EMBARGOED FOR RELEASE: 2:30 P.M. (CT) SUNDAY, OCTOBER 26, 2014
Media Advisory: To contact corresponding author George Thanassoulis, M.D., email Julie Robert at julie.robert@muhc.mcgill.ca or Jane-Diane Fraser at JFraser@hsf.ca.

Genetic Predisposition to Elevated LDL-C Associated With Narrowing of the Aortic Valve

In an analysis that included approximately 35,000 participants, genetic predisposition to elevated low-density lipoprotein cholesterol (LDL-C) was associated with aortic valve calcium and narrowing of the aortic valve, findings that support a causal association between LDL-C and aortic valve disease, according to a study appearing in JAMA. The study is being released to coincide with its presentation at the Canadian Cardiovascular Congress.

Aortic valve disease remains the most common form of heart valve disease in Europe and North America and is the most common indication for valve replacement. Despite the heavy disease burden, no medical treatments are known to stop or slow disease progression. Plasma LDL-C has been associated with aortic stenosis (narrowing) in observational studies; however, randomized trials with cholesterol-lowering therapies in individuals with established valve disease have failed to demonstrate reduced disease progression. If LDL-C plays a causal role in the earlier stages of aortic valve disease, this could have important implications for prevention, according to background information on the article.

Because of the random allocation of genetic information that occurs at conception, genetic variation can be used as an effective tool to distinguish potentially causal from noncausal biomarkers. Termed “Mendelian randomization,” this approach has been successfully applied to assess for causality of several biomarkers with various clinical end points. Using this approach, J. Gustav Smith, M.D., of Lund University, Lund, Sweden, and colleagues, evaluated whether weighted genetic risk scores (GRSs), a measure of the genetic predisposition to elevations in plasma lipids, were associated with aortic valve disease. The researchers included community-based cohorts participating in the CHARGE consortium (n = 6,942), including the Framingham Heart Study (cohort inception to last follow-up: 1971-2013; n = 1,295), Multi-Ethnic Study of Atherosclerosis (2000-2012; n = 2,527), Age Gene/Environment Study–Reykjavik (2000-2012; n = 3,120), and the Malmö Diet and Cancer Study (MDCS, 1991-2010; n = 28,461).

Aortic valve calcium was quantified by computed tomography; prevalent and new diagnoses of aortic stenosis and aortic valve replacement were identified by record linkage with nationwide registers on hospitalizations and causes of death.

The researchers found that in the subgroup of the MDCS where lipid fractions were measured (n = 5,269), baseline LDL-C, but not high-density lipoprotein cholesterol (HDL-C) or triglycerides (TG) levels, was significantly associated with new aortic stenosis. Also, the LDL-C GRS, but not HDL-C or TG GRS, was significantly associated with presence of aortic valve calcium in CHARGE and with new aortic stenosis in MDCS.

“Our findings link a genetically mediated increase in plasma LDL-C with early subclinical valve disease, as measured by aortic valve calcium, and incident clinical aortic stenosis, providing supportive evidence for a causal role of LDL-C in the development of aortic stenosis,” the authors write. “These data suggest that, in addition to the established risks for myocardial infarction and other vascular diseases, increases in LDL-C are also associated with increased risk for aortic stenosis.”

“Whether earlier intervention to reduce LDL-C could prevent aortic valve disease merits further investigation.”
(doi:10.1001/jama.2014.13959; 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, OCTOBER 21, 2014
Media Advisory: To contact Pieter A. Cohen, M.D., call David Cecere at 617-591-4044 or email dcecere@challiance.org.

Study Finds High Percentage of Recalled Dietary Supplements Still Have Banned Ingredients

About two-thirds of FDA recalled dietary supplements analyzed still contained banned drugs at least 6 months after being recalled, according to a study in the October 22/29 issue of JAMA.

The U.S. Food and Drug Administration (FDA) initiates class I drug recalls when products have the reasonable possibility of causing serious adverse health consequences or death. Recently, the FDA has used class I drug recalls in an effort to remove dietary supplements adulterated with pharmaceutical ingredients from U.S. markets. Prior research has found that even after FDA recalls, dietary supplements remain available on store shelves. However, it has not been known if the supplements on sale after FDA recalls are free of the adulterants, according to background information in the article.

Pieter A. Cohen, M.D., of Harvard Medical School, Boston, and colleagues conducted a study to determine if banned drugs were still present in dietary supplements purchased at least six months after a recall. The FDA recalled 274 dietary supplements between January 2009 and December 2012. Twenty-seven of the 274 recalled supplements (9.9 percent) met inclusion criteria for the study and were analyzed using the same methods at the FDA’s laboratories (e.g., gas chromatography/mass spectrometry). Supplements were purchased an average of 34.3 months (range 8-52 months) after the FDA recall. Seventy-four percent of supplements (20/27) were produced by U.S. manufacturers.

The researchers found that one or more pharmaceutical adulterant was identified in 66.7 percent of recalled supplements still available for purchase (18/27). Supplements remained adulterated in 85 percent (11/13) of those for sports enhancement, 67 percent (6/9) for weight loss, and 20 percent (1/5) for sexual enhancement. Of the subset of supplements produced by U.S. manufacturers, 65 percent (13/20) remained adulterated with banned ingredients.

Sixty-three percent of analyzed supplements contained the same adulterant identified by the FDA. Six (22.2 percent) supplements contained 1 or more additional banned ingredients not identified by the FDA. Some supplements contained both the previously identified adulterant as well as additional pharmaceutical ingredients.

Banned substances identified in recalled supplements included sibutramine, sibutramine analogs, sildenafil, fluoxetine, phenolphthalein, aromatase inhibitor, and various anabolic steroids.

“To our knowledge, this is the first study to determine if adulterants remain in supplements sold after FDA recalls,” the authors write.

“Action by the FDA has not been completely effective in eliminating all potentially dangerous adulterated supplements from the U.S. marketplace. More aggressive enforcement of the law, changes to the law to increase the FDA’s enforcement powers, or both will be required if sales of these products are to be prevented in the future.”
(doi:10.1001/jama.2014.10308; 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, OCTOBER 21, 2014
Media Advisory: To contact James C. Robinson, Ph.D., M.P.H., call Sarah Yang at 510- 643-7741 or email scyang@berkeley.edu.

Study Examines Differences Between Types of Physician Practice Ownership and Expenditures

From the perspective of the insurers and patients, between 2009 and 2012, hospital-owned physician organizations in California incurred higher expenditures for commercial health maintenance organization enrollees for professional, hospital, laboratory, pharmaceutical and ancillary services than did physician-owned organizations, according to a study in the October 22/29 issue of JAMA.

Hospitals and multihospital systems are acquiring medical groups and physician practices as part of a strategy to build integrated delivery systems capable of providing the full range of professional, facility, laboratory, and pharmaceutical services to affiliated patients. This consolidation may foster cooperation and thereby reduce expenditures, but also may lead to higher expenditures through greater use of hospital-based ambulatory services and through greater hospital pricing leverage against health insurers. The policy debate about consolidation has gained new policy attention due to the financial incentives provided by the Affordable Care Act for physicians to join hospital-affiliated accountable care organizations, according to background information in the article.

James C. Robinson, Ph.D., M.P.H., of the University of California, School of Public Health, Berkeley, and Kelly Miller, B.A., of the Integrated Healthcare Association, Oakland, conducted a study to determine whether total expenditures per patient were higher in physician organizations owned by local hospitals or multihospital systems compared with physician organizations owned by participating physicians. Data were obtained on total expenditures for the care provided to 4.5 million patients treated by integrated medical groups and independent practice associations in California between 2009 and 2012.The patients were covered by commercial health maintenance organization (HMO) insurance and the data did not include patients covered by commercial preferred provider organization (PPO) insurance, Medicare, or Medicaid.

Of the 158 organizations, 118 physician organizations (75 percent) were physician-owned and provided care for 3,065,551 patients, 19 organizations (12 percent) were owned by local hospitals and provided care for 728,608 patients and 21organizations (13 percent) were owned by multihospital systems and provided care for 693,254 patients. The researchers found that the average expenditure per patient across all physician organizations increased by 16.5 percent between 2009 and 2012, from $2,954 to $3,443. By 2012, expenditures per patient had increased to an average of $3,066 in physician-owned organizations, $4,312 in local hospital-owned organizations, and $4,776 in multihospital system-owned organizations. These represent a 40.6 percent relative difference in expenditures per patient associated with hospital ownership and 55.8 percent relative difference associated with ownership by a multihospital system compared with ownership by member physicians.

After adjusting for patient severity and other factors over the period, local hospital-owned physician organizations incurred expenditures per patient 10.3 percent higher than did physician-owned organizations. Organizations owned by multihospital systems incurred expenditures 19.8 percent higher than physician-owned organizations. The largest physician organizations incurred expenditures per patient 9.2 percent higher than the smallest organizations.

“These findings are in contrast to the hope and expectation that organizational consolidation of physicians with hospitals would result in greater coordination, and hence lower expenditures. Policymakers must strive to ensure that hospital acquisition of medical groups and physician practices does not lead to higher expenditures. Antitrust law and policy need to find the appropriate balance between permitting hospital acquisitions that improve efficiency, on the one hand, and preventing acquisitions that increase expenditures, on the other. Reform of payment methods by Medicare and private insurers should focus on the total expenditures made on behalf of patients by the physicians and facilities involved in their care to promote coordination but also to create incentives for efficiency and price reductions,” the authors write.
(doi:10.1001/jama.2014.14072; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: Support for this research was obtained from the Robert Wood Johnson Foundation. 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, OCTOBER 21, 2014
Media Advisory: To contact Laurence C. Baker, Ph.D., call Becky Bach at 530-415-0507 or email retrout@stanford.edu.

