterization of bacterial pathogens during an outbreak of diarrheal disease. Challenges include speeding up and simplifying workflows, reducing costs, and improving diagnostic sensitivity, all of which are likely to depend in turn on improvements in sequencing technologies.”

(JAMA. 2013;309(14):1502-1510; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc.

Editorial: Metagenomics, Infectious Disease Diagnostics, and Outbreak Investigations – Sequence First, Ask Questions Later?

David A. Relman, M.D., of the Stanford University School of Medicine, Stanford, Calif., comments on the findings of this study in an accompanying editorial.

“Microbial genome and community sequence data are destined to affect clinical and public health decision making in a profound manner. However, clinician-investigators know that there remain many critical, clinically relevant questions that demand more than genome sequence data, requiring biological measurements and a deeper understanding of the ecological and clinical setting.”

(JAMA. 2013;309(14):1531-1532; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: The author has completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr. Relman reported serving as a consultant to Cepheid Corporation, NanoBio Corporation, Novartis Vaccines, and Procter & Gamble; and owning stock in Cepheid Corporation.

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, APRIL 2, 2013

The Inevitable Application of Big Data to Health Care

“The amount of data being digitally collected and stored is vast and expanding rapidly. As a result, the science of data management and analysis is also advancing to enable organizations to convert this vast resource into information and knowledge that helps them achieve their objectives. Computer scientists have invented the term big data to describe this evolving technology,” writes Travis B. Murdoch, M.D., M.Sc., of the University of Calgary, and Allan S. Detsky, M.D., Ph.D., of the University of Toronto.

In this Viewpoint,  the authors “discuss the application of big data to health care, using an economic framework to highlight the opportunities it will offer and the roadblocks to implementation. We suggest that leveraging the collection of patient and practitioner data could be an important way to improve quality and efficiency of health care delivery.”

(JAMA. 2013;309[13]:1351-1352. Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: Please see the article for additional information, financial disclosures, funding and support, etc.

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, APRIL 2, 2013

Media Advisory: To contact Vance G. Fowler Jr., M.D., M.H.S., call Sarah Avery at 919-660-1306 or email sarah.avery@duke.edu. To contact editorial author Preeti N. Malani, M.D., M.S.J., call Beata Mostafavi at 734-764-2220 or email bmostafa@med.umich.edu.

CHICAGO – Use of a vaccine to prevent Staphylococcus aureus infections among patients undergoing cardiothoracic surgery did not reduce the rate of serious postoperative S aureus infections compared with placebo and was associated with increased mortality among patients who developed S aureus infections, according to a study in the April 3 issue of JAMA.

Infections with S aureus following median sternotomy (incision through the midline of the sternum) cause substantial illness and death. “A safe vaccine that provides protection against a majority of S aureus strains during the postoperative period would address an important unmet medical need,” according to background information in the article. A novel vaccine candidate (V710) is immunogenic and generally well tolerated in volunteers, with elevated antibody responses persisting for at least 1 year after vaccination in most patients.

Vance G. Fowler Jr., M.D., M.H.S., of Duke University Medical Center, Durham, N.C., and colleagues conducted a phase 2b/3 study to evaluate the efficacy and safety of preoperative V710 vaccination in preventing serious postoperative S aureus infection in patients undergoing cardiothoracic surgery. The randomized trial was conducted between December 2007 and August 2011 among 8,031 patients 18 years of age or older who were scheduled for full median sternotomy within 14 to 60 days of vaccination at 165 sites in 26 countries. Participants were randomly assigned to receive a single intramuscular injection of either V710 vaccine (n=4,015) or placebo (n=4,016).

The independent data monitoring committee recommended termination of the study after the second interim analysis because of safety concerns and low efficacy. In the primary modified intention-to-treat analysis, V710 vaccine was not significantly more efficacious than placebo in preventing the prespecified primary end point (S aureus bacteremia and/or deep sternal wound infection through postoperative day 90) (22 adjudicated cases in 3,528 evaluable V710 recipients vs. 27 adjudicated cases in 3,517 evaluable placebo recipients). No significant differences in efficacy between the vaccine and placebo groups were observed at any point during the study.

The researchers also found that the V710 vaccine was not significantly more efficacious than placebo in preventing the secondary end points (all S aureus surgical site and invasive infections through postoperative day 90).

Compared with placebo, the V710 vaccine was associated with more adverse experiences during the first 14 days after vaccination (30.8 percent vs. 21.8 percent), including injection site reactions (20.1  percent vs. 9.5 percent) and serious adverse events (1.7 percent vs. 1.3 percent), and a significantly higher rate of multiorgan failure during the entire study (31 vs. 17 events).

Although the overall incidence of vaccine-related serious adverse events (1 in each group) and the all-cause mortality rate (201/3,958 vs. 177/3,967) were not statistically different between groups, the mortality rate in patients with staphylococcal infections was significantly higher among V710 vaccine than placebo recipients (15/73 vs. 4/96).

“In our study of adult patients undergoing cardiothoracic surgery, preoperative vaccination with V710 did not significantly reduce the composite incidence of S aureus bacteremia and deep sternal wound infection,” the authors write. “These findings do not support the use of the V710 vaccine for patients undergoing surgical interventions.”

(JAMA. 2013;309(13):1368-1378; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: The study was sponsored and funded by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co. Inc., Whitehouse Station, New Jersey. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, etc.

Editorial: Preventing Postoperative Staphylococcus aureus Infections – The Search Continues

Preeti N. Malani, M.D., M.S.J., of the University of Michigan Health System, Ann Arbor, Mich., (and Contributing Editor, JAMA), comments on the findings of this study in an accompanying editorial.

“While the prevention of S aureus infections should remain a priority for future investigation, novel approaches must move beyond vaccine strategies—and for that matter, beyond S aureus. Even if a viable staphylococcal vaccine were to be developed, this would not address non-S aureus infections. Burgeoning antimicrobial resistance results in an urgent, worldwide public health mandate. Progress in this arena will require expansion of preventive efforts and interventions that cover all organisms.”

(JAMA. 2013;309(13):1408-1409; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: The author has completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, APRIL 2, 2013

Media Advisory: To contact Ciaran J. McMullan, M.D., call Tom Langford at 617-534-1605 or email tlangford@partners.org.

CHICAGO – With previous evidence suggesting that melatonin may have a role in glucose metabolism, researchers have found an independent association between decreased secretion of melatonin and an increased risk for the development of type 2 diabetes, according to a study in the April 3 issue of JAMA.

“Melatonin receptors have been found throughout the body in many tissues including pancreatic islet cells, reflecting the widespread effects of melatonin on physiological functions such as energy metabolism and the regulation of body weight,” according to background information in the article. “Loss-of-function mutations in the melatonin receptor are associated with insulin resistance and type 2 diabetes. Additionally, in a cross-sectional analysis of persons without diabetes, lower nocturnal melatonin secretion was associated with increased insulin resistance.” A prospective association between melatonin secretion and type 2 diabetes has not been previously reported.

Ciaran J. McMullan, M.D., of Brigham and Women’s Hospital, Boston, and colleagues conducted a study to investigate the association of melatonin secretion and the incidence of type 2 diabetes. The analysis consisted of a case-control study nested within the Nurses’ Health Study cohort. Among participants without diabetes who provided urine and blood samples at baseline in 2000, the researchers identified 370 women who developed type 2 diabetes from 2000-2012 and matched 370 controls. Statistical analyses for determining associations between melatonin secretion at baseline and incidence of type 2 diabetes included controlling for demographic characteristics, lifestyle habits, measures of sleep quality, and biomarkers of inflammation and endothelial dysfunction.

Secretion of melatonin varied widely among participants in the study; the median (midpoint) urinary ratio of 6-sulfatoxymelatonin to creatinine was 67.0 ng/mg in the highest category compared with 14.4 ng/mg in the lowest category. The median ratio was significantly higher among controls (36.3 ng/mg) than among cases (28.2 ng/mg). Insulin sensitivity was higher among women with higher urinary ratios of 6-sulfatoxymelatonin to creatinine.

The researchers found that after controlling for body mass index and other lifestyle factors, menopausal status, family history of diabetes, history of hypertension, use of beta-blockers or non-steroidal anti-inflammatory drugs, region of the United States, and plasma biomarkers of diabetes risk, participants in the lowest category of urinary ratio of 6-sulfatoxymelatonin to creatinine had a 2.2 times higher odds of developing type 2 diabetes compared to participants in the highest category.

Women in the lowest category of melatonin secretion had an estimated diabetes incidence rate that was more than double that of women in the highest category (as measured by cases per 1,000 person-years).

“It is interesting to postulate from these data, in combination with prior literature, whether there is a causal role for reduced melatonin secretion in diabetes risk. Further studies are needed to determine whether increasing melatonin levels (endogenously via prolonged nighttime dark exposure or exogenously via supplementation) can increase insulin sensitivity and decrease the incidence of type 2 diabetes,” the authors conclude.

(JAMA. 2013;309(13):1388-1396; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: This work was supported by grants from the National Institutes of Health. The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr. Hu reported serving as a consultant to Novo Nordisk; and receiving grants from Merck and the Walnut Commission. No other author reported disclosures.

Please Note: An author podcast on this study will be available post-embargo on the JAMA website.

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, APRIL 2, 2013

Media Advisory: To contact Karen E. Joynt, M.D., M.P.H., call Todd Datz at 617-432-8413 or email tdatz@hsph.harvard.edu. To contact editorial author John P. A. Ioannidis, M.D., D.Sc., call Margarita Gallardo at 650-723-7897 or email mjgallardo@stanford.edu.

CHICAGO – In an analysis that included data on more than 10 million Medicare beneficiaries admitted to acute care hospitals with a heart attack, congestive heart failure, or pneumonia between 2002 and 2010, 30-day mortality rates for those admitted to critical access hospitals (designated hospitals that provide inpatient care to individuals living in rural communities) increased during this time period compared with patients admitted to other acute care hospitals, according to a study in the April 3 issue of JAMA.

“More than 60 million Americans live in rural areas and face challenges in accessing high-quality inpatient care. In 1997, the U.S. Congress created the Critical Access Hospital (CAH) program in response to increasing rural hospital closures,” according to background information in the article. “Hundreds of hospitals have joined the program over the past decade—by 2010, nearly 1 in 4 of the nation’s hospitals were CAHs. … These hospitals are at high risk of falling behind with respect to quality improvement, owing to their limited resources and vulnerable patient populations. How they have fared on patient outcomes during the past decade is unknown.”

Karen E. Joynt, M.D., M.P.H., of the Harvard School of Public Health, Boston, and colleagues conducted a study to evaluate trends in mortality for patients receiving care at CAHs and compared these trends with those for patients receiving care at non-CAHs. The study included data from Medicare fee-for-service patients admitted to U.S. acute care hospitals with acute myocardial infarction (heart attack; 1,902,586 admissions), congestive heart failure (4,488,269 admissions), and pneumonia (3,891,074 admissions) between 2002 and 2010. In 2010, 1,264 of 4,519 (28 percent) of U.S. hospitals providing acute care services to Medicare beneficiaries and reporting hospital characteristics to the American Hospital Association were designated as CAHs.

The researchers found that there were differences in trends in 30-day mortality rates over time between CAHs and non-CAHs for the 3 conditions examined. “When a composite across the 3 conditions was formally tested, adjusting for teaching status, ownership, region, rurality, poverty, and local physician supply, composite baseline mortality was similar between CAHs and non-CAHs (12.8 percent vs. 13.0 percent). However, between 2002 and 2010, mortality rates increased at CAHs at a rate of 0.1 percent per year, whereas at non-CAHs they decreased 0.2 percent per year, for a difference in change in mortality of 0.3 percent per year. Thus, by 2010, CAHs had higher overall mortality rates (13.3 percent vs. 11.4 percent). In total, CAH admissions were associated with 10.4 excess deaths per 1,000 admissions during the study period.”

The researchers note that although CAHs had higher mortality rates by 2010 for each of the conditions examined, the absolute difference was only 1.8 percent.

Patterns were similar for each of the 3 conditions individually. Comparing CAHs with other small, rural hospitals, similar patterns were found.

“Given the substantial challenges that CAHs face, new policy initiatives may be needed to help these hospitals provide care for U.S. residents living in rural areas,” the authors conclude.

(JAMA. 2013;309(13):1379-1387; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: Dr. Joynt was supported by a grant from the National Heart, Lung, and Blood Institute, National Institutes of Health.  All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.

Editorial: Are Mortality Differences Detected by Administrative Data Reliable and Actionable?

In an accompanying editorial, John P. A. Ioannidis, M.D., D.Sc., of the Stanford University School of Medicine, Stanford, Calif., writes that “to rigorously test potential interventions about how to improve the mortality rates at CAHs, cluster randomized controlled trials are needed.”

“These trials could randomize CAHs to different interventions regarding quality improvement initiatives, performance recording, or payment practices. Given the large volume of admissions, with about 20 randomized hospitals, a follow-up of about a year should suffice to obtain conclusive answers about specific tested interventions. If clinicians, administrators, and policy makers believe that administrative database results such as those reported by Joynt et al are clinically meaningful and relevant and not just spurious products of tenuous analyses, the modest cost of conducting such confirmatory randomized trials on health system changes is fully justified.”

(JAMA. 2013;309(13):1410-1411; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: Dr. Ioannidis is supported in part by an unrestricted gift from Sue and Robert O’Donnell. The author has completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, APRIL 2, 2013

Media Advisory: To contact Ellen M. Lavoie Smith, Ph.D., call Nicole Fawcett at 734-764-2220 or email nfawcett@umich.edu; or call Mary Beth Lewis at 734-763-1682 or email lewismb@umich.edu.

CHICAGO –Among patients with painful chemotherapy-induced peripheral neuropathy, use of the anti-depressant drug duloxetine for 5 weeks re­sulted in a greater reduction in pain compared with placebo, according to a study in the April 3 issue of JAMA.