More Competition Among Physicians Related to Lower Prices Paid By Private PPOs For Office Visits

An examination of the relationship between physician competition and prices paid by private preferred provider organizations (PPOs) for common office visits finds that more competition is associated with lower prices paid to physicians in 10 large specialties, according to a study in the October 22/29 issue of JAMA.

Physicians are increasingly moving away from solo and smaller practices toward larger organizations. These changes may be beneficial if larger practices with more resources are better able to coordinate care, adopt process improvements, increase use of information technology, or take other actions that improve quality of care. At the same time, a trend toward fewer and larger groups could increase what economists refer to as “market concentration,” resulting in fewer practices facing less competition and with greater economic power. This in turn could lead health plans to pay higher prices for physician services. However, there is little evidence on the relationship between competition and prices paid for physician services, according to background information in the study.

Laurence C. Baker, Ph.D., of the Stanford University School of Medicine, Stanford, Calif., and colleagues conducted a study that included data from 1,058 U.S. counties in urbanized areas, representing all 50 states. The researchers determined the average price paid by county to physicians in 10 specialties by private PPOs for office visits with established patients and a price index measuring the county-weighted average price for 10 types of office visits with new and established patients relative to national average prices. The specialties were internal medicine, family practice, cardiology, dermatology, gastroenterology, neurology, general surgery, orthopedics, urology, and otolaryngology.

The researchers found that less competition among physician practices was associated with higher prices paid by private PPOs to physicians for office visits. Across 10 types of office visits, the difference in the Hirschman-Herfindahl Index (HHI; an economic competition measure) was associated with average prices for office visits 8.3 percent to 16.1 percent higher. In a more conservative model, this difference in the HHI was associated with 3.5 percent to 5.4 percent higher average prices. “This is consistent with the hypothesis that greater market power allows physicians to bargain for higher prices from private insurance companies.”

Examining changes in prices between 2003 and 2010, prices increased more rapidly in areas where practices were initially less competitive than in other areas. In some specialties, declining competition was also associated with larger increases in prices in areas that were initially more competitive. “This pattern suggests the possibility that the results we observe in 2010 may be related to the ability of practices in low-competition areas to negotiate larger price increases over time as well as related to changes in competition over time. This suggests that a lack of competition could have long­lasting effects, continuing to drive future price increases even without further changes in Hirschman-Herfindahl Index,” the authors write.

“An association between competition and prices may have important implications for health policy, as pressures to increase practice size persist or even increase in the future. We saw substantial amounts of concentration in the markets we studied, which raises concerns about potentially harmful implications for consumers. Higher health care spending due to increased prices paid to physicians without accompanying improvements in quality, satisfaction, or outcomes would generate inefficiency in the health care system.”

“These results may inform the development or adaptation of policies that influence practice competition,” the authors conclude.
(doi:10.1001/jama.2014.10921; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: The National Institute for Health Care Management provided funding to support this work. 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, OCTOBER 21, 2014
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 David M. Cutler, Ph.D., email Peter Reuell at preuell@fas.harvard.edu.

Hospital Switch to For-Profit Status Associated With Improvements in Financial Health, But Not With Differences in Quality of Care, Mortality Rates

Hospital conversion from nonprofit to for-profit status in the 2000s was associated with better subsequent financial health but had no relationship to the quality of care delivered, mortality rates, or the proportion of poor or minority patients receiving care, according to a study in the October 22/29 issue of JAMA.

During the past decade, there has been increasing attention to the growing number of nonprofit or public hospitals that have become for-profit. These conversions are controversial. Advocates argue that for-profit organizations bring needed resources and experienced management to struggling institutions, improving the quality an d efficiency of the care that these hospitals provide. Critics are concerned that once hospitals become “for­profit” they will focus on financial metrics such as improving payer mix and increasing volume, shunning disadvantaged patients and providing less attention to the provision of high­ quality care. There is little contemporary empirical evidence on what happens to patient care or to patient mix when hospitals convert, according to background information in the article.

Karen E. Joynt, M.D., M.P.H., of the Harvard School of Public Health, Boston, and colleagues examined characteristics of U.S. acute care hospitals associated with conversion to for-profit status and changes following conversion. The study included 237 converting hospitals and 631 matched control hospitals. Participants were 1,843,764 Medicare fee-for-service beneficiaries at converting hospitals and 4,828,138 patients at control hospitals.

The researchers found that converting hospitals improved their total margins (ratio of net income to net revenue plus other income) more than controls (2.2 percent vs 0.4 percent improvement). Hospitals that converted had similar performance on process quality indicators for heart attack, congestive heart failure, and pneumonia compared with controls at baseline (84.3 percent vs 85.5 percent). Both groups improved their process quality metrics (6.0 percent vs 5.6 percent).

Mortality rates did not change at converting hospitals relative to controls for Medicare patients overall or for dual-eligible (Medicare and Medicaid eligible) or disabled patients. There was also no change in converting hospitals relative to controls in annual Medicare volume, the proportion of patients with Medicaid, or the proportion of patients who were black or Hispanic.

“We found no evidence that conversion was associated with worsening care, as measured by processes of care, nurse staffing, or outcomes. On the other hand, for-profit hospitals have often argued that conversion will provide resources that will lead to better care, and our study failed to find any evidence to support this notion, either. In fact, our findings suggest that as regulators and policy makers consider for-profit conversions, the likely changes that could be anticipated will primarily be in the financial health of the institution, with little relationship, either positive or negative, to the quality of care provided or the institution’s mortality rates. Although there may be individual instances in which quality or outcomes improve or decline after a conversion, we did not find any consistent pattern during the past decade,” the authors write.
(doi:10.1001/jama.2014.13336; 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. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, etc.

Editorial: Who Benefits From Health System Change?

In an accompanying editorial, David M. Cutler, Ph.D., of Harvard University, Cambridge, Mass., comments on the three studies in this issue of JAMA that examine the effect of hospital conversions, physician competition, and physician practice ownership.

“The data from the 3 studies reported in this issue of JAMA are all from the period when payments were largely on a fee-for-service basis and patient cost sharing was relatively low. These findings may not necessarily translate to the current rapidly changing environment, in which payments are increasingly rewarded on a value basis, not a volume basis, and in which patients have significant cost sharing for services received. Such a payment system could lead to more systematic cost savings.”

“The experience so far is that consolidation has been good for many health care organizations and entities and for many clinicians and practitioner groups, with little clarity on how it has affected patients. Understanding how consolidation is related to resource use and quality of care, and how consolidated institutions will change in a changing health care system, will be fundamental in measuring the winners and losers in the new organization of care.”
(doi:10.1001/jama.2014.13491; 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, OCTOBER 21, 2014
Media Advisory: To contact Neeraj Sood, Ph.D., call Robert Perkins at 213-740-9226 or email perkinsr@usc.edu. To contact editorial author Uwe E. Reinhardt, Ph.D., email B. Rose Huber at brhuber@Princeton.EDU.

Making Health Services Prices Available Linked to Lower Total Claims Payments

Searching a health service pricing website before using the service was associated with lower payments for clinical services such as advanced imaging and laboratory tests, according to a study in the October 22/29 issue of JAMA.

Recent changes in the health care insurance market have resulted in commercially insured patients bearing a greater proportion of their health care costs. As patients have an increasing responsibility to pay for their care, they will likely demand access to prices charged for that care. Several state-administered initiatives have increased price transparency by reporting hospital charges or average reimbursement rates. Pricing information made available to patients reflects actual out-of-pocket costs for each individual patient by accounting for billed charge discounts, health benefit design, and deductibles, according to background information in the article.

Neeraj Sood, Ph.D., of the University of Southern California, Los Angeles, Christopher Whaley, B.A., of the University of California, Berkeley, and colleagues examined the association between the availability of health service prices to patients and the total claims payments (the total amount paid by patient and insurer) for these services (laboratory tests, advanced imaging services and clinician office visits). Payments for clinical services provided were compared between patients who searched a pricing website before using the service with patients who had not researched prior to receiving this service. The study included medical claims from 2010-2013 of 502,949 patients who were insured in the United States by 18 employers who provided a price transparency platform to their employees.

The researchers found that patients who searched the platform 14 days before receiving care had lower claim payments than those who did not. Adjusted payments were approximately 14 percent lower for laboratory tests, 13 percent lower for advanced imaging, and 1 percent lower for clinician office visits, with the relative differences translating into lower absolute dollar payments of $3.45 for laboratory tests, $124.74 for advanced imaging, and $1.18 for clinician office visits.

In the period before either group had access to the price transparency platform, payments for searchers were about 4 percent higher for laboratory tests and 6 percent higher for advanced imaging but were 0.26 percent lower for clinician office visits than for nonsearchers.

The authors write that tools such as this price transparency platform may affect use of care. “For example, knowing that some prices are very high, some patients may forego care. Conversely, cost savings from price shopping might enable patients to increase use, which may lead to improved adherence to recommended treatments but also to overuse of services. For this reason, our study cannot determine whether the price transparency technology reduces overall health care spending. Future research should extend this analysis to services beyond the three used in this study. It should also examine how use is affected to better understand the broader effect of price transparency on health care spending and population health.”
(doi:10.1001/jama.2014.13373; 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: Health Care Price Transparency and Economic Theory

“The findings reported by Whaley et al indicate that price transparency works as economists would expect it would,” writes Uwe E. Reinhardt, Ph.D., of Princeton University, Princeton, N.J., in an accompanying editorial.

“However, one important caveat on price transparency must be registered. As Brand et al of the Federal Trade Commission properly have noted, greater transparency about prices and quality in health care are not helpful if the relevant market for health care is monopolized. Transparency can promote savings and encourage better quality only if there are enough competing entities that provide health care in a market. It is a point that is sometimes overlooked but is an essential ingredient for patients to benefit from knowing the price and quality of the health care services they purchase.”
(doi:10.1001/jama.2014.14276; 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: 10 A.M. (CT) SATURDAY, OCTOBER 18, 2014
Media Advisory: To contact corresponding author Christine M. Eng, M.D., call Glenna Picton at 713-798-7973 or email picton@bcm.edu.