“Approximately 20 percent to 40 percent of patients with cancer who re­ceive neurotoxic chemotherapy (e.g., taxanes, platinums, vinca alkaloids, bortezomib) will develop pain­ful chemotherapy-induced peripheral neuropathy. Painful chemotherapy-induced neuropathy can persist from months to years beyond chemotherapy completion, causing significant challenges for cancer survivors due to its negative in­fluence on function and quality of life. Chemotherapy-induced pe­ripheral neuropathy is difficult to manage, and most randomized controlled trials testing a variety of drugs with diverse mechanisms of action revealed no effective treatment,” according to background information in the article.

There is evidence that serotonin and norepinephrine dual reuptake inhibitors are effective in treat­ing neuropathy-related pain. Several phase 3 stud­ies have shown that duloxetine is an effec­tive treatment for painful diabetic neu­ropathy.

Ellen M. Lavoie Smith, Ph.D., of the University of Michigan School of Nursing, Ann Arbor, and colleagues conducted a ran­domized phase 3 trial to examine whether duloxetine would lessen chemotherapy-induced peripheral neuropathic pain. The study included 231 patients who were 25 years or older being treated at community and academic settings between April 2008 and March 2011. Study follow-up was com­pleted July 2012. Stratified by chemotherapeutic drug and comorbid pain risk, pa­tients were randomized to receive either duloxetine followed by placebo or placebo followed by duloxetine. Eligibility required that patients have a pain score of at least 4 on a scale of 0 to 10, representing average chemotherapy-induced pain, after paclitaxel, other taxane, or oxaliplatin treatment.

The initial treatment consisted of taking 1 capsule daily of either 30 mg of duloxetine or placebo for the first week and 2 capsules of either 30 mg of du­loxetine or placebo daily for 4 additional weeks.

The researchers found that at the end of the initial treatment pe­riod, patients in the duloxetine-first group reported a larger decrease in av­erage pain (average change score, 1.06) than those in the placebo-first group (average change score 0.34). The observed average differ­ence in the average pain score between the duloxetine-first and placebo-first groups was 0.73. Of the patients treated with dulox­etine first, 59 percent reported any decrease in pain vs. 38 percent of patients treated with placebo first. Thirty percent of duloxetine-treated patients reported no change in pain and 10 percent reported in­creased pain.

The authors note that the results sug­gested that patients who received plati­nums (oxaliplatin) may have experienced more benefit from duloxetine than those who received taxanes.

Pain-related quality-of-life im­proved to a greater degree for those treated with duloxetine during the ini­tial treatment than for those treated with placebo.

“In conclusion, 5 weeks of duloxetine treatment was associated with a statisti­cally and clinically significant improve­ment in pain compared with placebo. Exploratory analyses raise the possibility that duloxetine may work better for oxaliplatin-induced rather than taxane-induced painful chemotherapy-induced peripheral neuropathy,” the researchers write.

(JAMA. 2013;309(13):1359-1367; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: This study was supported by a grant from the NCI Division of Cancer Preven­tion, the Alliance Statistics and Data Center, and the Alliance Chairman. Drug and placebo were supplied by Eli Lilly. The NCI provided funding for data man­agement and statistical analysis. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, etc.

There will also be a digital news release available for this study, including the JAMA Report video, embedded and downloadable video, audio files, text, documents, and related links. This content will be available at 3 p.m. CT Tuesday, April 2 at this link.

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, MARCH 26, 2013

Media Advisory: To contact Josje Altenburg, M.D., email j.altenburg@mca.nl. To contact David J. Serisier, M.B.B.S., D.M., F.R.A.C.P., email david.serisier@mater.org.au. To contact editorial co-author J. Stuart Elborn, M.D., email s.elborn@qub.ac.uk.

CHICAGO – Among patients with the lung disorder non-cystic fibrosis bronchiectasis, treatment with the antibiotic azithromycin or erythromycin resulted in improvement in symptoms but also increased the risk of antibiotic resistance, according to two studies appearing in the March 27 issue of JAMA.

Bronchiectasis is characterized by abnormal widening of the bronchi (air tubes that branch deep into the lungs) and can cause recurrent lung infections, a disabling cough, shortness of breath, and coughing up blood. “If progressive, this process may lead to respiratory failure and the need for lung transplantation or to death,” according to background information in one study. Macrolide (a class of antibiotics) antibiotics have antibacterial and anti-inflammatory properties that conceivably would provide effective treatment of bronchiectasis. These antibiotics have been shown beneficial in treating cystic fibrosis (CF), and findings from small studies suggest a benefit in non-CF bronchiectasis.

Josje Altenburg, M.D., of the Medical Centre Alkmaar, the Netherlands, and colleagues conducted a multicenter trial to investigate whether 1 year of low-dose macrolide treatment added to standard therapy is effective in reducing exacerbation frequency in patients with non-CF bronchiectasis. The randomized, placebo-controlled trial was conducted between April 2008 and September 2010 in 14 hospitals in the Netherlands among 83 outpatients with non-CF bronchiectasis and 3 or more lower respiratory tract infections in the preceding year. Patients received azithromycin (250 mg daily) or placebo for 12 months.

Forty-three participants (52 percent) received azithromycin and 40 (48 percent) received placebo and were included in the modified intention-to-treat analysis. A total of 117 exacerbations treated with antibiotics were reported during 1 year of treatment, 78 of which occurred in the placebo group. “During the treatment period, the median [midpoint] number of exacerbations in the azithromycin group was 0, compared with 2 in the placebo group. Of the 40 participants receiving placebo, 32 (80 percent) had at least 1 exacerbation during the study period. In the 43 participants receiving azithromycin, 20 (46.5 percent) had at least 1 exacerbation in the same period, yielding an absolute risk reduction of 33.5 percent. The number of patients needed to treat with azithromycin to maintain clinical stability was 3.0,” the authors write.

“Gastrointestinal adverse effects occurred in 40 percent of patients in the azithromycin group and in 5 percent in the placebo group but without need for discontinuation of study treatment. A macrolide resistance rate of 88 percent was noted in azithromycin-treated individuals, compared with 26 percent in the placebo group.”

“We conclude that macrolide maintenance therapy was effective in reducing exacerbations in patients with non-CF bronchiectasis. In this trial, azithromycin treatment resulted in improved lung function and better quality of life but involved an increase in gastrointestinal adverse effects and high rates of macrolide resistance,” the authors write.

(JAMA. 2013;309(12):1251-1259; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc.

In another study, David J. Serisier, M.B.B.S., D.M., F.R.A.C.P., of Mater Adult Hospital, South Brisbane, Australia, and colleagues tested the hypothesis that low-dose erythromycin would reduce pulmonary exacerbations in patients with non-CF bronchiectasis with a history of frequent exacerbations.

The study consisted of a 12-month randomized controlled trial of erythromycin in currently nonsmoking, adult patients with non-CF bronchiectasis with a history of 2 or more infective exacerbations in the preceding year. The study was undertaken between October 2008 and December 2011 in a university teaching hospital. Patients received twice-daily erythromycin ethylsuccinate (400 mg) or matching placebo. The primary measured outcome was the annualized average rate of protocol-defined pulmonary exacerbations (PDPEs) per patient. Secondary outcomes included macrolide resistance and lung function.

Six-hundred seventy-nine patients were screened, 117 were randomized (58 placebo, 59 erythromycin), and 107 (91.5 percent) completed the study. The researchers found that erythromycin significantly reduced PDPEs (76 for the erythromycin group vs. 114 for the placebo group; average 1.29 vs. 1.97 respectively, per patient per year). The number of patients treated with erythromycin who had zero PDPEs was 20 (vs. 16 for placebo), and 10 patients had more than 2 PDPEs (vs. 18, respectively).

Erythromycin also reduced PDPEs in the prespecified subgroup with baseline Pseudomonas aeruginosa airway infection. In addition, there were significantly fewer total respiratory events (total PDPEs plus non-PDPEs) in the erythromycin group (111 vs. 176 for placebo; average, 1.88 vs. 3.03 per patient per year).

“Erythromycin reduced 24-hour sputum production and attenuated [lessened] lung function decline compared with placebo. Erythromycin increased the proportion of macrolide-resistant oropharyngeal streptococci,” the authors write.

“In conclusion, long-term low-dose erythromycin significantly reduced exacerbations, protected against lung function decline, reduced sputum production, and significantly increased macrolide resistance in oropharyngeal streptococci. The bacterial resistance caused by macrolide therapy mandates a cautious application of this therapy in clinical practice. Further studies are needed to evaluate the possibility that P aerugmosa-infected individuals with frequent exacerbations may represent an appropriate subgroup for limitation of this therapy.”

(JAMA. 2013;309(12):1260-1267; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: This study was internally funded by the Mater Adult Respiratory Research Trust Fund. No pharmaceutical company or other agency (including medical writers) had any role in this study. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, etc.

Editorial: Macrolides and Bronchiectasis – Clinical Benefit With a Resistance Price

“The important issues for clinicians are to determine which patients with bronchiectasis should be prescribed a macrolide and which macrolide should be used,” writes J. Stuart Elborn, M.D., and Michael M. Tunney, Ph.D., of Queen’s University Belfast, United Kingdom, in an accompanying editorial.

“In the trials in this issue of JAMA, patients were recruited if they had frequent exacerbations, defined as at least 2 or 3 exacerbations in the previous year. Therefore, patients with bronchiectasis who have 2 or more exacerbations in the previous year should be considered for treatment. Erythromycin and azithromycin are both effective for reducing exacerbations and have similar effects on antimicrobial resistance. The effect of long-term macrolide use on antibiotic resistance in these patients is not clear but should dissuade clinicians from prescribing macrolides for patients whose clinical characteristics differ from those for whom a positive effect was seen in these studies.”

(JAMA. 2013;309(12):1295-1296; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, MARCH 26, 2013

The Economics of Genomic Medicine – Insights From the IOM Roundtable on Translating Genomic-Based Research for Health

In this Viewpoint, W. Gregory Feero, M.D., Ph.D., of the Maine-Dartmouth Family Medicine Residency, Augusta, Maine (Dr. Feero is also Contributing Editor, JAMA), and colleagues discuss several of the issues that became apparent from the July 2012 Institute of Medicine’s (IOM’s) Roundtable on Translating Genomic-Based Research for Health, a meeting designed to identify critical gaps unique to understanding the economics of adopting whole-genome or exome sequence information into health care. “The meeting report, published by the IOM, highlights that genome-scale information challenges traditional economic assessment much as it challenges approaches of traditional health care delivery.”

“The dialogue started at the 2012 IOM meeting should be continued. Immediate next steps could include additional IOM-sponsored stakeholder meetings to further the discussion, publication of articles with detailed proposals for filling knowledge gaps identified by stakeholder groups, and stakeholder engagement in focused efforts to create standardized approaches for clinical use and economic assessment in this area. Additionally, there is an important role for an independent, impartial organization or organizations to help prioritize translational research, understand evidence thresholds, and mediate the development of a consensus approach for assigning value to genome sequencing.”

“Resolving and effectively managing economic factors influencing the use of genome sequencing in health care is a critical task facing the public and private sectors. Early and prompt attention to these issues could prove to be deterministic for both genomics and the U.S. health care system in the decades to come.”

(JAMA. 2013;309[12]:1235-1236. Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: Please see the articles for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc.

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, MARCH 26, 2013

Media Advisory: To contact Sandra Y. Lin, M.D., call David March at 410-955-1534 or email dmarch1@jhmi.edu. To contact editorial author Harold S. Nelson, M.D., call Adam Dormuth at 303-398-1082 or email DormuthA@NJHealth.org.

CHICAGO – In an examination of a type of treatment for allergic rhinitis and asthma that is used in Europe but not approved by the U.S. Food and Drug Administration, researchers found moderate strength in the evidence from previous studies to support the use of sublingual immunotherapy for the treatment of these conditions, according to an article in the March 27 issue of JAMA. Sublingual immunotherapy involves administration of aqueous allergens under the tongue for local absorption to desensitize the allergic individual over an extended treatment period to diminish allergic symptoms.

Allergic rhinitis (an allergic reaction with symptoms similar to a cold) affects approximately 20 percent to 40 percent of the U.S. population. Considerable interest has emerged in the use of sublingual immunotherapy as a treatment. Compared with subcutaneous (under the skin) immunotherapy, sublingual immunotherapy is easy to administer, does not involve administration of injections, and may be administered at home, avoiding office visits. “In 1996, a World Health Organization Task Force on Immunotherapy cited the emerging clinical data on sublingual immunotherapy, and recognized its potential as a viable alternative to subcutaneous therapy,” according to background information in the article. Some physicians in the U.S. use subcutaneous aqueous (watery) allergens, off-label, for sublingual desensitization.

Sandra Y. Lin, M.D., of the Johns Hopkins University School of Medicine, Baltimore, and colleagues conducted a systematic review of previous studies to examine the effectiveness and safety of aqueous sublingual immunotherapy for allergic rhinoconjunctivitis and asthma. After a review of the medical literature, the researchers identified 63 studies with 5,131 participants that met the inclusion criteria for the review. Participants’ ages ranged from 4 to 74 years. Twenty studies (n=1,814 patients) enrolled only children.

The researchers found strong evidence supporting that sublingual immunotherapy improves asthma symptoms, with 8 of 13 studies reporting greater than 40 percent improvement vs. the comparator. “Moderate evidence supports that sublingual immunotherapy use decreases rhinitis or rhinoconjunctivitis symptoms, with 9 of 36 studies demonstrating greater than 40 percent improvement vs. the comparator. Medication use for asthma and allergies decreased by more than 40 percent in 16 of 41 studies of sublingual immunotherapy with moderate grade evidence. Moderate evidence supports that sublingual immunotherapy improves conjunctivitis symptoms (13 studies), combined symptom and medication scores (20 studies), and disease-specific quality of life (8 studies).”

Evidence was similar in strength to support the use of sublingual immunotherapy in children (< 18 years of age) for allergic rhinitis and asthma.

Local reactions were frequent, but there were no reported episodes of anaphylaxis, life-threatening reactions, or death in any treated patients across studies.

“Our review found moderate strength in the evidence to support the use of sublingual immunotherapy for allergic rhinitis and asthma. This indicates moderate confidence that the evidence reflects a true efficacy. However, future research could change the estimate. High-quality studies are needed to answer questions of optimal dosing strategies,” the authors conclude.

(JAMA. 2013;309(12):1278-1288; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: This study was funded by a grant from the Agency for Healthcare Research and Quality (AHRQ) and is based on research conducted at the Johns Hopkins University Evidence-based Practice Center. The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr. Lin reported serving as a consultant to Wellpoint. No other author reported disclosures.

Editorial: Is Sublingual Immunotherapy Ready for Use in the United States?

Harold S. Nelson, M.D., of National Jewish Health, Denver, writes in an accompanying editorial that “although the publication of many studies has been reassuring regarding issues of efficacy and safety of sublingual immunotherapy, as reported by Lin et al, several concerns regarding use of sublingual immunotherapy in the United States remain.”

“There are no extracts licensed by the U.S. Food and Drug Administration (FDA) available for sublingual administration of immunotherapy. In the absence of any product for which appropriate dosing and safety have been established in the United States, there is no Current Procedural Terminology code for administering sublingual immunotherapy to patients in the United States.”

“Until sublingual immunotherapy gains FDA approval, physicians who choose to administer off-label sublingual immunotherapy will have limited guidance in selecting effective dosing. In addition, clinicians should be aware that the evidence for efficacy of sublingual immunotherapy is derived from studies of treatment with a single allergen extract, not with combinations of unrelated allergens.”

(JAMA. 2013;309(12):1297-1298; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: The author has completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr. Nelson reported receiving honoraria from Merck Research Laboratories and Circassia Ltd. for advisory activities; and receiving a research grant from Circassia Ltd.

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, MARCH 26, 2013

Media Advisory: To contact Gervasio A. Lamas, M.D., call Joanna Palmer at 305-674-2589 or email Jpalmer2@msmc.com. To contact editorial co-author Howard Bauchner, M.D., call Jann Ingmire at 312-464-2499 or email jann.ingmire@jamanetwork.org. To contact editorial author Steven E. Nissen, M.D., call Wyatt DuBois at 216-445-9946 or email duboisw@ccf.org.

CHICAGO – Although chelation therapy with the drug disodium EDTA has been used for many years with limited evidence of efficacy for the treatment of coronary disease, a randomized trial that included patients with a prior heart attack found that use of a chelation regimen modestly reduced the risk of a composite of adverse cardiovascular outcomes, but the findings do not support the routine use of chelation therapy for treatment of patients who have had a heart attack, according to a study in the March 27 issue of JAMA.

Chelation therapy is an intravenous administration of chelating agents (such as disodium ethylene diamine tetraacetic acid [EDTA]) to treat heavy metal toxicity. Based on favorable anecdotal and case report experience, chelation therapy has evolved in recent decades to include treatment for coronary and peripheral artery disease. “Three small clinical trials have assessed the effects of chelation on surrogate outcomes, such as walking distance in patients with claudication and time to exercise-induced ischemia in patients with coronary disease. These studies did not find any evidence of treatment efficacy but were underpowered for evaluation of clinical events,” according to background information in the article.

“As a consequence, mainstream medical organizations consider the therapeutic value of chelation for atherosclerotic vascular disease unproven and the use of this therapy potentially dangerous. Disodium EDTA, particularly when infused too rapidly, may cause hypocalcemia [abnormally low level of calcium in the blood] and death,” the authors write. Chelation therapy with disodium EDTA has been used for more than 50 years to treat atherosclerosis.

Gervasio A. Lamas, M.D., of the Columbia University Division of Cardiology at Mount Sinai Medical Center, Miami Beach, Fla., and colleagues conducted the Trial to Assess Chelation Therapy (TACT) to determine if an EDTA-based chelation regimen reduces cardiovascular events. The randomized trial enrolled 1,708 patients 50 years of age or older who had experienced a myocardial infarction (MI; heart attack) at least 6 weeks prior. Participants were recruited at 134 U.S. and Canadian sites. Enrollment began in September 2003 and follow-up took place until October 2011. Two hundred eighty-nine patients (17 percent of total; n=115 in the EDTA group and n=174 in the placebo group) withdrew consent during the trial. The median (midpoint) age was 65 years. The primary end point for the trial was a composite of total mortality, recurrent MI, stroke, coronary revascularization, or hospitalization for angina. Qualifying previous heart attacks occurred a median of 4.6 years before enrollment.

Patients were randomized to receive 40 infusions of a 500-mL chelation solution (3 g of disodium EDTA, 7 g of ascorbate, B vitamins, electrolytes, procaine, and heparin) (n=839) vs. placebo (n=869) and an oral vitamin-mineral regimen vs. an oral placebo. Infusions were administered weekly for 30 weeks, followed by 10 infusions 2 to 8 weeks apart. Fifteen percent discontinued infusions (n=38 [16 percent] in the chelation group and n=41 [15 percent] in the placebo group) because of adverse events.

The researchers found that the primary end point occurred in 222 (26 percent) of the chelation group and 261 (30 percent) of the placebo group. “There was no effect on total mortality (chelation: 87 deaths [10 percent]; placebo, 93 deaths [11  percent]), but the study was not powered for this comparison. The effect of EDTA chelation on the components of the primary end point other than death was of similar magnitude as its overall effect (MI: chelation, 6 percent; placebo, 8 percent; stroke: chelation, 1.2 percent; placebo, 1.5 percent; coronary revascularization: chelation, 15 percent; placebo, 18 percent; hospitalization for angina: chelation, 1.6 percent; placebo, 2.1  percent).”

Revascularizations accounted for 45 percent of the primary end point events. The composite of cardiovascular death, nonfatal MI, or nonfatal stroke occurred in 96 chelation patients (11 percent) and 113 placebo patients (13 percent).

The authors note that the study had several limitations, including an unusually high number of patients withdrawing consent.

“In stable patients with a history of MI, the use of an intravenous chelation regimen with disodium EDTA, compared with placebo, modestly reduced the risk of a composite of adverse cardiovascular outcomes, many of which were revascularization procedures. These results provide evidence to guide further research but are not sufficient to support the routine use of chelation therapy for treatment of patients who have had an MI,” the authors conclude.

(JAMA. 2013;309(12):1241-1250; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: The National Center for Complementary and Alternative Medicine and the National Heart, Lung, and Blood Institute provided sole support for this study. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, etc.

There will also be a digital news release available for this study, including the JAMA Report video, embedded and downloadable video, audio files, text, documents, and related links. This content will be available at 3 p.m. CT Tuesday, March 26 at this link.

Editorial: Evaluation of the Trial to Assess Chelation Therapy – The Scientific Process, Peer Review, and Editorial Scrutiny

In an accompanying editorial, Howard Bauchner, M.D., Editor-in-Chief, JAMA, and colleagues discuss some of the concerns regarding the TACT trial and the factors involved in deciding to publish the study.

“Clinical decision making is complex, reflecting a synthesis of evidence, physician experience, and patient preference, bound together by societal norms. As such, very few studies should immediately change clinical practice but, rather, most add incremental knowledge to the complex puzzle of a clinical decision. However, based on full consideration of the strengths and limitations of TACT, the conclusion is clear and should influence practice—these findings do not support the routine use of chelation therapy as secondary prevention for patients with previous myocardial infarction and established coronary disease. Whether chelation therapy may have any role in the prevention and treatment of cardiovascular disease remains to be determined.”

(JAMA. 2013;309(12):1291-1292; Available pre-embargo to the media at https://media.jamanetwork.com)

Editorial: Concerns About Reliability in the Trial to Assess Chelation Therapy

Steven E. Nissen, M.D., of the Cleveland Clinic Foundation, writes in an accompanying editorial that “TACT represents a situation in which many important limitations in the design and execution of a clinical trial compromise the reliability of the study and render the results difficult to interpret.”

“Nonetheless, all randomized controlled trials should be published because even failed trials provide valuable scientific lessons for the medical community. Accordingly, TACT provides useful insights into the overwhelming challenges faced when trying to determine the effectiveness of an unusual and controversial therapy.”

“Given the numerous concerns with this expensive, federally funded clinical trial, including missing data, potential investigator or patient unmasking, use of subjective end points, and intentional unblinding of the sponsor, the results cannot be accepted as reliable and do not demonstrate a benefit of chelation therapy. The findings of TACT should not be used as a justification for increased use of this controversial therapy.”

(JAMA. 2013;309(12):1293-1294; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: The author has completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr. Nissen reports grants/grants pending to his institution from Lilly, the Medicines Company, Amgen, Takeda, Novo Nordisk, Vivus, Orexigen, Novartis, Pfizer, and Resverlogix.

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, MARCH 19, 2013

Health Services Innovation – The Time is Now

“Biomedical innovation has improved prevention, diagnosis, and treatment resulting in reduction in mortality for most diseases. However, health and health care disparities remain across the life-span because these advances have not been matched by advances in delivering care, patient engagement, adherence, or access to these advanced care strategies,” writes Barry Zuckerman, M.D., of the Boston University School of Medicine, Boston, and colleagues. In this Viewpoint, the authors examine the opportunities and challenges of clinician-led innovation.

“Developing approaches to support innovation and non-incremental improvements are important to make the health system work better at the front-lines of care where patients and physicians meet. The current model of producing change through clinical research is costly and not effective at solving many modem delivery system problems. The time is now for a health services innovation incubator where physicians can rapidly address frontline health care delivery problems and improve health.”

(JAMA. 2013;309[11]:1113-1114. Available pre-embargo to the media at https://media.jamanetwork.com)

Educating Physicians About Responsible Management of Finite Resources

“Despite the enormous resources at stake, physicians receive little education in how to manage and steward finite resources, making formal education of physicians in ‘program integrity’ an essential component of medical professionalism,” writes Shantanu Agrawal, M.D., of the Centers for Medicare & Medicaid Services, Baltimore, and colleagues.

“Addressing shortcomings in program integrity education will require a comprehensive solution across numerous stakeholders. This issue is central to medical professionalism and ethics because it speaks directly to the trust placed in the medical profession by patients and society. Payment reforms will no doubt alter the program integrity landscape and shift incentives, but they will not supplant the need for physician awareness. While federal and state governments are vital participants, leaders in medical education, licensure, and specialty certification would ideally work together to ensure that all physicians have sufficient awareness to safeguard public and private health care programs, patients, and themselves.”

(JAMA. 2013;309[11]:1115-1116. Available pre-embargo to the media at https://media.jamanetwork.com)

Can Accountable Care Organizations Improve Population Health? Should They Try?

Douglas J. Noble, M.D., M.P.H., and Lawrence P. Casalino, M.D., Ph.D., of Weill Cornell Medical College, New York, write that there are a number of difficult issues regarding accountable care organizations (ACOs) and the improvement of population health.

“Should ACOs be given incentives to improve the health of the population in their geographic area? Who would give these incentives? Should there be incentives for accountable health communities, and, if so, who would provide them? It will only be possible to have this debate if the phrase population health is used clearly, and not as a vague way of referring to what ACOs are currently doing.”

(JAMA. 2013;309[11]:1119-1120. Available pre-embargo to the media at https://media.jamanetwork.com)

Bridging the Divide Between Health and Health Care

Stephen M. Shortell, Ph.D., M.P.H., M.B.A., of the University of California, Berkeley, writes that “consensus is developing that truly controlling health care costs and improving the overall health of the American people will require a much closer partnership, permeable boundaries, and increased interdependence among the health care delivery system, the public health sector, and the community development and social service sectors. … If the goal is improved overall population health, all 3 sectors need to take certain actions.”

“Like a hologram in which the whole is embedded in each part, health care delivery is embedded into population health and population health is embedded into health care delivery. It is now the responsibility of clinicians and health care delivery organizations to help maintain the health of the community and the responsibility of the community to help maintain the health of the individual.”

(JAMA. 2013;309[11]:1121-1122. Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: Please see the articles for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc.

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, MARCH 19, 2013

Media Advisory: To contact Steven M. Opal, M.D., call David Orenstein at 401-863-1862 or email david_orenstein@brown.edu.

CHICAGO – Administration of the drug eritoran to patients with severe sepsis and septic shock failed to demonstrate a significant effect on reducing all-cause 28-day mortality or 1-year mortality, compared with placebo, according to a study in the March 20 issue of JAMA.

Severe sepsis, a syndrome of acute infection complicated by organ dysfunction, is caused by a dysregulated systemic inflammatory response. Sepsis can progress to systemic hypotension (septic shock), multiple organ dysfunction, and death. “Lipopolysaccharide (LPS) or endotoxin, the major component of the outer membrane of gram-negative bacteria, is a potent stimulator of the inflammatory response. LPS triggers inflammation in gram-negative sepsis,” according to background information in the article. Eritoran, a synthetic analog (a substance that is similar, but not identical, to another) of lipid A, is a potent and specific antagonist of LPS action. In a phase 2 trial, eritoran-treated patients at high risk of death had lower mortality that was not statistically significant.

Steven M. Opal, M.D., of the Alpert Medical School of Brown University, Providence, R.I., and colleagues conducted a phase 3 trial to evaluate the safety and efficacy of eritoran in reducing mortality in patients with severe sepsis. The randomized, multinational trial was conducted in 197 intensive care units. Patients were enrolled from June 2006 to September 2010 and final follow-up was completed in September 2011. Patients with severe sepsis (n=1,961) were randomized and treated within 12 hours of onset of first organ dysfunction in a 2:1 ratio with a 6-day course of either eritoran tetrasodium (105 mg total) or placebo, with n=1,304 and n=657 patients, respectively. The primary end point for the study was 28-day all-cause mortality. The secondary end points were all-cause mortality at 3, 6, and 12 months after beginning treatment.

The researchers found that treatment with eritoran did not result in significant reductions in the primary study end point of 28-day mortality in the modified intent-to-treat analysis (randomized patients who received at least 1 dose) population; 28.1 percent (366/1,304) of patients in the eritoran group vs. 26.9 percent (177/657) of patients in the placebo group.

There was also no significant difference in the secondary end point of 1-year all-cause mortality: 44.1 percent (290/657) in the eritoran group vs. 43.3 percent (565/1,304) in the placebo group.

Eritoran was well tolerated with comparable numbers of treatment-emergent adverse events (TEAEs) and serious TEAEs between eritoran and placebo groups.