To place an electronic embedded link to this study in your story This link for the study will be live at the embargo time: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2014.14601

Whole-Exome Sequencing Shows Potential as Diagnostic Tool

Among a group of 2,000 patients referred for evaluation of suspected genetic conditions, whole-exome sequencing provided a potential molecular diagnosis for 25 percent, including detection of a number of rare genetic events and new mutations contributing to disease, according to a study appearing in JAMA. The study is being released to coincide with the American Society of Human Genetics annual meeting.

Whole-exome sequencing analyzes the exons or coding regions of thousands of genes simultaneously using next-generation sequencing techniques. By sequencing the exome of a patient and comparing it with a normal reference sequence, variations in an individual’s DNA sequence can be identified and related back to the individual’s medical concerns in an effort to discover the genetic cause of the medical disorder, according to background information in the article.

Yaping Yang, Ph.D., and Christine M. Eng, M.D., of the Baylor College of Medicine, Houston, and colleagues, had previously conducted a pilot study of whole-exome sequencing that included 250 patients. This current study included 2,000 patients (primarily pediatric, 88 percent), with clinical whole-exome sequencing analyzed between June 2012 and August 2014. Tests were ordered by the patient’s physician for suspected genetic conditions. Peripheral blood, tissue, or extracted DNA samples were collected from patients or their parents. The majority of the patients had neurological disorders or developmental delay (87.8 percent; neurological, neurological plus other organ systems, and specific neurological groups) and 12.2 percent of patients had nonneurological disorders (nonneurological group).

A molecular diagnosis was reported for 504 patients (25.2 percent) with 58 percent of the diagnostic mutations not previously reported. Molecular diagnosis rates for each phenotypic (physical manifestations) category were 143/526 (27.2 percent) for the neurological group, 282/1,147 (24.6 percent) for the neurological plus other organ systems group, 30/83 (36.1 percent) for the specific neurological group, and 49/244 (20.1 percent) for the nonneurological group.

In the 2,000 cases, 95 medically actionable incidental findings were reported in 92 patients (4.6 percent). Three patients had more than 1 such finding. In 59 patients (3 percent), the incidental findings occurred in genes included in the American College of Medical Genetics and Genomics list of 56 genes recommended to be disclosed. The remaining 33 patients (1.7 percent) had mutations in genes reported based on the researcher’s local criteria for reporting of medically actionable results.

“A molecular diagnosis rate of 25 percent was observed in our pilot study of 250 cases and has remained consistent in this larger series of predominantly pediatric patients with diverse clinical presentations most notable for intellectual disability and neurological phenotypes,” the authors write.

They add that approximately 30 percent of positive cases reported herein harbored presumptive causative mutations in disease genes discovered since 2011, reflecting the benefits of an accelerating pace of disease gene discovery. “Whole-exome sequencing testing is a platform suitable for timely incorporation of new disease genes because it interrogates entire coding regions, making it possible to automate the updating of disease gene annotation for clinical reporting, even after the initial analysis is completed.”

The researchers conclude that the “observed flexibility and yield of whole-exome sequencing may offer advantages over traditional molecular diagnosis approaches in certain patients.”
(doi:10.1001/jama.2014.14601; 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: 10 A.M. (CT) SATURDAY, OCTOBER 18, 2014
Media Advisory: To contact corresponding author Stanley F. Nelson, M.D., call Elaine Schmidt at 310-794-2272 or email ESchmidt@mednet.ucla.edu. To contact editorial co-author Jonathan S. Berg, M.D., Ph.D., call Katy Jones at 919-962-3405 or email katy_jones@med.unc.edu.

To place an electronic embedded link to this study and editorial in your story This link to the study will be live at the embargo time: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2014.14604.
This will be the link to the editorial: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2014.14665.

Type of Exome Sequencing Associated With Higher Molecular Diagnostic Yield than Certain Other Diagnostic Methods

In a sample of patients with undiagnosed, suspected genetic conditions, a certain type of exome sequencing method was associated with a higher molecular diagnostic yield than traditional molecular diagnostic methods, according to a study appearing in JAMA. The study is being released to coincide with the American Society of Human Genetics annual meeting.

Exome sequencing, which sequences the protein­coding region of the genome (the complete set of genes or genetic material present in a cell or organism), has been rapidly applied in research settings and recent increases in accuracy have enabled the development of clinical exome sequencing (CES) for mutation identification in patients with suspected genetic diseases. Early in 2012, the Clinical Genomics Center at the University of California, Los Angeles, launched a CES program with the goal of delivering a more comprehensive method for determining a molecular diagnosis for patients with presumed rare Mendelian disorders (a genetic disease showing a certain pattern of inheritance) that have remained undiagnosed despite exhaustive genetic, biochemical, and radiological testing. Researchers at this center have introduced a new test, called trio-CES, in which the whole exome of the affected proband (first identified individual affected with the disorder among other family members) and both parents are sequenced, according to background information in the article.

Hane Lee, Ph.D., of the University of California, Los Angeles, and colleagues report the results of clinical exome sequencing performed on 814 patients with undiagnosed, suspected genetic conditions at the Clinical Genomics Center between January 2012 and August 2014. Clinical exome sequencing was conducted as trio-CES (both parents and their affected child sequenced simultaneously) or as proband-CES (only the affected individual sequenced) when parental samples were not available.

Overall, a molecular diagnosis (with the causative variant(s) identified in a well-established clinical gene) was provided for 213 of the 814 total cases (26 percent). There was a significantly higher molecular diagnostic yield from cases performed as trio-CES (127 of 410 cases; 31 percent) relative to proband-CES (74 of 338 cases; 22 percent) in the overall group of cases.

In cases of developmental delay in children (<5 years, n = 138), the molecular diagnosis rate was 41 percent (45 of 109) for trio-CES cases and 9 percent (2 of 23) for proband-CES cases. “In this sample of patients with undiagnosed, suspected genetic conditions, trio-CES was associated with higher molecular diagnostic yield than proband-CES or traditional molecular diagnostic methods. Additional studies designed to validate these findings and to explore the effect of this approach on clinical and economic outcomes are warranted. Clinical implications of these findings need to be better understood before CES should be routinely adopted,” the authors conclude. (doi:10.1001/jama.2014.14604; 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. [ama_toc_item id="28506"] Editorial: Genome-Scale Sequencing in Clinical Care In an accompanying editorial, Jonathan S. Berg, M.D., Ph.D., of the University of North Carolina at Chapel Hill, comments on the two JAMA studies that examined exome sequencing. “Ultimately, it will be essential to know who will benefit from clinical genomic sequencing, including the role of sequencing in a variety of settings, such as oncology, prenatal diagnosis, newborn screening, or population screening in healthy adults. The National Institutes of Health and other funding agencies are supporting a broad portfolio of research projects investigating these and other questions about genomic medicine. In the meantime, physicians should be judicious in considering when to obtain clinical exome sequencing; should effectively communicate the risks, benefits, and limitations of such testing; should be able to clearly communicate the results to patients and their families; and should avoid unnecessarily burdening patients with the cost of such testing if not covered by insurance. The application of genomic sequencing will ultimately contribute to progress in clinical care, from molecular diagnosis to improved outcomes, but there is much to learn before it can be applied more universally.” (doi:10.1001/jama.2014.14665; 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. [ama_toc_item id="28502"] # # #

EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, OCTOBER 14, 2014
Media Advisory: To contact Renee Y. Hsia, M.D., M.Sc., email Elizabeth Fernandez at efernandez@pubaff.ucsf.edu.

To place an electronic embedded link to this study in your story This link for the study will be live at the embargo time: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2014.9905

Study Shows Increase in Use of Emergency Departments by Children and Teens, Regardless of Insurance Type, Status

In contrast to previous research that documented decreases or no change in children’s rates of emergency department (ED) use in the 1990s and the early 2000s, an analysis of ED visits by children, adolescents, and young adults in California by insurance status from 2005-2010 found that rates increased across all insurance groups and the uninsured, according to a study in the October 15 issue of JAMA.

Concerns regarding cost, continuity of care, and crowding continue to bring ED use under nationwide scrutiny. Although many hope that increasing insurance coverage through the Affordable Care Act will lead to decreases in ED visits, recent evidence in adults suggests that increasing access to specifically Medicaid insurance may actually be associated with increased ED use. Most prior research on trends in ED use in children, adolescents, and young adults predates the recent economic downturn and associated changes in insurance coverage, according to background information in the article.

Renee Y. Hsia, M.D., M.Sc., of the University of California, San Francisco, and colleagues analyzed data of ED visits by youths (children, adolescents, and young adults 18 years of age and younger) to acute care hospitals across California between 2005 and 2010. ED visits were grouped into 4 categories: Medicaid, private insurance, uninsured, and other.

The number of visits to California EDs by youths increased from 2.5 million in 2005 to 2.8 million in 2010, a change of 11 percent. Children covered by Medicaid accounted for 44 percent of all ED visits. The distribution of visits across payer groups changed significantly between 2005 and 2010, with Medicaid accounting for a larger share over time. After adjusting for population (given a 3 percent decrease in the pediatric population during the study period) to obtain ED visit rates, the rate of ED use increased across all insurance groups.

Uninsured youths living in California exhibited the fastest increase in ED visit rates, followed by those privately insured. The rate of ED use among youths covered by Medicaid exhibited the slowest growth, but remained the highest in absolute terms.

The authors write that even though Medicaid patients have the fastest-growing rates of ED use among adults, the largest increases in ED visit rates for youths are not among Medicaid beneficiaries but rather among those individuals who are privately insured or uninsured. “Shifts in insurance (from private and no insurance to Medicaid) during the recession (December 2007-June 2009) likely influenced the trends during this time.”