“These findings are in contrast with several preclinical studies and in phase 1 clinical trials in which eritoran terminated lipopolysaccharide-associated molecular and clinical events when administered in adequate doses. Despite these promising early results, no evidence of significant benefit was observed with eritoran in this large phase 3 trial,” the authors write. “Eritoran joins a long list of other experimental sepsis treatments that do not improve outcomes in clinical trials in these critically ill patients.”

(JAMA. 2013;309(11):1154-1162; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: Eisai Inc., Woodcliff Lake, N.J., provided financial support for the initial design, study medications and conduct of the study. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, etc.

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, MARCH 19, 2013

Media Advisory: To contact corresponding author Frank-Erik de Leeuw, M.D., Ph.D., email H.deLeeuw@neuro.umcn.nl. To contact editorial author Graeme J. Hankey, M.D., F.R.C.P., F.R.C.P. Edin., F.R.A.C.P., email graeme.hankey@uwa.edu.au.

CHICAGO – In an examination of long-term mortality after stroke, adults 50 years of age and younger who experienced a stroke had a significantly higher risk of death in the following 20 years compared with the general population, according to a study in the March 20 issue of JAMA.

“Stroke is one of the leading causes of mortality, with an annual 6 million fatal events worldwide. Stroke mainly affects elderly people, yet approximately 10 percent of strokes occur in patients younger than 50 years. Despite this considerable proportion, only limited data exist on long-term prognosis after stroke in adults aged 18 through 50 years. It is exactly this long-term prognosis that is particularly important in adults in these ages, given that they have a long life expectancy during a demanding time of life in which they are beginning their families and building their careers,” according to background information in the article.

Loes C. A. Rutten-Jacobs, M.Sc., of Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands, and colleagues conducted a study to investigate long-term mortality and cause of death after first acute stroke among adults 18 through 50 years of age and to compare this with nationwide age- and sex-matched mortality rates. The study included adults with transient ischemic attack (TIA), ischemic stroke, or hemorrhagic stroke admitted to a medical center between January 1980 and November 2010. The survival status of 959 patients with a first-ever TIA (n=262), ischemic stroke (n =606), or intracerebral hemorrhage (n=91) was assessed as of November 1, 2012. Average follow-up duration was 11.1 years. Observed mortality was compared with the expected mortality, derived from mortality rates in the general population with similar age, sex, and calendar-year characteristics.

During the follow-up period, 192 patients (20.0 percent) had died. The researchers found that the cumulative 20-year mortality risk was 24.9 percent for patients with TIA; 26.8 percent for patients with ischemic stroke; and 13.7 percent for patients with ICH. Analysis of the data indicated that after surviving the first 30 days after ischemic stroke, the cumulative mortality was increased compared with expected based on nationwide population mortality data. “This mortality remained at this higher level even in the second and third decade after young [18-50 years of age] stroke. In patients who survived the first 30 days after an ICH, mortality gradually coincided with that expected.”

The cumulative 20-year mortality for ischemic stroke among 30-day survivors was higher in men than in women (33.7 percent vs. 19.8 percent).

The authors point out that their study showed an excess in mortality compared with the general population (in which half of deaths were attributable to a vascular cause), even decades after stroke. “This may suggest that the underlying (vascular) disease that caused the stroke at relatively young age continues to put these patients at an increased risk for vascular disease throughout their lives. It may also be noted that risk factors indicated in the study group, such as smoking and alcohol consumption, seem likely to confer risk as well.”

“Although data are currently lacking, the observation of long-term increased risk for vascular disease could have important implications for the implementation of secondary prevention (both medical and lifestyle) treatment strategies. Future studies should address the role of this stringent implementation in these patients with young stroke.”

(JAMA. 2013;309(11):1136-1144; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: This study was supported by the Dutch Epilepsy Fund and by a Vidi innovational grant from the Netherlands Organization for Scientific Research. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, etc.

Please Note: An author podcast on this study will be available post-embargo on the JAMA website.

Editorial: Stroke in Young Adults – Implications of the Long-term Prognosis

Graeme J. Hankey, M.D., F.R.C.P., F.R.C.P. Edin., F.R.A.C.P., of the University of Western Australia, Perth, writes in an accompanying editorial that the “implications for researchers of the results reported by Rutten-Jacobs et al are that efforts to reduce the burden of stroke among young adults should extend beyond acute treatment and early secondary prevention into the long-term.”

“Hence, studies evaluating the effectiveness, safety, and cost of interventions to prevent recurrent cardiovascular events and death among adults younger than 50 years with stroke should acknowledge the continuing augmented risk of death throughout subsequent decades and continue the intervention and follow-up in the long term, when substantial yields are likely to be realized. The study by Rutten-Jacobs et al indicates that secondary prevention after stroke in young adults is a long-term, and probably lifelong, endeavor.”

(JAMA. 2013;309(11):1171-1172; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: The author has completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and reported receiving honoraria from Bayer Pharmaceuticals for lectures at sponsored scientific symposia on new oral anticoagulants for stroke prevention in atrial fibrillation.

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, MARCH 19, 2013

Media Advisory: To contact Maria C. Raven, M.D., M.P.H., M.Sc., call Elizabeth Fernandez at 415-514-1592 or email efernandez@pubaff.ucsf.edu. To contact editorial author James G. Adams, M.D., call Erin White at 847-491-4888 or email ewhite@northwestern.edu.

CHICAGO – Among patients with emergency department (ED) visits with the same presenting complaint as those with visits ultimately given a primary care-treatable diagnosis based on the ED discharge diagnosis, a substantial proportion required immediate emergency care or hospital admission, findings that do not support use of discharge diagnosis as the basis for policies discouraging ED use, according to a study in the March 20 issue of JAMA.

“With increasing medical care costs, policymakers have turned to ED utilization as a potential source for cost savings,” according to background information in the article. “One approach aimed at reducing ED use has been to deny or limit payment if the patient’s diagnosis on discharge from the ED appears to reflect a ‘nonemergency’ condition. … For this approach to be effective at reducing nonemergency ED use without discouraging ED use for more serious conditions, it would be necessary to predict discharge diagnosis based on information available before the patient is seen in the ED—i.e., based on presenting symptoms. Many have questioned whether this approach is possible.”

Maria C. Raven, M.D., M.P.H., M.Sc., of the University of California, San Francisco, and colleagues conducted a study to determine the association between ED presenting complaint and ED discharge diagnosis. The researchers applied the New York University emergency department algorithm to publicly available ED visit data from the 2009 National Hospital Ambulatory Medical Care Survey (NHAMCS) for the purpose of identifying all “primary care-treatable” visits. This algorithm has been commonly used to identify nonemergency ED visits. The 2009 NHAMCS data set contains 34,942 records, each representing a unique ED visit. For each visit with a discharge diagnosis classified as primary care treatable, the authors identified the chief complaint. To determine whether these chief complaints correspond to nonemergency ED visits, all ED visits were examined with this same group of chief complaints to ascertain the ED course, final disposition, and discharge diagnoses.

Of the 34,942 ED visits included in the study, an estimated 6.3 percent had primary care-treatable diagnoses based on the ED discharge diagnosis and modification of the algorithm. “However, the presenting complaints associated with the ED visits (i.e., nonemergency complaints) were also the presenting complaints for 88.7 percent of all ED visits, reflecting poor correspondence between ED discharge diagnosis and chief complaint. These findings were similar for age-stratified subgroups,” the authors write.

Of the ED visits for chief complaints that were identical to chief complaints generated by the group of ED visits with primary care-treatable diagnoses, 11.1 percent  had been triaged as needing immediate or emergency care. In addition, 79.7 percent of patients had at least 1 abnormal triage vital sign recorded, with the most common vital sign abnormalities being respiratory rate and blood pressure.

“Regarding disposition of patients with nonemergency-complaint ED visits, 12.5 percent were admitted to the hospital. Of admitted patients, 11.2 percent were admitted to a critical care unit, 22.9 percent required step-down or telemetry monitoring, 3.4 percent required the operating room, and 7.0 percent were admitted to an observation unit,” the researchers write. For patients with nonemergency-complaint ED visits, the 3 most common diagnoses identified were abdominal pain, unspecified site, acute respiratory infection, and chest pain, unspecified.

The authors add that based on the findings of this study, if a triage nurse were to redirect patients away from the ED based on nonemergency complaints, 93 percent of the redirected ED visits would not have had primary care-treatable diagnoses.

“These results highlight the flaws of a conceptual framework that fails to distinguish between information available at arrival in the ED and information available at discharge from the ED. The results call into question reimbursement policies that deny or limit payment based on discharge diagnosis. Attempting to discourage patients from using the ED based on the likelihood that they would have nonemergency diagnoses risks sending away patients who require emergency care. The majority of Medicaid patients, who stand to be disproportionately affected by such policies, visit the ED for urgent or more serious problems.”

(JAMA. 2013;309(11):1145-1153; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc.

There will also be a digital news release available for this study, including the JAMA Report video, embedded and downloadable video, audio files, text, documents, and related links. This content will be available at 3 p.m. CT Tuesday, March 19 at this link.

Editorial: Emergency Department Overuse – Perceptions and Solutions

“This article by Raven et al indicates that some intuitive, oversimplified, yet enduring beliefs about nonurgent patients in the ED should be abandoned,” writes James G. Adams, M.D., of the Northwestern University Feinberg School of Medicine, Chicago, in an accompanying editorial.

“Trying to discern low-acuity conditions and putting up barriers to receiving care or denying payment after receiving care will work no better in future generations than in the past. Attention should be redirected away from penalizing patients, physicians, or hospitals when a condition turns out to be minor. Instead, the emphasis should be on integration across sites of care, especially for the most complex and most expensive patients. Such initiatives are developing in many regions, but are not yet the norm. This is perhaps something of a new approach, especially for emergency caregivers whose primary focus is currently on diagnosis and treatment of the immediate issue in question, not assessment and guidance of the long-term use and care coordination. The ED needs to become a willing and able partner in this regard. It is not the low-acuity visits contributing to the national cost crisis, but the high-acuity ones. Fortunately, many high-acuity visits are often preventable. Better coordination across services will help the U.S. health care system achieve more cost-effective and high-quality outcomes.”

(JAMA. 2013;309(11):1173-1174; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: The author has completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, MARCH 12, 2013

Teaching Physicians to Care Amid Chaos

Allan S. Detsky, M.D., Ph.D., of the University of Toronto, and Donald M. Berwick, M.D., of Harvard Medical School, Boston, examine the changes that have taken place in patient care in recent decades. “In 2013, inpatient medical care in teaching hospitals is different: far more complex, more intense, and, simply put, faster.” One of the results of these changes is that “inpatient care in teaching hospitals has become a relay race for the responsible physicians and consultants, and patients are the batons.”

In this Viewpoint, the authors offer suggestions on how to address the issues of rapid turnover and diffused responsibility among hospital staff.

“We are certain that today’s trainees are not a whit less dedicated to their professional mission than those of an earlier era were at their best, but we cannot help wonder whether the very definition of caring changes in undesirable and unintended ways when responsibility becomes a rapidly revolving door. If that risk exists, it warrants conversation.”

(JAMA. 2013;309[10]:987-988. Available pre-embargo to the media at https://media.jamanetwork.com)

Putting Health IT on the Path to Success

William A. Yasnoff, M.D., Ph.D., of NHII Advisors, Arlington, Va., and colleagues discuss the problems with the current approach to health information technology (HIT), and suggest an alternative that is “simpler, scalable, less expensive, and more secure and can provide lifetime records: patient-centric community health record banks (HRBs).”

“The idea of HRBs is not new. What is new is appreciating how HRBs can help achieve the HIT vision while most current health information exchange (HIE) pursuits cannot. It is time for physicians to insist that HIT be pursued with realistic, achievable, and measurable goals that will produce readily available, comprehensive electronic records that can actually improve patient care. To do so requires implementation of model health record banks and then refinement of those models to allow them to achieve the sustainability and scalability that have prevented the success of distributed HIEs. Otherwise, HIT may become its own sociopolitical, legal, and economic disease.”

(JAMA. 2013;309[10]:989-990. Available pre-embargo to the media at https://media.jamanetwork.com)

Improving the Electronic Health Record— Are Clinicians Getting What They Wished For?

James J. Cimino, M.D., of the Laboratory for Informatics Development, National Institutes of Health Clinical Center, Bethesda, Md., examines the “promise and perils” regarding the increase in adoption of electronic health records (EHRs).

“EHRs had to start someplace, and they have delivered the wishes of many. Rather than complain about the challenges they have introduced, clinicians should recognize that current EHRs are illuminating the opportunities for the next generation of systems that will support clinicians as active partners across the spectrum of health care settings and tasks. The resulting improvements in documentation will, in turn, support patients, administrators, and researchers as we move towards a true learning health system.”

(JAMA. 2013;309[10]:991-992. Available pre-embargo to the media at https://media.jamanetwork.com)

Helping Smokers Quit Around the Time of Surgery

In this Viewpoint, Dhruv Khullar, B.A., of the Yale University School of Medicine, New Haven, Conn., and colleagues discuss the reasons many physicians do not routinely counsel patients to stop smoking before an operation or do not refer them to appropriate cessation services.

“As accrediting agencies and public and private payers search more intensely for value in health care, surgeons must aim to improve postoperative outcomes. An effective strategy will be to encourage patients to stop smoking preoperatively, thereby potentially reducing postoperative complications and length of hospital stay. Collaborations with primary care physicians, anesthesiologists, nurses, and others can facilitate smoking cessation and the delivery of better surgical care.”

(JAMA. 2013;309[10]:993-994. Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: Please see the articles for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc.

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, MARCH 12, 2013

Media Advisory: To contact Adnan K. Chhatriwalla, M.D., call Kerry A. O’Connor at 816-932-8646 or email koconnor@saint-lukes.org.

CHICAGO – In a study that included 3.3 million percutaneous coronary intervention (PCI; procedures such as balloon angioplasty or stent placement used to open narrowed coronary arteries) procedures, major bleeding after PCI was associated with significantly increased in-hospital mortality, with an estimated 12 percent of deaths after PCI related to bleeding complications, according to a study appearing in the March 13 issue of JAMA.

“Bleeding represents the most common noncardiac complication of PCI. Postprocedural bleeding is associated with short- and long-term death, nonfatal myocardial infarction, stroke, blood transfusion, prolonged hospital stay, rehospitalization, and increased hospital costs. Post-PCI bleeding is predictable, using tools such as the bleeding risk algorithm derived from the CathPCI Registry. Bleeding risk is modifiable through the use of established bleeding avoidance strategies such as bivalirudin anticoagulation, arterial closure devices, and radial artery access,” according to background information in the article. “The incidence of bleeding-related mortality after PCI has not been described in a nationally representative population. Furthermore, the relationships among bleeding risk, bleeding site, and mortality are unclear.”

Adnan K. Chhatriwalla, M.D., of Saint Luke’s Mid America Heart Institute, Kansas City, Mo., and colleagues conducted a study to estimate the adjusted population attributable risk of bleeding-related mortality in the U.S. PCI population. The study included data from 3,386,688 procedures in the CathPCI Registry performed in the United States between 2004 and 2011. The population attributable risk was calculated after adjustment for baseline demographic, clinical, and procedural variables. Also, the number needed to harm (NNH) for bleeding-related mortality was calculated.

In the total study population, there were 57,246 major bleeding events (1.7 percent) and 22,165 in-hospital deaths (0.65 percent). The adjusted population attributable risk of in-hospital mortality related to major bleeding was 12.1 percent. The propensity-matched population consisted of 56,078 procedures with major bleeding and 224,312 matched controls. The researchers found that patients with major bleeding had significantly higher in-hospital mortality relative to patients without bleeding (5.3 percent vs. 1.9 percent). Both access-site and non-access-site bleeding were associated with increased in-hospital mortality (2.7 percent vs. 1.9 percent; and 8.3 percent vs. 1.9 percent, respectively). The association between major bleeding and in-hospital mortality was observed in all levels of bleeding risk (low-, intermediate-, and high-risk groups).

The researchers conducted an analysis regarding the number of major bleeding events associated with 1 in-hospital mortality (NNH) in selected subgroups. “The NNH varied between 16 and 117, depending on bleeding risk and bleeding site, and was lowest in patients at high risk for bleeding (NNH = 21) or with non-access-site bleeding (NNH=16). NNH values were lowest in the following patient subgroups: age 75 years or older, ST-segment elevation myocardial infarction [a certain pattern on an electrocardiogram following a heart attack], or low glomerular filtration rate.”

“In this study of more than 3.3 million PCI procedures, we found that major bleeding was associated with significantly increased in-hospital mortality after PCI. The novel findings are that adjusted population attributable risk estimates for an unselected and nationally representative U.S. PCI population suggest that 12.1 percent of all in-hospital mortality after PCI may be related to bleeding complications and may therefore be modifiable…”, the authors write.

(JAMA. 2013;309(10):1022-1029; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: This research was supported by the American College of Cardiology Foundation’s National Cardiovascular Data Registry (NCDR). Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, etc.

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, MARCH 12, 2013

Media Advisory: To contact co-author R. Doug McEvoy, M.D., email doug.mcevoy@health.sa.gov.au.

CHICAGO – Among patients who were identified as likely having moderate to severe obstructive sleep apnea, treatment based in primary care was not clinically inferior to treatment at a specialist sleep center for improvement in daytime sleepiness scores, according to a study appearing in the March 13 issue of JAMA.

“Obstructive sleep apnea with accompanying daytime sleepiness was estimated during the early 1990s to affect between 2 percent and 4 percent of middle-aged adults. With growing awareness of the public health implications of untreated disease and rising obesity rates that have increased the prevalence of obstructive sleep apnea, there has been a steady demand for sleep service provision in specialist centers and growing waiting lists for sleep physician consultation and laboratory-based polysomnography (PSG),” according to background information in the article. “One-third of primary care patients report symptoms suggestive of obstructive sleep apnea. With appropriate training and simplified management tools, primary care physicians and practice nurses might be ideally positioned to take on a greater role in diagnosis and management.” However, whether an ambulatory approach would be noninferior (outcome not worse than treatment compared to) in a primary care setting is unknown.

Ching Li Chai-Coetzer, M.B.B.S., Ph.D., of the Adelaide Institute for Sleep Health, Repatriation General Hospital, Daw Park, South Australia, and colleagues conducted a study to compare the clinical efficacy and within-trial costs of a simplified model of diagnosis and care in primary care relative to that in specialist sleep centers. The randomized, controlled, noninferiority study included 155 patients with obstructive sleep apnea who were treated at primary care practices (n = 81) in metropolitan Adelaide, three rural regions of South Australia or at a university hospital sleep medicine center in Adelaide, Australia (n = 74), between September 2008 and June 2010. Both interventions (primary care management vs. usual care in a specialist sleep center) included continuous positive airway pressure, mandibular (lower jaw) advancement splints, or conservative measures only. The primary outcome measure was 6-month change in scores on the Epworth Sleepiness Scale (ESS). Secondary outcomes included disease-specific and general quality of life measures, obstructive sleep apnea symptoms, adherence to using continuous positive airway pressure, patient satisfaction, and health care costs.

The researchers found that there were significant improvements in ESS scores from baseline to 6 months in both groups. “The mean [average] ESS for the entire study population was 12.6. The mean ESS scores in the primary care group improved from 12.8 at baseline to 7.0 at 6 months, for an adjusted mean difference of 5.8 and in the specialist group from a baseline mean of 12.5 to 7.0 at 6 months, for an adjusted mean difference of 5.4. After controlling for baseline ESS score and region, the adjusted difference in the mean change in the ESS score was -0.13.” The results the support noninferiority of primary care management.

There were no differences in secondary outcome measures between groups. Seventeen patients (21 percent) withdrew from the study in the primary care group vs. 6 patients (8 percent) in the specialist group. Adherence to CPAP use among those using it at 6 months was no different between the 2 groups.

Analysis of within-trial sleep-related diagnostic and treatment costs revealed that primary care management of obstructive sleep apnea was approximately 40 percent less expensive than specialist care. The equivalent total average costs per patient were estimated at U.S. $1,819 in the primary care group and U.S. $3,068 in the specialist group. Sleep study costs, sleep physician consultations, and travel costs appeared to be the main contributors to the increased within-trial costs in the specialist group.

“In conclusion, in this randomized controlled study, a simplified management strategy for obstructive sleep apnea based in primary care was not clinically inferior to standard care in a specialist sleep center. It possibly could be delivered at a lower cost. Thus, with adequate training of primary care physicians and practice nurses and with appropriate funding models to support an ambulatory strategy, primary care management of obstructive sleep apnea has the potential to improve patient access to sleep services. This would be particularly beneficial for rural and remote regions, as well as developing nations, where access to specialist services can be limited,” the authors write.

(JAMA. 2013;309(10):997-1004; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc.

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, MARCH 12, 2013

Media Advisory: To contact Richard M. Martin, Ph.D., email richard.martin@bristol.ac.uk.

CHICAGO – In research that included nearly 14,000 healthy infants in Belarus, an intervention that succeeded in improving the duration and exclusivity of breastfeeding during infancy did not result in a lower risk of overweight or obesity among the children at age 11.5 years, according to a study appearing in the March 13 issue of JAMA.

Observational studies suggest that greater duration and exclusivity of having been breastfed reduces child obesity risk. “However, breastfeeding and growth are socially patterned in many settings,” and observed associations between these variables are at least partly explained by confounding factors, according to background information in the article.

Richard M. Martin, Ph.D., of the University of Bristol, England, and colleagues investigated the effects of an intervention to promote increased duration and exclusivity of breastfeeding on child adiposity (body fat) and circulating insulin-like growth factor 1 (IGF-1), which regulates growth. The randomized controlled trial was conducted in 31 Belarusian maternity hospitals and their affiliated clinics. Participants were randomized into 1 of 2 groups: breastfeeding promotion intervention or usual practices. Participants were 17,046 breastfeeding mother-infant pairs enrolled in 1996 and 1997, of whom 13,879 (81.4 percent) were followed up between January 2008 and December 2010 at a median (midpoint) age of 11.5 years. The breastfeeding promotion intervention was modeled on the WHO/UNICEF Baby-Friendly Hospital Initiative (World Health Organization/United Nations Children’s Fund). The main outcome measures were body mass index (BMI), fat and fat-free mass indices (FMI and FFMI), percent body fat, waist circumference, triceps and subscapular skinfold thicknesses, overweight and obesity, and whole-blood IGF-1.

As previously reported, the researchers found that infants in the intervention group had substantially increased breastfeeding duration and exclusivity vs. the control group: at 3 months, exclusively (43.3 percent vs. 6.4 percent) and predominantly (51.9 vs. 28.3 percent) breastfed; at 6 months, both exclusive (7.9 percent vs. 0.6 percent) and predominant breastfeeding (10.6 percent vs. 1.6) were lower, but more common in the intervention group; and at 12 months, 19.7 percent (intervention) vs. 11.4 percent (control), were still breastfeeding to any degree.

At followup, when children were a median 11.5 years age, there were no significant differences between the experimental vs. control groups for the main outcomes, with the cluster-adjusted mean [average] differences of 0.19 (95 percent CI, -0.09 to 0.46) for BMI; 0.12 for FMI; 0.04 for FFMI; 0.47 percent for percent body fat; 0.30 cm for waist circumference; -0.07 mm for triceps and -0.02 mm for subscapular skinfold thicknesses; and -0.02 standard deviations for IGF-1.

The cluster-adjusted odds ratio for overweight/obesity (BMI ≥85th vs. <85th percentile) was 1.18 (95 percent CI, 1.01 to 1.39) and for obesity (BMI ≥95th vs. <85th percentile) was 1.17 (95 percent CI, 0.97 to 1.41).

“Among healthy term infants in Belarus, an intervention to improve the duration and exclusivity of infant breastfeeding did not prevent overweight or obesity, nor did it affect IGF-1 levels among these children when they were aged 11.5 years. Nevertheless, breastfeeding has many health advantages for the offspring, including beneficial effects demonstrated by our PROBIT trial on gastrointestinal infections and atopic eczema in infancy and improved cognitive development at age 6.5 years. Although breastfeeding is unlikely to stem the current obesity epidemic, its other advantages are amply sufficient to justify continued public health efforts to promote, protect, and support it,” the researchers conclude.

(JAMA. 2013;309(10):1005-1013; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc.

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, MARCH 12, 2013

Media Advisory: To contact corresponding author Carole Clair, M.D., M.Sc., email carole.willi@gmail.com. To contact co-author James B. Meigs, M.D., M.P.H., call Ryan Donovan at 617-724-6433 or email rcdonovan@partners.org. To contact editorial co-author Michael C. Fiore, M.D., M.P.H., M.B.A., call Christopher Hollenback at 608-262-3902 or email ch3@ctri.wisc.edu.

CHICAGO – Among adults without diabetes, quitting smoking, compared with continuing smoking, was associated with a lower risk of cardiovascular disease despite subsequent weight gain, according to a study appearing in the March 13 issue of JAMA.

“Cigarette smoking is the leading cause of preventable mortality in the United States and a major risk factor for cardiovascular disease (CVD). Smoking cessation substantially reduces the risks of CVD; however, quitting smoking is associated with a small number of adverse health consequences, weight gain being one of smokers’ major concerns,” according to background information in the article. The average postcessation weight gain varies between 6.6 lbs. and 13.2 lbs. in North America, happens within 6 months after smoking cessation, and persists over time. Obesity is also a risk factor for CVD. Weight gain following smoking cessation therefore might lessen the benefits of quitting smoking on CVD outcomes. In addition, among people with type 2 diabetes, weight gain following smoking cessation has potential to be of greater concern because it is a risk factor for poor diabetes control and increased risk of illness and death. “The effect on CVD of potential weight gain following smoking cessation is not well understood,” the authors write.

Carole Clair, M.D., M.Sc., of the University of Lausanne, Switzerland, and colleagues conducted a study to assess the association between 4-year weight gain following smoking cessation and CVD event rate among adults with and without diabetes. The study included data from the Framingham Offspring Study collected from 1984 through 2011. At each 4-year examination, self-reported smoking status was assessed and categorized as smoker, recent quitter (≤ 4 years), long-term quitter (>4 years), and nonsmoker. Models were used to estimate the association between quitting smoking and 6-year CVD events and to test whether 4-year change in weight following smoking cessation modified the association between smoking cessation and CVD events. The primary outcome measure was the incidence over 6 years of total CVD events, comprising coronary heart disease, cerebrovascular events, peripheral artery disease, and congestive heart failure.

Weight gain occurred over 4 years in participants without and with diabetes. Among participants without diabetes, recent quitters gained significantly more weight (median [midpoint], 5.9 lbs.) than long-term quitters (1.9 lbs.), smokers (1.9 lbs.), and nonsmokers (3 lbs.). Among patients with diabetes, recent quitters also gained significantly more weight (7.9 lbs.) than smokers (1.9 lbs.), long-term quitters (0.0 lbs., and nonsmokers (1.1 lbs.).

After an average follow-up of 25 years, 631 CVD events occurred among 3,251 participants. The researchers found that among participants without diabetes, the age- and sex-adjusted CVD incidence rates were lower for nonsmokers, recent quitters, and long-term quitters, compared with smokers.

After adjustment for CVD risk factors, compared with smokers, recent quitters had a 53 percent lower risk for CVD and long-term quitters had a 54 percent lower risk for CVD; these associations had only a minimal change after further adjustment for weight change. “Among participants with diabetes, there were similar point estimates that did not reach statistical significance,” the authors write.

The researchers observed similar benefits associated with smoking cessation for total CVD and for fatal and non-fatal coronary heart disease, with the cessation benefits not offset by weight gain.

“In conclusion, among adults without diabetes, quitting smoking was associated with a lower risk of CVD compared with continuing smoking. There were qualitatively similar lower risks among participants with diabetes that did not reach statistical significance, possibly because of limited study power. Weight gain that occurred following smoking cessation was not associated with a reduction in the benefits of quitting smoking on CVD risk among adults without diabetes. This supports a net cardiovascular benefit of smoking cessation, despite subsequent weight gain,” the authors write.

(JAMA. 2013;309(10):1014-1021; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc.

There will also be a digital news release available for this study, including the JAMA Report video, embedded and downloadable video, audio files, text, documents, and related links. This content will be available at 3 p.m. CT Tuesday, March 12 at this link.