“These findings suggest that the drivers for ED use differ significantly between youths and adults and that policies regarding insurance expansion may also have varying effects. The divergence from older trends in ED use among youths may also reflect the increasingly central role of the ED in the U.S. health care system, especially during a period of severe economic recession, and could signal an overall deterioration in access to primary care across payer groups, or that even privately insured youths with greater access to primary care physicians are being directed to the ED for care.”
(doi:10.1001/jama.2014.9905; 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, OCTOBER 14, 2014
Media Advisory: To contact Mark D. Neuman, M.D., M.Sc., email Lee-Ann Donegan at Leeann.Donegan@uphs.upenn.edu. To contact editorial co-author Elizabeth A. McGlynn, Ph.D., call Albert Martinez at 510-625-2124 or email albert.martinez@kp.org.

To place an electronic embedded link to this study and editorial in your story This link to the study will be live at the embargo time: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2014.13513. This will be the link to the editorial: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2014.12819.

Better Performance on Quality Measures for Skilled Nursing Facilities May Not Result in Better Outcomes for Patients

Among fee-for-service Medicare beneficiaries who received care at a skilled nursing facility following hospital discharge, better performance on various measures of quality of care was not consistently associated with a lower risk of hospital readmission or death at 30 days, according to a study in the October 15 issue of JAMA.

One in five Medicare beneficiaries is readmitted to the hospital within 30 days of discharge. These readmissions are costly and potentially preventable. Skilled nursing facilities (SNFs) represent the most common setting for postacute care in the United States. Little is known about the association between available SNF performance measures and the risk of hospital readmission, according to background information in the article.

Mark D. Neuman, M.D., M.Sc., of the University of Pennsylvania, Philadelphia, and colleagues used national Medicare data on fee-for-service beneficiaries discharged to a SNF after an acute care hospitalization to examine the association between SNF performance on publicly available metrics and the risk of readmission or death 30 days after discharge to a SNF. The metrics were SNF staffing intensity, health deficiencies identified through site inspections, and the percentages of SNF patients with delirium, moderate to severe pain, and new or worsening pressure ulcers.

Of 1,530,824 discharges to SNFs, 321,709 were followed by readmission within 30 days (21.0 percent), and 72,472 were followed by a death within 30 days (4.7 percent). The overall rate of 30-day readmission or death was 23.3 percent. Although better performance on several available SNF performance measures (including better staffing ratings and better facility inspection ratings) was associated with improved outcomes in unadjusted analyses, these associations were diminished substantially after adjustment for patient factors, the discharging hospital, and SNF facility characteristics.

In fully adjusted models, SNFs with better facility inspection ratings demonstrated a slightly lower adjusted risk of readmission or death; however, adjusted outcomes did not vary meaningfully across SNFs that differed in terms of staffing ratings or their performance on clinical measures related to pain or delirium. Other measures did not predict clinically meaningful differences in the adjusted risk of readmission or death.

“Our results provide new information to inform the efforts of hospitals, health systems, and insurers to reduce rates of hospital readmission through more effective use of postacute care. Ultimately, although SNF performance measurement plays an important role in promoting transparency and accountability in the U.S. health care system, our findings suggest that in their current form they are unlikely to serve as a sole basis for large-scale reductions in readmissions unless accompanied by other strategies,” the authors write.
(doi:10.1001/jama.2014.13513; 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: What Makes a Good Quality Measure?

In an accompanying editorial, Elizabeth A. McGlynn, Ph.D., and John L. Adams, Ph.D., of the Kasier Permanente Center for Effectiveness and Safety Research, Pasadena, Calif., comment on the two JAMA studies that examined quality indicators.

“Neither study looked at other processes as potential predictors of the outcomes of interest (readmission, death, childbirth outcomes) and therefore missed an opportunity to identify areas for future measure development. Further, careful consideration of the ultimate goal of a quality measure must be made. The information required for consumers to choose among nursing homes or hospitals may be different than the information required to improve clinical outcomes. Measures that work for one purpose and not another are still valuable. Future studies of quality measures should establish a clear framework and expectations for the intended goals of quality measures. Both reports make it clear that a great deal of additional work is needed to achieve the quality measures necessary for a more complete characterization of system performance and potential improvement opportunities.”
(doi:10.1001/jama.2014.12819; 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, OCTOBER 14, 2014
Media Advisory: To contact Elizabeth A. Howell, M.D., M.P.P., call Sid Dinsay at 212-241-9200 or email Sid.Dinsay@mountsinai.org.

To place an electronic embedded link to this study in your story This link for the study will be live at the embargo time: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2014.13381

Study Indicates Need for More Obstetric Quality of Care Measures at Hospitals

In an analysis of data on more than 100,000 deliveries and term newborns from New York City hospitals, rates for certain quality indicators and complications for mothers and newborns varied substantially between hospitals and were not correlated with performance measures designed to assess hospital-level obstetric quality of care, according to a study in the October 15 issue of JAMA.

Severe maternal complications occurs in about 60,000 women (1.6 per 100 deliveries) annually in the United States, and 1 in 10 term infants experience neonatal complications. In an effort to improve the quality of care, several obstetric-specific quality measures are now monitored and publicly reported. The extent to which these measures are associated with maternal and neonatal complications has not been known, according to background information in the article.

Elizabeth A. Howell, M.D., M.P.P., of the Icahn School of Medicine at Mount Sinai, New York, and colleagues used New York City discharge and birth certificate data sets from 2010 to determine whether two Joint Commission obstetric quality indicators (elective, nonmedically indicated deliveries performed at 37 weeks or more of gestation and prior to 39 weeks and cesarean deliveries performed in low-risk women) were associated with severe maternal or neonatal complications. Published algorithms were used to identify severe maternal complications (delivery associated with a life-threatening complication or performance of a lifesaving procedure) and complications in term newborns without birth defects (births associated with complications such as birth trauma, hypoxia [a lower-than-normal concentration of oxygen in arterial blood], and prolonged length of stay).

Severe maternal complications occurred among 2,372 of 115,742 deliveries (2.4 percent), and neonatal complications occurred among 8,057 of 103,416 term newborns without birth defects (7.8 percent). Rates for elective deliveries performed before 39 weeks of gestation ranged from 15.5 to 41.9 per 100 deliveries among 41 hospitals. There were 11.7 to 39.3 cesarean deliveries per 100 deliveries performed in low-risk mothers. Severe maternal complication rates varied 4- to 5-fold between hospitals, and there was a 7-fold variation in neonatal complications at term between hospitals.

The maternal quality indicators of elective delivery before 39 weeks of gestation and cesarean delivery performed in low-risk mothers were not associated with severe maternal or neonatal complications.

“Current quality indicators may not be sufficiently comprehensive for guiding quality improvement in obstetric care,” the authors conclude.
(doi:10.1001/jama.2014.13381; 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, October 14 at this link.

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EMBARGOED FOR RELEASE: 2 P.M. (CT) SATURDAY, OCTOBER 11, 2014
Media Advisory: To contact Ilan Youngster, M.D., M.M.Sc., call Noah Brown at 617- 643-3907 or email nbrown9@partners.org.

To place an electronic embedded link to this study in your story This link for the study will be live at the embargo time: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2014.13875

Study Shows Feasibility of Treating Clostridium difficile Infection With Oral Administration of Frozen Encapsulated Fecal Material

A preliminary study has shown the potential of treating recurrent Clostridium difficile infection (a bacterium that is one of the most common causes of infection of the colon) with oral administration of frozen encapsulated fecal material from unrelated donors, which resulted in an overall rate of resolution of diarrhea of 90 percent, according to a study published in JAMA. The study is being released early online to coincide with its presentation at IDWeek 2014.

Recurrent Clostridium difficile infection (CDI) is a major cause of illness and death, with a recent increase in the number of adult and pediatric patients affected globally. Standard treatment with oral administration of the antibiotics metronidazole or vancomycin is increasingly associated with treatment failures. Fecal microbiota transplantation (FMT)—i.e., reconstitution of normal flora (gut bacteria) by a stool transplant from a healthy individual—has been shown to be effective in treating relapsing CDI. The majority of reported FMT procedures have been performed with fresh stool suspensions from related donors; however practical barriers and safety concerns have prevented its widespread use, according to background information from the article.

To address these barriers, the use of frozen fecal matter from carefully screened healthy donors has been used for FMT; nasogastric tube (a tube that is passed through the nasal passages and into the stomach) administration of the frozen product was comparable with colonoscopic delivery. Building on this work, the researchers generated a capsulized version of the frozen inoculum that can be administered orally and obviates the need for any gastrointestinal procedures.

Ilan Youngster, M.D., M.M.Sc., of Massachusetts General Hospital, Boston, and colleagues conducted a study to evaluate the safety and rate of diarrhea resolution associated with oral administration of frozen FMT capsules for patients with recurrent CDI. The study included 20 patients with at least three episodes of mild to moderate CDI and failure of a 6- to 8-week taper with oral vancomycin or at least 2 episodes of severe CDI requiring hospitalization. Healthy volunteers were screened as potential donors and FMT capsules were generated and frozen. Patients received 15 capsules on 2 consecutive days and were followed up for symptom resolution and adverse events for up to 6 months.

Among the 20 patients, 14 had clinical resolution of diarrhea after the first administration of capsules (70 percent) and remained symptom free at 8 weeks. All 6 non­responders were retreated at an average 7 days after the first procedure; 4 obtained resolution of diarrhea, resulting in an overall 90 percent rate of clinical resolution of diarrhea.

Daily number of bowel movements decreased from a median of 5 the day prior to administration to 2 at day 3 and 1 at 8 weeks. Self-reported health rating using a standardized questionnaire scale of l to 10 improved significantly over the study period, from a median of 5 for overall health and 4.5 for gastrointestinal health the day prior to FMT, to 8 for both ratings at 8 weeks after the administration.