Editorial: Should Clinicians Encourage Smoking Cessation for Every Patient Who Smokes?

In an accompanying editorial, Michael C. Fiore, M.D., M.P.H., M.B.A., and Timothy B. Baker, Ph.D., of the University of Wisconsin School of Medicine and Public Health, Madison, suggest ways in which the findings of this study can be used by physicians.

“First, data from the study by Clair et al can be used to reassure patients concerned about the health effects of cessation-related weight gain. About 50 percent of female smokers and about 25 percent of male smokers are ‘weight concerned,’ which may discourage quit attempts and quitting success. Although such reassurance may not assuage concerns about the effects of weight gain on appearance, it may nevertheless be helpful. Furthermore, even though no treatments have been shown to reliably prevent cessation-related weight gain, exercise regimens may be beneficial, and use of nicotine replacement medications can suppress weight gain during their use. Second, physicians should use this information to reinforce their commitment to provide or arrange evidence based treatment for all of their patients who smoke.”

(JAMA. 2013;309(10):1032-1033; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: This Editorial was supported by grants from the National Cancer Institute and National Heart, Lung, and Blood Institute. Dr. Fiore reported institutional support from Pfizer for a phase 4 study of varenicline. Dr. Baker reported no disclosures.

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EMBARGOED FOR EARLY RELEASE: 1:15 P.M. (CT) MONDAY, MARCH 11, 2013

Media Advisory: To contact Mihai Gheorghiade, M.D., call Erin White at 847-491-4888 or email ewhite@northwestern.edu.

CHICAGO – Among patients hospitalized for heart failure (HF) with reduced left ventricular ejection fraction (LVEF; a measure of how well the left ventricle of the heart pumps with each contraction), initiation of the medication aliskiren in addition to standard therapy did not reduce cardiovascular death or HF rehospitalization at 6 or 12 months after discharge, according to a study published online by JAMA. The study is being released early to coincide with its presentation at the American College of Cardiology’s annual Scientific Sessions.

“Inhibition of the renin-angiotensin-aldosterone system [RAAS; the regulation of sodium balance, fluid volume, and blood pressure by secretion of renin in response to reduced perfusion of the kidney] has long been recognized as a life-prolonging therapy for patients with chronic heart failure with reduced LVEF, and angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), and mineralocorticoid receptor antagonists (MRAs) are recommended by all major national guidelines. However, although the benefits of these treatments are undisputed, these agents induce a compensatory increase in renin [an enzyme secreted by the kidneys] and downstream RAAS intermediaries that may partially offset RAAS blocking effects,” according to background information in the article.

The direct renin inhibitors (DRIs) represent another pharmacologically distinct method for RAAS blockade. Aliskiren, an orally active DRI, has demonstrated a favorable hemodynamic and neurohormonal profile in patients with HF. “Despite current evidence-based therapies, patients with hospitalization for HF (HHF) face postdischarge mortality and rehospitalization rates as high as 15 percent and 30 percent, respectively, within 60 to 90 days. Incomplete suppression of the RAAS may contribute to the exceptionally high postdischarge event rate,” the authors write.

Mihai Gheorghiade, M.D., of the Northwestern University Feinberg School of Medicine, Chicago, and colleagues conducted a study (the ASTRONAUT randomized trial) to examine whether the addition of a DRI (aliskiren) to standard therapy would improve long-term outcomes in HHF patients. The study included hemodynamically stable HHF patients a median (midpoint) 5 days after admission who met certain criteria. Patients were recruited from 316 sites across North and South America, Europe, and Asia between May 2009 and December 2011. The follow-up period ended in July 2012.

All patients received 150 mg (increased to 300 mg as tolerated) of aliskiren or placebo daily, in addition to standard therapy. The study drug was continued after discharge for a median 11.3 months.

The final group for efficacy analyses included 1,615 patients (808 assigned to aliskiren, 807 assigned to placebo). At randomization, patients were receiving diuretics (95.9 percent), beta-blockers (82.5 percent), ACE inhibitors or ARBs (84.2 percent), and MRAs (57.0 percent).There were no major differences between the 2 treatment groups at the time of randomization. The average age was 65 years.

“In total, 24.9 percent of patients receiving aliskiren (77 cardiovascular [CV] deaths, 153 HF hospitalizations) and 26.5 percent of patients receiving placebo (85 CV deaths, 166 HF rehospitalizations) experienced the primary end point [cardiovascular death or HF rehospitalization] at 6 months. At 12 months, the event rates were 35.0 percent for the aliskiren group (126 CV deaths, 212 HF rehospitalizations) and 37.3 percent for the placebo group (137 CV deaths, 224 HF rehospitalizations),” the authors write.

During the overall follow-up period (ranging from 0.1 to 31.2 months), the total hospitalization rates (i.e., percentage of patients hospitalized for any reason) in the aliskiren and placebo groups were 48.1 percent and 49.1 percent, respectively. The HF hospitalization rates within 12 months were 26.2 percent in the aliskiren group and 27.8 percent in the placebo group.

The researchers also found that the rates of hyperkalemia (higher than normal levels of potassium in the circulating blood), hypotension, and renal impairment/renal failure were higher in the aliskiren group compared with placebo.

“The results of the ASTRONAUT study do not support the routine administration of aliskiren, in addition to evidence-based therapy, to patients hospitalized for worsening chronic HF. Subgroup analysis is consistent with previous reports of poor outcomes with the use of aliskiren in patients with diabetes mellitus [DM] already taking RAAS inhibitors. Further investigations are needed to evaluate the effects of renin inhibition in a large cohort of HHF patients that excludes patients with DM,” the authors conclude.

(doi:10.1001/jama.2013.1954; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: The ASTRONAUT study is funded by Novartis Pharma AG, Basel, Switzerland, under the guidance of the ASTRONAUT Executive Committee. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, etc.

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EMBARGOED FOR EARLY RELEASE: 1:30 P.M. (CT) MONDAY, MARCH 11, 2013

Media Advisory: To contact Margaret M. Redfield, M.D., call Traci Klein at 507-990-1182 or email klein.traci@mayo.edu.

CHICAGO – Among patients with heart failure with preserved ejection fraction (a measure of heart function), administration of sildenafil for 24 weeks, compared with placebo, did not result in significant improvement in exercise capacity or clinical status, according to a study published online by JAMA. Some studies have suggested that phosphodiesterase-5 inhibitors (a class of drugs that includes sildenafil) may improve cardiovascular function. The study is being released early to coincide with its presentation at the American College of Cardiology’s annual Scientific Sessions.

Heart failure with preserved ejection fraction (HFPEF) or diastolic heart failure is a common condition with a high level of illness. “Clinical trials of renin-angiotensin system antagonists have not demonstrated improvement in outcomes or clinical status in HFPEF, and effective therapies are needed,” according to background information in the article. “Preclinical studies suggest that inhibition of phosphodiesterase-5 (PDE-5) reverses adverse cardiac structural and functional remodeling and enhances vascular, neuroendocrine, and renal function. In clinical studies, PDE-5 inhibitor therapy improved exercise tolerance and clinical status in patients with idiopathic pulmonary arterial hypertension and in patients with heart failure and reduced ejection fraction.”

Margaret M. Redfield, M.D., of the Mayo Clinic, Rochester, Minn., and colleagues conducted a study to test the hypothesis that, compared with placebo, therapy with the PDE-5 inhibitor sildenafil would improve exercise capacity in HFPEF after 24 weeks of therapy, assessed by the change in peak oxygen consumption. The multicenter, randomized clinical trial included 216 stable outpatients with heart failure, reduced exercise capacity and other certain criteria. Participants were randomized from October 2008 through February 2012 at 26 centers in North America. Sildenafil (n = 113) or placebo (n = 103) was administered orally at 20 mg 3 times daily for 12 weeks, followed by 60 mg 3 times daily for 12 weeks. Follow-up was through August 2012.

The primary end point for the study was change in peak oxygen consumption after 24 weeks of therapy. Secondary end points included change in 6-minute walk distance and a hierarchical composite clinical status score based on time to death, time to cardiovascular or cardiorenal hospitalization, and change in quality of life for participants without cardiovascular or cardiorenal hospitalization at 24 weeks. The median (midpoint) age was 69 years, and 48 percent of patients were women.

The researchers found that at 24 weeks, the median change in peak oxygen consumption from the beginning of the study was not significantly different in patients treated with placebo and patients treated with sildenafil. Also, there were no significant differences in the clinical rank score, change in 6-minute walk distance at 24 weeks, or change in peak oxygen consumption or 6-minute walk distance at 12 weeks between treatment groups .

Adverse events occurred in 78 patients (76 percent) who received placebo and 90 patients (80 percent) who received sildenafil. Serious adverse events occurred in 16 patients (16 percent) who received placebo and 25 patients (22 percent) who received sildenafil.

“To our knowledge, [this] trial is the first multicenter study to investigate the effect of PDE-5 inhibition in HFPEF. Contrary to our hypothesis, long-term PDE-5 inhibition in HFPEF had no effect on maximal or submaximal exercise capacity, clinical status, quality of life, left ventricular remodeling, diastolic function parameters, or pulmonary artery systolic pressure. Renal function worsened more and NT-proBNP, endothelin-1, and uric acid levels increased more in patients treated with sildenafil. Furthermore, there were more (but not significantly more) patients in the sildenafil group who withdrew consent, died, or were too ill to perform the cardiopulmonary exercise test, and patients treated with sildenafil had a higher incidence of vascular adverse events. These findings do not suggest that therapy with the PDE-5 inhibitor sildenafil provides clinical benefit in the general HFPEF population,” the authors write.

(doi:10.1001/jama.2013.2024; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc.

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EMBARGOED FOR EARLY RELEASE: 10 A.M. (CT) THURSDAY, MARCH 7, 2013

Media Advisory: To contact Jared M. O’Leary, M.D., call Jessica Maki at 617-534-1603 or email jmaki3@partners.org.

CHICAGO – Jared M. O’Leary, M.D., of Brigham and Women’s Hospital, Boston, and colleagues analyzed U.S. hospitalizations from 1998 through 2010 for children and adults with congenital heart disease. “There are more than 787,000 adults with congenital heart disease in the United States. Adults with congenital heart disease remain at risk for frequent hospitalizations,” the authors write in a Research Letter published online by JAMA to coincide with its presentation at the American College of Cardiology’s annual Scientific Sessions.

The researchers identified congenital heart disease admissions to acute care hospitals from 1998 through 2010 using the Nationwide Inpatient Sample, a stratified 20 percent sample of hospitalizations, including approximately 8 million admissions annually from approximately 1,000 hospitals. The primary outcome was the change in number of admissions for all congenital heart disease diagnoses for pediatric (less than 18 years of age) vs. adult patients. To minimize the effect of year-to-year variability, the number of hospitalizations were compared between the first and second halves of the study (January 1998 through June 2004; July 2004 through December 2010).

The authors found that the frequency of hospitalizations for adults with congenital heart disease has grown at a rate more than twice that for children. Adult admission volume was 87.8 percent higher during the second half of the study (n = 622,084) compared with the first half (n = 331,162), while pediatric admissions grew 32.8 percent (1,082,540 vs. 815,471). Adults accounted for 36.5 percent of congenital heart disease admissions in the latter era, up from 28.9 percent.

“The observed trend is likely due to a number of independent forces including better congenital heart disease survival, an aging population, and accumulating comorbidities. Limited availability of quality outpatient services may also contribute,” the researchers write. “Adult congenital heart disease admissions will have an increasing impact on resource utilization. Further research and focus on optimizing health care delivery is warranted to effectively care for adults with congenital heart disease.”

(doi:10.1001/jama.2013.564; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc.

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, MARCH 5, 2013

Index May Help Predict 10-Year Mortality Among Older Adults

“Recent guidelines recommend considering patients’ life expectancy when deciding whether to pursue preventive interventions with long lag times to benefit (≥ 7 years) such as colorectal cancer screening and intensive glycemic control for diabetes. However, most mortality indices have focused on short-term risk (≤ 5 years),” writes Marisa Cruz, M.D., of the University of California, San Francisco, and colleagues. The researchers examined whether their previously developed 4-year mortality index accurately predicted 10-year mortality.

As reported in a Research Letter, this analysis used 1998 data from the Health and Retirement Study (HRS), a nationally representative cohort of community-dwelling U.S. adults older than 50 years. The primary predictor was a 12-item mortality index, and participants received points depending on answers to the following: age; sex; current tobacco use; body mass index; diabetes; nonskin cancers; chronic lung disease; heart failure; difficulty bathing; difficulty managing finances; difficulty walking several blocks; and difficulty pushing/pulling large objects. The primary outcome was death through 2008 (10-year mortality). A risk score was calculated for each participant by summing the points for each risk factor present.

The researchers found that in the development cohort, 10-year mortality rates ranged from 2.5 percent (n=12/486) for participants with 0 points to 96 percent (n=298/310) for participants with 14 or more points. In the validation cohort, 10-year mortality rates ranged from 2.3 percent (n=8/354) to 93 percent (n= 239/257).

“We validated a mortality index that accurately stratified older adults into groups at varying risk for 10-year mortality,” the authors write. “Patients identified by this index as having a high risk of 10-year mortality may be more likely to be harmed by preventive interventions with long lag times to benefit, whereas patients identified as having a low risk of 10-year mortality may be good candidates for such interventions.”

(JAMA. 2013;309[9]:874-876. Available pre-embargo to the media at https://media.jamanetwork.com)

Viewpoints in This Issue of JAMA

Keeping an Eye on Distracted Driving

In 2003, cell phone use while driving was estimated to cause 333,000 total injuries, 12,000 serious to critical injuries, and 2,600 fatalities annually. From 2005 to 2009, fatalities associated with driver distraction increased by 22 percent. Jeffrey H. Coben, M.D., and Motao Zhu, M.D., Ph.D., of West Virginia University, Morgantown, write that new technological and regulatory approaches are needed to reduce handheld phone use and texting while driving.

“Strong and courageous action is needed to effectively deal with the problem of cell phone use while driving. Education, legislation, and voluntary guidelines are insufficient. The federal government should enact stringent new safety standards that require all handheld devices to be rendered inoperable when the motor vehicle is in motion. Failure to act in this manner will result in the continued loss of thousands of lives each year to this preventable public safety hazard. In this era of smartphones and smart cars, it is time to be smarter about keeping them apart from one another.