No serious adverse events attributed to FMT were observed.

“If reproduced in future studies with active controls, these results may help make FMT accessible to a wider population of patients, in addition to potentially making the procedure safer. The use of frozen inocula allows for screening of donors in advance. Furthermore, storage of frozen material allows retesting of donors for possible incubating viral infections prior to administration. The use of capsules obviates the need for invasive procedures for administration, further increasing the safety of FMT by avoiding procedure-associated complications and significantly reducing cost,” the authors write.

“Larger studies are needed to confirm these results and to evaluate long-term safety and effectiveness.”
(doi:10.1001/jama.2014.13875; 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: 8:45 A.M. (CT) FRIDAY, OCTOBER 10, 2014
Media Advisory: To contact Jeffrey S. Gerber, M.D., Ph.D., call Rachel Salis-Silverman at 267-426-6063 or email salis@email.chop.edu.

After Discontinuation of Audit and Feedback, Initial Benefits of Intervention to Reduce Unnecessary Antibiotic Prescriptions Lost

The initial benefits of an outpatient antimicrobial stewardship intervention designed to reduce the rate of inappropriate antibiotic prescriptions were lost after discontinuation of audit and feedback to clinicians, according to a study published in JAMA. The study is being released early online to coincide with the IDWeek 2014 meeting.

Antibiotics are the most frequently prescribed medications for children; most are prescribed for outpatient acute respiratory tract infections. Because antibiotic prescribing is often inappropriate, Jeffrey S. Gerber, M.D., Ph.D., of Children’s Hospital of Philadelphia, and colleagues recently conducted a randomized trial of an outpatient antimicrobial stewardship intervention that found a nearly 50 percent relative reduction in prescribing rates for broad-spectrum antibiotics, according to background information in the article.

To assess the durability of this intervention, the researchers followed antibiotic prescribing across intervention and control sites after termination of audit and feedback. The randomized trial was conducted within 18 community-based pediatric primary care practices using a common electronic health record. The intervention included clinician education, comprising a 1-hour review of current prescribing guidelines for the targeted conditions; and audit and feedback of antibiotic prescribing. Nine practices received the intervention and 9 practices received no intervention. Twelve months after initiating the study, the researchers stopped providing antibiotic prescribing audit and feedback to clinicians in the intervention group. As planned prior to the end of the intervention, the observation period was extended by an additional 18 months, bringing the total observation time to 50 months.

As previously reported, following the 12-month intervention of prescribing audit and feedback, broad-spectrum antibiotic prescribing decreased from 26.8 percent to 14.3 percent among intervention practices vs 28.4 percent to 22.6 percent in controls. Following termination of audit and feedback, however, prescribing of broad-spectrum antibiotics increased over time, reverting to above-baseline levels. After restandardization of the data set for the additional 18 months of data, antibiotic prescribing increased from 16.7 percent at the end of intervention to 27.9 percent at the end of observation in the intervention group and from 25.4 percent to 30.2 percent in controls.

“These data suggest that audit and feedback was a vital element of this intervention and that antimicrobial stewardship requires continued, active efforts to sustain initial improvements in prescribing. Our findings suggest that extending antimicrobial stewardship to the ambulatory setting can be effective but should include continued feedback to clinicians,” the authors write.
(doi:10.1001/jama.2014.14042; 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: 10 A.M. (CT) THURSDAY, OCTOBER 9, 2014
Media Advisory: To contact Andre C. Kalil, M.D., M.P.H., call Tom O’Connor at 402-559-4690 or email toconnor@unmc.edu.

Study Examines Effect of Different Levels of Antibiotic Susceptibility on Risk of Death Among Patients With Staphylococcus aureus Bloodstream Infection

In an analysis of more than 8,000 episodes of Staphylococcus aureus bloodstream infections, there were no significant differences in the risk of death when comparing patients exhibiting less susceptibility to the antibiotic vancomycin to patients with more vancomycin susceptible strains of S. aureus, according to a study published in JAMA. The study is being released early online to coincide with the IDWeek 2014 meeting.

Staphylococcus aureus is among the most common causes of health care-associated infection throughout the world. It causes a wide range of infections, with blood­stream infections (S aureus bacteremia [SAB]) among the most common and lethal. For more than 50 years, the primary therapy for S aureus infections has been either semisynthetic penicillins or vancomycin. More recent reports have documented an increase in the minimum inhibitory concentration (MIC; the lowest concentration of an antimicrobial agent that inhibits the growth of a microorganism) for vancomycin, referred to as vancomycin “MIC creep” (the development of reduced susceptibility to vancomycin). There have been reports suggesting that elevations in vancomycin MIC values may be associated with increased treatment failure and death, according to background information in the article.

Andre C. Kalil, M.D., M.P.H., of the University of Nebraska Medical Center, Omaha, and colleagues conducted a review and meta-analysis of the evidence regarding the association of vancomycin MIC elevation with mortality in patients with SAB. The researchers identified 38 studies that met criteria for inclusion.

Among 8,291 episodes of SAB included in the studies, overall mortality was 26.1 percent. The adjusted absolute risk of mortality among patients with SAB with high-vancomycin MIC (≥ 1.5 mg/L [less susceptible]; n = 2,740 patients; mortality, 26.8 percent) was not statistically different from patients with SAB with low-vancomycin MIC (< 1.5mg/L; [more susceptible] n = 5,551 patients; mortality, 25.8 percent). In studies that included only methicillin-resistant S aureus (MRSA) infections (n = 7,232), the mortality among SAB episodes in patients with high-vancomycin MIC was 27.6 percent, compared with a mortality of 27.4 percent among patients with low-vancomycin MIC. The authors note that the findings cannot definitely exclude an increased risk of death. No significant differences in risk of death were observed in subgroups with high-vancomycin MIC vs low-vancomycin MIC values across different study designs, types of microbiological susceptibility assays, MIC cutoffs, clinical outcomes, duration of bacteremia, previous vancomycin exposure, and treatment with vancomycin. The researchers write that the findings of this study may have implications for clinical practice and public health, including that standards for vancomycin MIC most likely do not need to be lowered; routine differentiation of MIC values between 1mg/L and 2 mg/L appears unnecessary; and the use of alternative antistaphylococcal agents may not be required for S aureus isolates with elevated but susceptible vancomycin MIC values. “These conclusions are consistent with current Infectious Disease Society of America treatment guidelines that recommend use of vancomycin for treatment of MRSA bacteremia with consideration for alternative agents based on the patient's clinical response and not the MIC.” (doi:10.1001/jama.2014.6364; 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. [ama_toc_item id="27976"] # # #

EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, OCTOBER 7, 2014
Media Advisory: To contact corresponding authors Carole Fakhry, M.D., M.P.H., or Gypsyamber D’Souza, Ph.D., M.S., M.P.H., call Stephanie Desmon at 410-955-7619 or email Sdesmon1@jhu.edu.

Tobacco Use Associated With Increased Risk of Oral HPV-16 Infection

Study participants who reported tobacco use or had higher levels of biomarkers of tobacco exposure had a higher prevalence of the sexually transmitted infection, oral human papillomavirus type 16 (HPV-16), according to a study in the October 8 JAMA, a theme issue on infectious disease.

Oral HPV-16 is believed to be responsible for the increase in incidence of oropharyngeal squamous cell cancers in the United States. An association between self-reported number of cigarettes currently smoked per day and oral HPV prevalence has been observed, according to background information in the article.

Carole Fakhry, M.D., M.P.H., of the Johns Hopkins University School of Medicine, Baltimore, and colleagues investigated associations between objective biomarkers reflective of all current tobacco exposures (environmental, smoking, and use of smoke­less tobacco) and oral HPV-16 prevalence. The researchers used data from the National Health and Nutrition Examination Survey (NHANES), a probability sample of the U.S. population. Mobile examination center participants ages 14 to 69 years were eligible for oral HPV DNA testing. Computer-assisted self-interviews were used to ascertain self-reported tobacco use and sexual behaviors. Self­reported tobacco use for the past 5 days included any nicotine­containing product. Biomarkers of recent tobacco use included serum cotinine, a major nicotine metabolite, and urinary 4- (methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), a tobacco­specific, carcinogenic metabolite.

This analysis included 6,887 NHANES participants, of whom 2,012 (28.6 percent) were current tobacco users and 63 (1.0 percent) had oral HPV-16 detected. Current tobacco users were more likely than nonusers to be male, younger, less educated, and to have a higher number of lifetime oral sexual partners. Self-reported and biological measures of tobacco exposure as well as oral sexual behavior were significantly associated with prevalent oral HPV-16 infection. Oral HPV-16 prevalence was greater in current tobacco users (2.0 percent) compared with never or former tobacco users (0.6 percent). Average cotinine and NNAL levels were higher in individuals with vs without oral HPV-16 infection.

“These findings highlight the need to evaluate the role of tobacco in the natural history of oral HPV-16 infection and progression to malignancy,” the authors write.
(doi:10.1001/jama.2014.13183; 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, OCTOBER 7, 2014
Media Advisory: To contact Lauren Epstein, M.D., M.Sc., call Melissa Brower at 404-639-4718 or email mbrower@cdc.gov. To contact editorial co-author William A. Rutala, PhD., M.P.H., call Tom Hughes at 984-974-1151 or email Tom.Hughes@unchealth.unc.edu.

E coli Outbreak at Hospital Associated With Contaminated Specialized Gastrointestinal Endoscopes

Despite no lapses in the disinfection process recommended by the manufacturer being identified, specialized gastrointestinal endoscopes called duodenoscopes had bacterial contamination associated with an outbreak of a highly resistant strain of E coli at a hospital in Illinois, according to a study in the October 8 JAMA, a theme issue on infectious disease.

The duodenoscope is different than that used for routine upper gastrointestinal endoscopy or colonoscopy. The procedure associated with these specialized scopes is endoscopic retrograde cholangiopancreatography (ERCP), an important and potentially lifesaving medical procedure that allows doctors to diagnose and treat life-threatening problems in the bile and pancreatic ducts.

Carbapenem-resistant Enterobacteriaceae (CRE) are multidrug-resistant organisms isolated predominantly from patients with exposures in health care facilities. CRE are a public health concern because treatment options are limited and invasive infections are associated with a risk of death. The New Delhi metallo-beta-lactamase (NDM) is a carbapenemase (an enzyme that breaks down antibiotics) that has been infrequently reported in the United States. However, NDM-producing CRE have the potential to add substantially to the total CRE burden. Understanding transmission and preventing further spread of CRE is a public health priority, according to background information in the article.

In March 2013, NDM-producing Escherichia coli was identified from a patient at a teaching hospital in Illinois. Between March 2013 and July 2013, 6 additional patients with a history of admission to this hospital had positive clinical cultures for NDM-producing E coli. In August 2013, Lauren Epstein, M.D., M.Sc., of the Centers for Disease Control and Prevention, Atlanta, and colleagues launched an investigation to identify the source and prevent further NDM¬-producing CRE transmission at this hospital. Interviews were conducted with health care personnel at the hospital.

A medical record review revealed that a history of ERCP procedures involving the use of a duodenoscope was common among initial cases. In total, 39 case patients were identified from January 2013 through December 2013, 35 with duodenoscope exposure. In this outbreak, 39 patients with NDM-producing CRE were identified from January 2013 – December 2013, 35 with duodenoscope exposure in 1 hospital. Some of those patients had positive blood cultures, often an indication of infection and others were found to be colonized with CRE but did not have a CRE infection.

NDM-producing E coli was recovered from a reprocessed duodenoscope and shared similarity to all case patient isolates. Based on a case-control study, case patients had significantly higher odds of being exposed to a duodenoscope. The authors write that the large number of exposed patients that ultimately had NDM-producing CRE isolated from clinical or screening cultures suggests that duodenoscopes were an efficient source of transmission.

An infection prevention assessment that focused on duodenoscope reprocessing (such as cleaning) was conducted, and it was found that the hospital followed all manufacturer-recommended procedures. After the hospital changed its duodenoscope reprocessing to a gas sterilization procedure, no additional case patients were identified.

“The complicated design of duodenoscopes makes cleaning difficult. It appears that these devices have the potential to remain contaminated with pathogenic bacteria even after recommended reprocessing is performed,” the researchers write. They add that another option for ensuring adequate duodenoscope reprocessing might be to conduct testing for residual contamination during reprocessing. “Many international professional societies recommend periodic microbiological surveillance testing of duodenoscopes after full reprocessing.”

“Facilities should be aware of the potential for transmission of antimicrobial-resistant organisms via this route and should conduct regular reviews of their duodenoscope reprocessing procedures to ensure optimal manual cleaning and disinfection.”
(doi:10.1001/jama.2014.12720; 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: Gastrointestinal Endoscopes – A Need to Shift From Disinfection to Sterilization?

William A. Rutala, PhD., M.P.H., and David J. Weber, M.D., M.P.H., of University of North Carolina Health Care, Chapel Hill, comment on the findings of this study in an accompanying editorial.

“Clinicians should be encouraged to report and publish cases of infectious diseases related to endoscopy, especially if current reprocessing methods were adhered to, so it can be determined if the report by Epstein et al is the tip of the iceberg or an isolated occurrence. If the former, then revision of the endoscope reprocessing guidelines will be necessary to ensure patient safety. However, regardless of when these issues are resolved, endoscopy will remain an important diagnostic and therapeutic modality and should continue to be used while clinicians strictly adhere to current endoscope reprocessing guidelines.”
(doi:10.1001/jama.2014.12559; 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, OCTOBER 7, 2014
Media Advisory: To contact Mark J. Mulligan, M.D., call Holly Korschun at 404-727-3990 or email Hkorsch@emory.edu. To contact Robert B. Belshe, M.D., call Nancy Solomon at 314-977-8017 or email solomonn@slu.edu. To contact editorial author John J. Treanor, M.D., call Emily Boynton at 585-273-1757 or email Emily_boynton@urmc.rochester.edu.

Studies Examine Vaccination Strategies For Prevention, Control of Avian Flu

Two randomized trials in the October 8 issue of JAMA examine new vaccination strategies for the prevention and control of avian influenza, often referred to as “bird flu.” This is a theme issue on infectious disease.

In one study, Mark J. Mulligan, M.D., of the Emory University School of Medicine, Atlanta, and colleagues compared the safety and antibody responses (immunogenicity) of different doses of influenza A/Shanghai/2/13 (H7N9) vaccine mixed with or without the MF59 adjuvant (a component that improves immunogenicity and enhances efficacy of inactivated influenza vaccines).

In 2013, human infections with a novel influenza subtype, A/H7N9, were identified in China. Infected patients had live poultry exposures. The virus did not produce disease in poultry; however, it caused severe pneumonia in humans, with hospitalization and mortality rates of 67 percent and 33 percent, respectively. A second wave of infections occurred in winter 2013-2014; through June 27, 2014, a total of 450 laboratory­ confirmed cases with 165 deaths (36.6 percent) have been reported, according to background information in the study.

This phase 2 trial was conducted at 4 U.S. sites, which enrolled 700 adults ages 19 to 64 years beginning in September 2013; 6-month follow-up was completed in May 2014. The H7N9 inactivated virus vaccine was administered at various doses with or without the MF59 adjuvant among the seven study groups.

Without the MF59 adjuvant, the highest antigen dosage of 45 µg induced minimal antibody responses against H7N9. Higher antigen doses were not associated with increased response. After receiving 2 doses of H7N9 vaccine at a dosage of 3.75 µg plus the MF59 adjuvant, day 42 seroconversion occurred in 58 (59 percent) participants.

Recent receipt of seasonal influenza vaccination and older age were associated with reduced response. No vaccine-related serious adverse events occurred. Postvaccination symptoms were generally mild with more local symptoms seen in participants who received the adjuvant.

“The significant antigen dose-sparing effect of MF59 is an important finding, potentially allowing for protection of many more people with limited vaccine. The study did not determine the optimal antigen dose to combine with MF59 because the lowest dose produced the maximum antibody seroconversion. This is an area for future research,” the authors write.

They note that even though these findings indicate potential value in this approach, the study is limited by absence of antibody data beyond 42 days and absence of clinical outcomes.
(doi:10.1001/jama.2014.12854; 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, Robert B. Belshe, M.D., of the Saint Louis University School of Medicine, and colleagues examined whether immunologic priming (initial presentation of an antigen to allow antibody responses on revaccination) with vaccine directed toward an older avian influenza H5 strain (A/Vietnam/1203/2004(H5N1) [Vietnam]) might lead to secondary antibody responses to a single dose of a more current H5 avian influenza vaccine (A/Anhui/01/2005 [Anhui]).

Study participants vaccinated 1 year previously (n = 72) with 1 or 2 doses of the Vietnam vaccine received low­dose Anhui vaccine with or without MF59 adjuvant. The researchers also studied the antibody response of 2 doses of Anhui vaccine at 5 different dose levels with or without MF59 in H5N1 vaccine­naive participants (n = 565).

The researchers found that previous receipt of a single dose of Vietnam vaccine was associated with sufficient immunologic priming to increase (boost) response to a different H5N1 antigen using low-dose Anhui vaccine. The secondary antibody responses were brisk (responses seen by day 7) and peaked at 14 days after the boosting vaccination.

This phenomenon was observed with the 2 H5N1 antigens; “participants who are exposed to a related antigen later in life respond with antibody to the initial (priming) antigen as well as to the second (boosting) antigen,” the authors write.

In participants who had not previously received H5 vaccine, low­ dose Anhui vaccine plus adjuvant was more immunogenic compared with higher doses of unadjuvanted vaccine. “In the present study, significant dose sparing was associated with the addition of MF59 adjuvant among vaccine­naive participants; among these participants, the advantage of adding an adjuvant to novel influenza vaccine antigens became apparent.”
(doi:10.1001/jama.2014.12609; 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: Expanding the Options for Confronting Pandemic Influenza

In an accompanying editorial, John J. Treanor, M.D., of the University of Rochester, New York, writes that these studies “provide important information that expands the available options for confronting pandemic influenza, and may help surmount those obstacles.”

“The current reports by Mulligan et al and Belshe et al, along with other similar studies, have shown that a prepandemic vaccination program is certainly feasible. What would be the components of the decision to implement such a strategy? One important question is the actual risk that an avian virus will emerge to cause a pandemic, and how to determine the risk presented by any new virus. Current research efforts are directed toward determining the molecular markers of virulence and transmission of emerging influenza viruses, and assessing the level of age-related population immunity. If the level of risk appeared to justify a prepandemic vaccination strategy, who should be vaccinated? Creating a priority list of individuals for whom a rapid response to vaccine would be important and might include first responders, health care workers, or possibly higher-risk individuals such as older adults, who appear particularly at risk for severe illness from H7N9 influenza.”
(doi:10.1001/jama.2014.12558; 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, OCTOBER 7, 2014
Media Advisory: To contact Shelley S. Magill, M.D., Ph.D., call Melissa Brower at 404-639-4718 or email mbrower@cdc.gov.

Antimicrobial Use in Hospitals Appears to Be Common

A one-day prevalence survey of 183 hospitals found that approximately 50 percent of hospitalized patients included in the survey were receiving antimicrobial drugs, and that about half of these patients were receiving 2 or more antimicrobial drugs, according to a study in the October 8 JAMA, a theme issue on infectious disease. Most antimicrobial use was for infection treatment.