(JAMA. 2013;309[9]:877-878. Available pre-embargo to the media at https://media.jamanetwork.com)

Please Note: An author podcast on this study will be available post-embargo on the JAMA website.

Improving Opioid Prescribing – The New York City Recommendations

“On January 10, 2013, New York City Mayor Michael Bloomberg announced new guidelines for the prescribing of opioid analgesics to patients being discharged from the city’s emergency departments. The guidelines were developed by a panel of emergency physicians and are intended to reduce opioid addiction and overdose deaths while preserving access to opioids for patients in whom the benefits are expected to exceed the harms,” writes David N. Juurlink, M.D., Ph.D., of the University of Toronto, and colleagues.

In this Viewpoint, the authors examine “why such guidelines are necessary and what complementary actions physicians, patients, and health authorities should take to address the increasing problem of opioid-related harm.”

(JAMA. 2013;309[9]:879-880. Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: Please see the articles for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc.

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, MARCH 5, 2013

Media Advisory: To contact corresponding author Raymond J. Kim, M.D., call Sarah Avery at 919-660-1306 or email sarah.avery@duke.edu. To contact editorial co-author Marc A. Pfeffer, M.D., Ph.D., call Jessica Maki at 617-534-1603 or email jmaki3@partners.org.

CHICAGO – Among patients with coronary artery disease referred for cardiovascular magnetic resonance  and found to have regional myocardial wall thinning (of the heart muscle), limited scar burden was associated with improved contraction of the heart and reversal of wall thinning after revascularization, suggesting that myocardial thinning is potentially reversible, according to a study appearing in the March 6 issue of JAMA.

Regional myocardial wall thinning is thought to represent chronic myocardial infarction. “However, recent case reports incorporating the use of delayed-enhancement cardiovascular magnetic resonance (CMR) imaging raise the possibility that this viewpoint is incorrect. These single-patient reports indicate that myocardial regions with severe wall thinning do not necessarily consist entirely of scar tissue but instead may have minimal or no scarring. Thus, some areas of myocardial thinning may represent viable myocardium and have the potential for recovery of function,” according to background information in the article.

Dipan J. Shah, M.D., of Duke University Medical Center, Durham, N.C., and colleagues conducted a study to evaluate patients with regional myocardial wall thinning and to determine scar burden and potential for functional improvement. The study, conducted from August 2000 through January 2008, included 1,055 patients with known coronary artery disease (CAD) who underwent CMR imaging.

“Of 201 patients [19 percent] identified by CMR as having wall thinning, most had significant left ventricular dysfunction, multivessel CAD, and thinning of a substantial portion of the left ventricle. Among this cohort, 18 percent of thinned regions had limited or no scarring observed using delayed-enhancement CMR. Because the lack of scarring was associated with significant contractile improvement and reverse remodeling with resolution of wall thinning following revascularization, we believe the data indicate that myocardial thinning is potentially reversible and therefore should not be considered a permanent state,” the authors write.

“… we believe our study provides new insights into the pathophysiology of thinned myocardium and more broadly the process of reversible ischemic injury. The data show that thinned myocardium may consist of limited scar tissue and can recover function— concepts that are both inconsistent with current views.

“The findings provide rationale for future experimental studies on reversible ischemic injury as well as for clinical studies prospectively testing whether CMR guidance for coronary revascularization decisions can improve patient outcome,” the researchers conclude.

(JAMA. 2013;309(9):909-918; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc.

Editorial: Cardiovascular Imaging in Clinical Practice

In an accompanying editorial, Deepak K. Gupta, M.D., of Brigham and Women’s Hospital, Boston, and colleagues write that the two cardiovascular imaging studies in this issue of JAMA “address the important issue of how supplemental noninvasive imaging studies can assist the cardiovascular specialist.”

“Together these reports provide a consistent message that detailed assessments of tissue composition, in particular fibrosis by late gadolinium enhancement (LGE), may provide superior information than morphologic parameters, in both ischemic and nonischemic cardiomyopathies. Collectively, these and other studies demonstrate that CMR with LGE imaging adds to the practitioner’s armamentarium for assessment of cardiac structure and function and augments diagnostic and prognostic capabilities.”

“However, the clinical challenge remains in deciding which patients to evaluate with CMR and LGE and what to do with the findings. Nevertheless, whether CMR with LGE imaging would provide better assessment for nonischemic or ischemic heart disease for guiding decisions regarding revascularization or implantable cardioverter defibrillator placement and the subsequent influence on prognosis remain intriguing and warrant further study. At this point, for the practicing physician, the incremental information gained from CMR with LGE imaging from these 2 studies, albeit novel and supportive, is not yet sufficient to alter clinical practice guidelines.”

(JAMA. 2013;309(9):929-930; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, MARCH 5, 2013

Media Advisory: To contact corresponding author Sanjay K. Prasad, M.D., email s.prasad@rbht.nhs.uk.

CHICAGO – Detection of midwall fibrosis (the presence of scar tissue in the middle of the heart muscle wall) via magnetic resonance imaging among patients with nonischemic dilated cardiomyopathy (a condition affecting the heart muscle) was associated with an increased likelihood of death, according to a study appearing in the March 6 issue of JAMA.

Nonischemic dilated cardiomyopathy is associated with significant illness and death due to progressive heart failure (HF) and sudden cardiac death (SCD). Despite therapeutic advances, 5-year mortality remains as high as 20 percent. “Risk stratification of patients with nonischemic dilated cardiomyopathy is primarily based on left ventricular ejection fraction [LVEF; a measure of how well the left ventricle of the heart pumps with each contraction]. Superior prognostic factors may improve patient selection for implantable cardioverter-defibrillators (ICDs) and other management decisions,” according to background information in the article.  Attention has recently focused on whether detection of myocardial replacement fibrosis (scarring of the heart muscle) may assist with risk stratification in dilated cardiomyopathy. Fibrosis is associated with contractile impairment.

Ankur Gulati, M.D., of Royal Brompton Hospital, London, and colleagues evaluated whether midwall fibrosis (detected by late gadolinium enhancement cardiovascular magnetic resonance [LGE-CMR] imaging) predicts risk of death, independently of LVEF and other established prognostic factors in dilated cardiomyopathy. The study included 472 patients with dilated cardiomyopathy referred to a U.K. center for CMR imaging between November 2000 and December 2008 after presence and extent of midwall replacement fibrosis (scarring of the heart muscle present in the middle of the heart muscle wall) were determined. Patients were followed up through December 2011.

During a median (midpoint) follow-up of 5.3 years, there were 73 deaths. Overall, 38 of 142 patients with midwall fibrosis (26.8 percent) died compared with 35 of 330 patients without midwall fibrosis (10.6 percent). After analysis, both the presence and percentage extent of midwall fibrosis were significant independent predictors of all-cause mortality. The arrhythmic composite end point (SCD or aborted SCD) occurred in 65 patients (14 percent). Analysis indicated that patients with midwall fibrosis were more than 5 times more likely to experience SCD or aborted SCD compared with patients without midwall fibrosis (29.6 percent vs. 7.0 percent).

“After adjustment for LVEF and other conventional prognostic factors, both the presence of fibrosis and the extent were independently and incrementally associated with all-cause mortality. Fibrosis was also independently associated with cardiovascular mortality or cardiac transplantation, SCD or aborted SCD, and the HF composite [HF death, HF hospitalization, or cardiac transplantation],” the authors write.

Also, the addition of fibrosis to LVEF significantly improved risk reclassification for all-cause mortality and the SCD composite.

“Our findings suggest that detection and quantification of midwall fibrosis by LGE-CMR may represent useful markers for the risk stratification of death, ventricular arrhythmia, and HF for patients with dilated cardiomyopathy,” the researchers write.

(JAMA. 2013;309(9):896-908; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: This work was supported by the National Institute for Health Research Cardiovascular Biomedical Research Unit at the Royal Brompton and Harefield NHS Foundation Trust and Imperial College, London, England. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc.

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, MARCH 5, 2013

Media Advisory: To contact Kevin L. Winthrop, M.D., M.P.H., call Mirabai Vogt at 503-494-7986 or email vogtmi@ohsu.edu.

CHICAGO – Although patients with rheumatoid arthritis (RA) have a disproportionately higher incidence of herpes zoster (shingles), an analysis that included nearly 60,000 patients with RA and other inflammatory diseases found that those who initiated anti-tumor necrosis factor therapies were not at higher risk of herpes zoster compared with patients who initiated nonbiologic treatment regimens, according to a study appearing in the March 6 issue of JAMA.

“For patients with rheumatoid arthritis, the risk of herpes zoster is elevated an additional 2- to 3-fold. The contribution of widely used biologic immunosuppressive therapy to this increased risk is not well understood. These therapies, including tumor necrosis factor (TNF) antagonists, are commonly used to treat RA and a variety of other immune-mediated inflammatory diseases and have clearly been associated with an increased risk of tuberculosis and other opportunistic infections,” according to background information in the article. “It is unclear whether anti-tumor necrosis factor (anti-TNF) therapy elevates herpes zoster risk.”

Kevin L. Winthrop, M.D., M.P.H., of Oregon Health and Science University, Portland, Ore., and colleagues conducted a study to determine whether initiation of anti-TNF therapy compared with non-biologic comparators is associated with increased herpes zoster risk. The researchers identified new users of anti-TNF therapy among groups of patients with RA, inflammatory bowel disease, and psoriasis, psoriatic arthritis, or ankylosing spondylitis from 1998 through 2007 within a large U.S. multi-institutional collaboration. The authors compared herpes zoster incidence between new anti-TNF users (n = 33,324) and patients initiating nonbiologic disease-modifying antirheumatic drugs (DMARDs) (n = 25,742) within each inflammatory disease cohort (last participant follow-up December 31, 2007).

Across all disease indications, there were 310 herpes zoster cases among anti-TNF and 160 among nonbiologic DMARD users. For patients with RA, the researchers found that adjusted incidence rates were similar between anti-TNF and nonbiologic DMARD initiators and comparable between all 3 anti-TNF therapies studied. Baseline use of corticosteroids of 10 mg/d or greater among all disease indications was associated with elevated risk compared with no baseline use.

After adjustment for various factors, no significant difference in herpes zoster rates was observed within any disease indication between patients initiating anti-TNF therapy and those initiating new DMARD regimens.

Within the RA group, herpes zoster risk was associated with increasing age, female sex, overall health status, and higher-dose corticosteroid use.

“In summary, among patients with RA and other select inflammatory diseases, those who initiated anti-TNF therapies were not at higher risk of herpes zoster compared with patients who initiated nonbiologic treatment regimens,” the authors write.

(JAMA. 2013;309(9):887-895; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc.

There will also be a digital news release available for this study, including the JAMA Report video, embedded and downloadable video, audio files, text, documents, and related links. This content will be available at 3 p.m. CT Tuesday, March 5 at this link.

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, FEBRUARY 26, 2013

Why the Ethics of Parsimonious Medicine Is Not the Ethics of Rationing

In this Viewpoint, Jon C. Tilburt, M.D., of the Mayo Clinic, Rochester, Minn., and Christine K. Cassel, M.D., of the American Board of Internal Medicine, Philadelphia, discuss the ethical differences between parsimonious medicine (limiting the use of wasteful tests and treatments) and rationing health care resources.

“Both parsimonious medicine and rationing aim to reduce resource use. Nevertheless, the ethical difference between the two is clear. Rationing requires principles of distributive justice, which is good and important in circumstances of resource scarcity; parsimonious medicine rests squarely on the principles of doing no harm and attending to the good of patients in need. This is an essential attribute of professionalism.”

(JAMA. 2013;309[8]:773-774. Available pre-embargo to the media at https://media.jamanetwork.com)

The Value of Low-Value Lists

 “An international groundswell of activity is seeking to identify and reduce the use of health care services that provide little or no benefit— whether through overuse or misuse,” writes Adam G. Elshaug, Ph.D., M.P.H., of Harvard Medical School, Boston, and colleagues.

A major challenge faced by initiatives to address this issue has been how to identify and prioritize candidate services for consideration in a reasoned and transparent manner. “Today, several lists compiled by prominent organizations have identified numerous services as potentially low value in certain clinical circumstances. The challenge facing payers and health care service providers such as physicians and hospitals is to develop and implement strategies to reduce the use of services that are identified in these lists, many of which are discretionary, if not potentially harmful.”

(JAMA. 2013;309[8]:775-776. Available pre-embargo to the media at https://media.jamanetwork.com)

 Editor’s Note: Please see the articles for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc.

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, FEBRUARY 26, 2013

Media Advisory: To contact corresponding author Burkert Pieske, M.D., email burkert.pieske@medunigraz.at. To contact editorial co-author John G. F. Cleland, M.D., Ph.D., F.R.C.P., email J.G.Cleland@hull.ac.uk.

CHICAGO – Among patients with heart failure with preserved ejection fraction, long-term treatment with the medication spironolactone improved left ventricular diastolic function but did not affect maximal exercise capacity, patient symptoms, or quality of life, according to a study appearing in the February 27 issue of JAMA.

“Heart failure (HF) with preserved ejection fraction [EF; the percentage of blood that is pumped out of a filled ventricle as a result of a heartbeat is 50 percent or greater] accounts for more than 50 percent of the total HF population,” according to background information in the article.  There is not an established therapy for this condition, and aldosterone (a hormone) stimulation may contribute to its progression.

Frank Edelmann, M.D., of the University of Gottingen, Germany, and colleagues conducted a study to examine the long-term effects of spironolactone, an aldosterone receptor blocker, on diastolic function and exercise capacity in patients with HF with preserved EF. The Aldo-DHF trial, a randomized, placebo-controlled trial, was conducted between March 2007 and April 2012 at 10 sites in Germany and Austria. The study included 422 patients (average age, 67 years) with chronic New York Heart Association class II or III heart failure, preserved left ventricular ejection fraction of 50 percent or greater, and evidence of diastolic dysfunction. Patients were randomly assigned to receive 25 mg of spironolactone once daily (n = 213) or matching placebo (n = 209) with 12 months of follow-up. The primary outcomes measured were changes in diastolic function (E/e’) on echocardiography and maximal exercise capacity (peak VO₂) on cardiopulmonary exercise testing.