Despite the evidence supporting early, appropriate antimicrobial therapy, a substantial proportion of antimicrobial use in U.S. acute care hospitals may be inappropriate, based on factors such as lack of indication or incorrect drug selection, dosing levels, or treatment duration. Exposure to antimicrobial drugs is a risk factor for the acquisition of resistant and difficult-to-treat pathogens, and is a leading cause of adverse drug events. It is important to understand patterns of inpatient antimicrobial drug use in order to improve use and reduce antimicrobial-resistant infections, according to background information in the article.

Shelley S. Magill, M.D., Ph.D., of the Centers for Disease Control and Prevention, Atlanta, and colleagues performed an antimicrobial-drug use prevalence survey to determine the prevalence of inpatient antimicrobial-drug use, the most common antimicrobial drug types, and the reasons for their use. The one-day prevalence surveys were conducted in 183 acute care hospitals in 10 states between May and September 2011. Patients were randomly selected from each hospital’s morning census on the survey date, and data were collected regarding antimicrobial drug use.

The study included 11,282 patients; of these, 5,635 (49.9 percent) were confirmed to have received 1 or more antimicrobial drugs at the time of the survey. Of this group of patients, 49.9 percent were receiving 1 antimicrobial drug; 32.7 percent, 2 antimicrobial drugs; 12.1 percent, 3 antimicrobial drugs; and 5.4 percent, 4 or more antimicrobial drugs.

Overall, of the patients receiving antimicrobial drugs, 75.9 percent were receiving them to treat infections; 19.0 percent for surgical prophylaxis; 6.9 percent for medical prophylaxis; and 6.9 percent for no documented rationale.

Although there were 83 different antimicrobial drugs administered to treat infections, just 4—parenteral vancomycin, piperacillin­tazobactam, ceftriaxone, and levofloxacin—made up approximately 45 percent of all antimicrobial drug treatment. These 4 drugs were not only the most common drugs for treating health care facility-onset infections and for treating patients in critical care units but were also the most common drugs for treating community-onset infections and patients outside of the critical care setting.

Additionally, approximately 54 percent of treatment antimicrobial drugs were given to treat lower respiratory tract, urinary tract, or skin and soft tissue infections only. “Taken together, focusing stewardship efforts on these 4 drugs and 3 infection syndromes could address more than half of all inpatient antimicrobial drug use,” the authors write

“Results from this prevalence survey provide patient-level information that augments data on antimicrobial drug consumption and points to specific areas where interventions to improve antimicrobial use may be needed, such as vancomycin prescribing and respiratory infection treatment, supporting the CDC’s recommendation that every acute care hospital implement an antimicrobial stewardship program.”

“To minimize patient harm and preserve effectiveness, it is imperative to critically examine and improve the ways in which antimicrobial drugs are used,” the researchers write. “Improving antimicrobial use in hospitals benefits individual patients and also contributes to reducing antimicrobial resistance nationally.”
(doi:10.1001/jama.2014.12923; 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, October 7 at this link.

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EMBARGOED FOR RELEASE: 7:10 A.M. (CT) WEDNESDAY, OCTOBER 1, 2014
Media Advisory: To contact Evelien A. N. Oostdijk, M.D., Ph.D., email e.a.n.oostdijk@umcutrecht.nl. To contact editorial co-author Marin H. Kollef, M.D., call Judy Martin at 314-286-0105 or email martinju@wustl.edu.

Study Compares Effect of Topical Antibiotics on Antibiotic Resistance, Patient Outcomes in ICUs

A comparison of prophylactic antibiotic regimens applied to an area in the mouth and throat and digestive tract were associated with low levels of antibiotic-resistant bacteria and no differences in patient survival and intensive care unit (ICU) length of stay, according to a study published in JAMA. The study is being posted early online to coincide with its presentation at the European Society of Intensive Care Medicine annual congress.

Reductions in the incidence of ICU-acquired respiratory tract infections have been achieved by some antibiotic regimens, such as selective decontamination of the digestive tract (SDD) and selective oropharyngeal (the mouth and throat) decontamination (SOD). Both SDD and SOD comprise nonabsorbable antibiotics with activity against gram-negative bacteria, yeasts, and Staphylococcus aureus; these agents are applied in the oropharynx every 6 hours throughout the ICU stay. Selective decontamination of the digestive tract also includes administration of topical antibiotics in the gastrointestinal tract, and a third-generation cephalosporin administered intravenously during the first four days in the ICU. Controversy exists regarding the relative effects of both measures on patient outcomes and antibiotic resistance, according to background information in the study.

Evelien A. N. Oostdijk, M.D., Ph.D., of the University Medical Center Utrecht, the Netherlands, and colleagues conducted a study that compared 12 months of administration of SOD or SDD in 16 Dutch ICUs between August 2009 and February 2013. Patients with an expected length of ICU stay longer than 48 hours were eligible to receive the regimens, and 5,881 and 6,116 patients were included in the clinical outcome analysis for SOD and SDD, respectively. Intensive care units were randomized to administer either regimen.

Respiratory and perianal (rectal) culture samples were performed and demonstrated that the prevalence of antibiotic-resistant gram-negative bacteria in perianal swabs and ICU-acquired bacteremia were significantly less common with SDD compared with SOD (5.6 percent vs 11.8 percent, respectively). During both interventions the prevalence of rectal carriage of aminoglycoside-resistant gram-negative bacteria increased 7 percent per month during SDD and 4 percent per month during SOD.

Day 28 mortality was 25.4 percent and 24.1 percent during SOD and SDD, respectively. Median length of stay in the ICU and hospital was determined for patients alive at day 28 and was similar for SOD and SDD. Intensive care unit-acquired bacteremia occurred in 5.9 percent and 4.6 percent of patients during SOD and SDD, respectively.

The authors note that because of the low incidence and minor absolute risk difference between the two study groups, the number needed to treat with SDD to prevent l episode of ICU-acquired bacteremia (as compared with SOD) was 77 and was 355 for ICU-acquired bacteremia caused by an aminoglycoside-resistant gram-negative bacterium. “It is therefore not surprising that the observed reduction in ICU-acquired bacteremia during SDD was not associated with a detectable effect on patient outcome.”
(doi:10.1001/jama.2014.7247; 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: Rational Use of Antibiotics in the ICU

Marin H. Kollef, M.D., of the Washington University School of Medicine, St. Louis, and Scott T. Micek, Pharm.D., of the St. Louis College of Pharmacy, comment on this study in an accompanying editorial.

“The investigation by Oostdijk et al represents another important study performed by expert investigators and aimed at determining the optimal use of topical antibiotic prophylaxis for ICU patients with a specific focus on intestinal and oropharyngeal decontamination. Despite a large amount of research in this area, clinicians are still unclear on the optimal use of SDD and SOD. For the time being in the United States, SOD seems to be a more reasonable approach for the prevention of pathogenic bacterial overgrowth in critically ill patients. The use of SDD in the United States should probably be avoided until multicenter studies demonstrate the overall efficacy of SDD in hospitals with more widespread background antibiotic resistance.”
(doi:10.1001/jama.2014.8427; 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: 2:40 A.M. (CT) TUESDAY, SEPTEMBER 30, 2014
Media Advisory: To contact Karin Amrein, M.D., M.Sc., email karin.amrein@medunigraz.at.

High-Dose Vitamin D for ICU Patients Who Are Vitamin D Deficient Does Not Improve Outcomes

Administration of high-dose vitamin D3 compared with placebo did not reduce hospital length of stay, intensive care unit (ICU) length of stay, hospital mortality, or the risk of death at 6 months among patients with vitamin D deficiency who were critically ill, according to a study published in JAMA. The study is being posted early online to coincide with its presentation at the European Society of Intensive Care Medicine annual congress.

A high prevalence of low vitamin D levels has been confirmed in patients who are critically ill. Many studies suggest that a low vitamin D status is a significant factor associated with disease severity, mortality, or a shorter survival time in the ICU. However, it is unknown whether a low vitamin D status is an independent contributor to the risk of illness or death for these patients, according to background information in the article.

Karin Amrein, M.D., M.Sc., of the Medical University of Graz, Austria, and colleagues randomly assigned 492 adult ICU patients with vitamin D deficiency to receive either high-dose vitamin D3 (n = 249) or a placebo (n = 243).

For the primary study outcome, length of hospital stay, the vitamin D3 group was not significantly different from the placebo group: 20.1 days vs 19.3 days. There was also no significant difference for length of ICU stay: 9.6 days for the vitamin D3 group vs 10.7 days for the placebo group.

Among the patients in the vitamin D3 group, 28.3 percent died in the hospital compared with 35.3 percent in the placebo group. After 6 months, 35.0 percent of the patients had died in the vitamin D3 group and 42.9 percent in the placebo group.

Lower hospital mortality was observed in a subgroup of patients with severe vitamin D deficiency, but this finding should be considered hypothesis generating and requires further study, the authors write.

“Among patients with vitamin D deficiency who are critically ill, administration of high-dose vitamin D3 compared with placebo did not improve hospital length of stay, hospital mortality, or 6-month mortality.”
(doi:10.1001/jama.2014.13204; 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: 9:00 A.M. (CT) MONDAY, SEPTEMBER 29, 2014
Media Advisory: To contact Giovanni Landoni, M.D., email Landoni.Giovanni@hsr.it.

Administration of Drug for Kidney Injury After Cardiac Surgery Does Not Reduce Need for Dialysis

Among patients with acute kidney injury after cardiac surgery, infusion with the antihypertensive agent fenoldopam, compared with placebo, did not reduce the need for renal replacement therapy (dialysis) or risk of death at 30 days, but was associated with an increased rate of abnormally low blood pressure, according to a study published in JAMA. The study is being posted early online to coincide with its presentation at the European Society of Intensive Care Medicine annual congress.