The researchers found that spironolactone improved some measures (left ventricular end-diastolic filling, left ventricular remodeling, and neurohumoral activation). Maximal exercise capacity did not significantly change with spironolactone vs. placebo, and spironolactone did not improve heart failure symptoms or quality of life and slightly reduced 6-minute walking distance. “Spironolactone also modestly increased serum potassium levels and decreased estimated glomerular filtration rate without affecting hospitalizations.”

The authors conclude that the “lack of accepted minimal clinically important differences in E/e’ or peak VO₂ in HF with preserved EF warrants additional prospective, randomized, adequately powered studies to further evaluate the effect of improving diastolic function on symptomatic, functional, and clinical end points.”

(JAMA. 2013;309(8):781-791; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc.

Editorial: Defining Diastolic Heart Failure and Identifying Effective Therapies

“Ultimately, Aldo-DHF trial provides valuable new information but is not particularly reassuring in terms of either the efficacy or safety of mineralocorticoid antagonists (MRAs) for patients with heart failure with preserved ejection fraction (HFpEF),”writes John G. F. Cleland, M.D., Ph.D., F.R.C.P., and Pierpaolo Pellicori, M.D., of the University of Hull, Kingston-upon-Hull, England, in an accompanying editorial.

“In the meantime, MRAs appear useful for managing congestion and preventing diuretic-induced hypokalemia [abnormally low level of potassium in the circulating blood] with the attendant risk of sudden arrhythmic death. It is likely that these benefits are independent of cardiac phenotype but might be more prominent in those with impaired aldosterone degradation due to hepatic congestion. Whether MRAs exert important benefits for patients with HFpEF through other mechanisms such as reducing fibrosis, inflammation, and adrenergic activity may take longer to unravel.”

(JAMA. 2013;309(8):825-826; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: Both authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, FEBRUARY 26, 2013

Media Advisory: To contact Simon G. Thompson, D.Sc., email sgt27@medschl.cam.ac.uk.

CHICAGO – In contrast to the commonly adopted surveillance intervals in current abdominal aortic aneurysm (AAA) screening programs, surveillance intervals of several years may be clinically acceptable for the majority of patients with small AAA, as the smallest AAAs often do not appear to change significantly over many years, according to a meta-analysis of previous studies reported in the February 27 issue of JAMA.

“The survival rate following rupture of an abdominal aortic aneurysm is only 20 percent, making AAAs an important cause of mortality,” according to background information in the article. “In patients with small AAA (diameter <5.5 cm), the risk of rupture is lower than the risk of surgery and surveillance is indicated. The majority of small AAAs grow slowly, but there is substantial variation in growth rates between different individuals. The intervals between ultrasound surveillance examinations used in randomized trials of screening depend on aneurysm size. However, no consensus exists regarding the optimal time intervals between ultrasounds.”

To better guide AAA surveillance efforts, Simon G. Thompson, D.Sc., of the University of Cambridge, England, and colleagues conducted a study to determine the rates at which small AAAs progress to reach the surgery threshold diameter of 5.5 cm and the risk of AAA rupture over time. Via a meta-analysis, the authors assessed individual patient data from studies of small AAA growth and rupture. A total of 18 studies containing records from 15,471 individual patients (13,728 men and 1,743 women) under surveillance for small AAAs were included in the analyses. Most studies used 5.5 cm as the threshold for surgical intervention, used only ultrasound scans, and recorded external aortic diameters.

The researchers found that AAA growth and rupture rates varied considerably across studies. Each 0.5-cm increase in baseline AAA diameter resulted in a 0.59-mm per year increase in average aortic growth rate. Rupture rates in men increased by a factor of 1.9 for every 0.5-cm increase in baseline AAA diameter. For men with a 3.0-cm AAA, the estimated average time taken to have a 10 percent chance of reaching the surgery threshold diameter 5.5 cm was 7.4 years. The corresponding average times for 4.0 cm- and 5.0 cm-AAAs were 3.2 years and 8 months, respectively.

To control the risk of rupture in men to below 1 percent, the corresponding estimated surveillance intervals are 8.5 years for a 3.0 cm and 17 months for a 5.0-cm AAA.

While absolute growth rates were similar for women and men (particularly for larger baseline AAA diameters), there were marked differences in the absolute risks of rupture. Women had a 4-fold greater rupture risk for all AAA sizes and reached a rupture risk of greater than 1 percent in a much shorter time than men.

“Current recommendations for surveillance intervals vary widely although the intervals usually decrease with increasing AAA diameter (for example, 1 year for AAAs measuring 3.0-4.4 cm and 3 months for those measuring 4.5-5.4 cm in the current screening program in England),” the authors write. The findings of this study indicate that for men “these surveillance intervals could be extended to 3 years for AAAs measuring 3.0 to 3.9 cm, 2 years for 4.0 to 4.4 cm, and yearly for 4.5 to 5.4 cm; the risk of rupture would be maintained at less than 1 percent. For a U.S. patient with a 3.0-cm AAA detected by screening, this would reduce the average number of surveillance scans from approximately 15 to 7.”

“There is a need for more research regarding women with aneurysms in the diameter range of 4.5 to 5.4 cm. Since national rates of AAA rupture are declining, recommended surveillance intervals may need to be reassessed. There is also a need to establish the cost effectiveness of different surveillance policies. Decreasing surveillance frequency would reduce surveillance costs. However, it may also slightly increase rupture rates and increase patient anxiety. This would decrease overall life expectancy and quality of life in AAA patients under surveillance and increase costs attributable to emergency surgery,” the researchers conclude.

(JAMA. 2013;309(8):806-813; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: This project was supported by the UK NIHR Health Technology Assessment Programme. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc.

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, FEBRUARY 26, 2013

Media Advisory: To contact Justin B. Dimick, M.D., M.P.H., call Shantell Kirkendoll at 734-764-2220 or email smkirk@umich.edu. To contact Caprice C. Greenberg, M.D., M.P.H., call Susan Lampert Smith at 608-890-5643 or email SSmith5@uwhealth.org.

CHICAGO – In an analysis of data on patients who underwent bariatric surgery 2004-2009, there was no significant difference in the rates of complications and reoperation for Medicare patients before vs. after a 2006 Centers for Medicare & Medicaid Services policy that restricted coverage of bariatric surgery to centers of excellence, according to a study appearing in the February 27 issue of JAMA.

“Prompted by concerns about perioperative safety with bariatric surgery, the Centers for Medicare & Medicaid Services (CMS) issued a national coverage decision in 2006 that limited coverage of weight loss surgery to centers of excellence (COEs),” according to background information in the article. These COEs were accredited by a surgical professional organization. “In addition to other structural measures and processes of care, the accreditation was based on a hospital volume threshold (>125 cases/year). Whether the CMS restriction of bariatric surgery to COEs is associated with improved outcomes remains uncertain.”

Justin B. Dimick, M.D., M.P.H., of the University of Michigan, Ann Arbor, and colleagues compared outcomes in Medicare patients before and after implementation of the CMS policy to determine whether the policy was associated with improved outcomes (rate of complications, reoperations). The study included 2004-2009 hospital discharge data from 12 states (n = 321,464 patients) and analyzed changes in outcomes in Medicare patients undergoing bariatric surgery (n = 6,723 before and n = 15,854 after implementation of the policy). A difference-in-differences analytic approach was used to evaluate whether the national coverage decision was associated with improved outcomes in Medicare patients above and beyond existing time trends in non-Medicare patients (n = 95,558 before and n = 155,117 after implementation of the policy).

The researchers found that bariatric surgery outcomes improved during the study period in both Medicare and non-Medicare patients; however, this change was already underway prior to the CMS coverage decision. “After accounting for patient factors, changes in procedure type and pre-existing trends toward improved outcomes, there were no measurable improvements in outcomes after (vs. before) implementation of the CMS national coverage decision for any complication (8.0 percent after vs. 7.0 percent before the policy), serious complications (3.3 percent vs. 3.6 percent), and reoperation (1.0 percent vs. 1.1 percent).”

In a direct comparison of outcomes at COEs (n = 179) vs. non-COEs (n = 519), COEs did not result in better outcomes than non-COEs. “After accounting for patient factors, procedure type, and the year of operation, patients undergoing bariatric surgery at hospitals with the COE designation (vs. hospitals without the COE designation) did not have significantly different rates for any complication (5.5 percent vs. 6.0 percent), serious complications (2.2 percent vs. 2.5 percent), and reoperation (0.83 percent vs. 0.96 percent).”

Also, the authors found no relationship between hospital COE designation and adverse outcomes in a sensitivity analysis that evaluated Medicare and non-Medicare patients separately.

“Rather than the CMS policy restricting bariatric surgery to COEs, we found that the improvement in outcomes over time could be explained in part by the evolution away from higher risk toward lower risk procedures,” the researchers note. They add that procedure mix changed in 2 important ways: first, there was a general shift away from open to laparoscopic surgery, which is consistent with broader trends in surgery toward less invasive procedures with more favorable safety profiles; and second, there was a dramatic increase in the use of laparoscopic gastric banding, a safer but less effective procedure.

The authors write that the “CMS policy restricting coverage to COEs has not been associated with improved outcomes for bariatric surgery, but may have had the unintended consequence of reducing access to care [because of potentially increased travel distance to undergo the procedure]. These findings suggest that the CMS should reevaluate this policy.”

(JAMA. 2013;309(8):792-799; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc.

There will be a digital news release available for this study, including the JAMA Report video, embedded and downloadable video, audio files, text, documents, and related links. This content will be available at 3 p.m. CT Tuesday, February 26 at this link.

Editorial: Promoting Quality Surgical Care – The Next Steps

In an accompanying editorial, Caprice C. Greenberg, M.D., M.P.H., of the University of Wisconsin Hospitals and Clinics,  Madison, writes that because of the results of studies such as Dimick et al, the CMS is currently re-evaluating the need for bariatric surgery COEs.

Dr. Greenberg notes that COE accreditation relies on measures of structure and processes of care that duplicate accreditation functions of the Joint Commission. Measuring outcomes is difficult when relying on manual collection of information, delaying interventions when there is a need for improvement.

“As the CMS and the surgical societies re-examine the COE policy in bariatric surgery, there is an opportunity for them to be creative; to catapult surgical outcomes science forward through scalable approaches to data sharing, measurement, collaborative networks, and CER; and to design a program that can not only identify high-quality hospitals, but also provide a sustained mechanism for quality improvement.”

(JAMA. 2013;309(8):827-828; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: The author has completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr. Greenberg reported receiving an honorarium from the Michigan Bariatric Quality Collaborative to attend one of its collaboratives and discuss issues related to system performance and safety.

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, FEBRUARY 26, 2013

Media Advisory: To contact Rebecca H. Johnson, M.D., call Alyse Bernal at 206-987-5213 or email alyse.bernal@seattlechildrens.org.

CHICAGO – An analysis of breast cancer trends in the U.S. finds a small but statistically significant increase in the incidence of advanced breast cancer for women 25 to 39 years of age, without a corresponding increase in older women, according to a study appearing in the February 27 issue of JAMA.

“In the United States, breast cancer is the most common malignant tumor in adolescent and young adult women 15 to 39 years of age, accounting for 14 percent of all cancer in men and women in the age group. The individual average risk of a woman developing breast cancer in the United States was 1 in 173 by the age of 40 years when assessed in 2008. Young women with breast cancer tend to experience more aggressive disease than older women and have lower survival rates. Given the effect of the disease in young people and a clinical impression that more young women are being diagnosed with advanced disease, we reviewed the national trends in breast cancer incidence in the United States,” the authors write.

Rebecca H. Johnson, M.D., of Seattle Children’s Hospital and University of Washington, Seattle, and colleagues conducted a study in which breast cancer incidence, incidence trends, and survival rates as a function of age and extent of disease at diagnosis were obtained from 3 U.S. National Cancer Institute Surveillance, Epidemiology, and End Results (SEER) registries. These registries provide data spanning 1973-2009, 1992-2009, and 2000-2009. SEER defines localized as disease confined to the breast, regional to contiguous and adjacent organ spread (e.g., lymph nodes, chest wall), and distant disease to remote metastases (bone, brain, lung, etc).

Since 1976, there has been a steady increase in the incidence of distant disease breast cancer in 25- to 39-year-old women, from 1.53 per 100,000 in 1976 to 2.90 per 100,000 in 2009. The researchers note that this is an absolute difference of 1.37 per 100,000, representing an average compounded increase of 2.07 percent per year over the 34-year interval, a relatively small increase, “but the trend shows no evidence for abatement and may indicate increasing epidemiologic and clinical significance.”

“The trajectory of the incidence trend predicts that an increasing number of young women in the United States will present with metastatic breast cancer in an age group that already has the worst prognosis, no recommended routine screening practice, the least health insurance, and the most potential years of life,” the authors write.

The researchers also found that the rate of increasing incidence of distant disease was inversely proportional to age at diagnosis. The greatest increase occurred in 25- to 34-year-old women. Progressively smaller increases occurred in older women by 5-year age intervals and no statistically significant incidence increase occurred in any group 55 years or older.

“For young women aged 25 to 39 years, the incidence of distant disease increased in all races/ethnicities assessed since at least 1992, when race/ethnicity became available in the SEER database,” the authors write. These increases occurred in both metropolitan and nonmetropolitan areas, and were statistically significant in African American and non-Hispanic white populations.

Incidence for women with estrogen receptor-positive subtypes increased more than for women with estrogen receptor-negative subtypes.

“Whatever the causes—and likely there are more than 1—the evidence we observed for the increasing incidence of advanced breast cancer in young women will require corroboration and may be best confirmed by data from other countries. If verified, the increase is particularly concerning, because young age itself is an independent adverse prognostic factor for breast cancer, and the lowest 5-year breast cancer survival rates as a function of age have been reported for 20- to 34-year-old women. The most recent national 5-year survival for distant disease for 25- to 39-year-old women is only 31 percent according to SEER data, compared with a 5-year survival rate of 87 percent for women with locoregional breast cancer,” the authors write.

(JAMA. 2013;309(8):800-805; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc.

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