More than 1 million patients undergo cardiac surgery every year in the United States and Europe. One of its most common complications is acute kidney injury. Because of its hemodynamic effects, fenoldopam has been widely promoted for the prevention and therapy of acute kidney injury, with apparent favorable results in cardiac surgery. However, the absence of a definitive trial leaves clinicians uncertain as to whether fenoldopam should be prescribed after cardiac surgery to prevent deterioration in kidney function, according to background information in the article.

Tiziana Bove, M.D., of the IRCCS San Raffaele Scientific Institute, Milan, Italy, and colleagues randomly assigned 667 patients admitted to intensive care units after cardiac surgery with early acute kidney injury to receive fenoldopam infusion (338 patients) or placebo (329 patients). The study was conducted from March 2008 to April 2013 in 19 cardiovascular intensive care units in Italy.

The study was stopped for futility as recommended by the safety committee after a planned interim analysis. Acute kidney injury progressed to treatment with dialysis in 69 of 338 patients (20 percent) in the fenoldopam group and 60 of 329 patients (18 percent) in the placebo group. Thirty-day mortality was 78 of 338 (23 percent) in the fenoldopam group and 74 of 329 (22 percent) in the placebo group. The number of patients experiencing hypotension (abnormally low blood pressure) during study drug infusion was 85 (26 percent) in the fenoldopam group vs 49 (15 percent) in the placebo group.

“Given the cost of fenoldopam, the lack of effectiveness, and the increased incidence of hypotension, the use of this agent for renal protection in these patients is not justified,” the authors conclude.
(doi:10.1001/jama.2014.13573; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: This work was supported by a grant from the Italian Ministry of Health. 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, SEPTEMBER 30, 2014
Media Advisory: To contact Megan A. Adams, M.D., J.D., call Shantell Kirkendoll at 734-764-2220 or email smkirk@umich.edu.

Study Examines Medical Professional Liability Claims Related to Esophageal Cancer Screening

An analysis of liability claims related to esophageal cancer screening finds that the risks of claims arising from acts of commission (complications from screening procedure) as well as acts of omission (failure to screen) are similarly low, according to a study in the October 1 issue of JAMA.

Endoscopic screening for esophageal cancer has been recommended for patients with chronic symptoms of gastroesophageal reflux disease, but only if they have additional risk factors. Surveys of gastroenterologists indicate that concern about litigation for missing a cancer may drive endoscopy use in patients at low risk for esophageal cancer. However, the perception of medical professional liability may not accurately reflect the true incidence of liability claims, according to background information in the article. Although the rate of serious adverse events arising from esophagogastroduodenoscopies (esophageal cancer screening procedure) is small, 6.9 million were performed in the United States in 2009.

Megan A. Adams, M.D., J.D., of the University of Michigan, Ann Arbor, and colleagues, using data from a medical professional liability claims database, identified all claims relating to a diagnostic esophagogastroduodenoscopy (1985-2012), and then restricted to claims alleging inadequate indication for esophagogastroduodenoscopy. They also identified claims related to esophageal cancer restricted to those alleging delay in diagnosis, and excluded claims in which the presenting condition was an alarm symptom or sign (defined as weight loss, dysphagia [difficulty swallowing], or iron deficiency anemia), and those in which the presenting condition was a cancer of the esophagus or cardia (top portion of the stomach) or an abnormal radiographic finding.

A total of 761 claims filed from 1985-2012 against physicians were related to esophagogastroduodenoscopy. The leading types of misadventure (error) alleged were improper performance (n = 267), errors in diagnosis (n = 186), and no medical misadventure (i.e., claims that did not involve a purely medical error, such as abandonment, breach of confidentiality, or consent issues) (n = 147). Seventeen claims (2.2 percent) alleged inadequate indication for esophagogastroduodenoscopy. A total of 268 claims in 1985-2012 involved esophageal malignancies, including 122 in 2002-2012. Of these, 62 (50.8 percent) alleged delay in diagnosis. Nineteen claims reported nonalarm presenting symptoms.

“We found a low incidence of reported medical professional liability claims against physicians for failure to screen for esophageal cancer in patients without alarm features (19 claims in 11 years, 4 paid). In contrast, in 28 years, there were 17 claims for complications from esophagogastroduodenoscopies with questionable indication (8 paid). This suggests that the risks of medical professional liability claims arising from acts of commission as well as acts of omission in endoscopic screening are similarly low,” the authors write.

“There may be legitimate reasons to screen for esophageal cancer in some patients, but our findings suggest that the risk of a medical professional liability claim for failing to screen is not one of them. Physicians need to balance the risk of complications from diagnostic procedures, even if those complications are rare.”
(doi:10.1001/jama.2014.7960; 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, SEPTEMBER 30, 2014
Media Advisory: To contact corresponding author Joanna Chikwe, M.D., call Lauren Woods at 646-634-0869 or email Lauren.woods@mountsinai.org.

Comparison of Long-Term Outcomes for Types of Aortic Valve Replacements Finds No Significant Difference in Rates of Death, Stroke

Among patients ages 50 to 69 years who underwent aortic valve replacement with bioprosthetic (made primarily with tissue) compared with mechanical prosthetic valves, there was no significant difference in 15-year survival or stroke, although patients in the bioprosthetic valve group had a greater likelihood of reoperation but a lower likelihood of major bleeding, according to a study in the October 1 issue of JAMA.

Approximately 50,000 patients undergo aortic valve replacement annually in the United States. In older patients, bioprosthetic valves pose a low lifetime risk of reoperation for structural degeneration and avoid many of the complications associated with mechanical prostheses; bioprosthetic valves are therefore recommended in patients older than 70 years. The optimal prosthesis type for younger patients is less clear, according to background information in the article.

Yuting P. Chiang, B.A., of The Mount Sinai Hospital, New York, and colleagues used a statewide administrative database to quantify differences in long-term survival, stroke, reoperation, and major bleeding episodes after aortic valve replacement according to prosthesis type. The analysis included 4,253 patients ages 50 to 69 years who underwent primary isolated aortic valve replacement using bioprosthetic vs mechanical valves in New York State from 1997 through 2004. Median follow-up time was 10.8 years; the last follow-up date for mortality was November 30, 2013.

The researchers found no significant difference in long-term survival or stroke rates. Fifteen-year survival was 60.6 percent in the bioprosthesis group compared with 62.1 percent in the mechanical prosthesis group. The cumulative incidence of stroke at 15 years was 7.7 percent for patients who received a bioprosthetic valve, compared with 8.6 percent for those who received a mechanical prosthetic valve.

Bioprostheses were associated with a significantly higher rate of aortic valve reoperation than mechanical prostheses: the cumulative incidence of aortic valve reoperation at 15 years was 12.1 percent in the bioprosthesis group and 6.9 percent in the mechanical prosthesis group.

Mechanical prostheses were associated with a significantly higher rate of major bleeding at 15 years compared with bioprostheses: 13.0 percent for the mechanical prosthesis group vs. 6.6 percent for the bioprosthesis group.

“The absence of a significant survival benefit associated with one prosthesis type over another focuses decision making on lifestyle considerations, including the burden of anticoagulation medication and monitoring, and the relative risks of major morbidity—primarily stroke, reoperation, and major bleeding events,” the authors write.

They add that these findings suggest that bioprosthetic valves may be a reasonable choice in patients 50 to 69 years of age.
(doi:10.1001/jama.2014.12679; 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, SEPTEMBER 30, 2014
Media Advisory: To contact Irfan A. Dhalla, M.D., M.Sc., call Leslie Shepherd at 416-864-6094 or email shepherdl@smh.ca. To contact editorial author Peter A. Boling, M.D., call Cassie Williams Jones at 804-828-7028 or email cwjones@vcu.edu.

Following Hospital Discharge, Use of a ‘Virtual Ward’ Model of Care Does Not Reduce Readmissions, Risk of Death

In a trial involving patients at high risk of hospital readmission or death, use of a virtual ward model of care (using some elements of hospital care in the community) after hospital discharge did not significantly reduce the rate of readmission or death up to a year following discharge, according to a study in the October 1 issue of JAMA.

Hospital readmissions are common and costly, and no single intervention or bundle of interventions has reliably reduced readmissions. The virtual ward model of care is a way of providing care to patients with complex needs who are not hospitalized. This model takes many elements of hospital care that are appreciated by patients or clinicians (e.g., an interprofessional team, a daily team meeting, a single point of contact for patients, etc.) and incorporates them into community-based care, with a goal of improving health outcomes and patient experience while also providing better value for money. Despite the virtual ward’s conceptual appeal and its increasingly common implementation, it has not been rigorously evaluated, according to background information in the article.

Irfan A. Dhalla, M.D., M.Sc., of the University of Toronto and St. Michael’s Hospital, Toronto, and colleagues randomly assigned 1,923 high-risk adult hospital discharge patients in Toronto to either the virtual ward (n = 963) or usual care (n = 960). Patients assigned to the virtual ward received care coordination plus direct care provision (via a combination of telephone, home visits, or clinic visits) from an interprofessional team for several weeks after hospital discharge. The interprofessional team met daily at a central site to design and implement individualized management plans. Patients assigned to usual care typically received a structured discharge summary, prescription for new medications if indicated, counseling from the resident physician, arrangements for home care as needed, and recommendations, appointments, or both for follow-up care with physicians as indicated.

The researchers found no significant between-group difference for the primary measured outcome for the study: within the 30-day period following discharge, 24.6 percent of patients assigned to usual care and 21.2 percent of patients assigned to the virtual ward had been readmitted to hospital or died. There were 47 deaths in the usual care group and 40 deaths in the virtual ward group (4.9 percent vs 4.2 percent).

By 90 days after discharge, 38.0 percent of patients assigned to usual care and 37.1 percent of patients assigned to the virtual ward had been readmitted to a hospital or died. There were no significant between-group differences in any of the outcomes (including nursing home admission and emergency department visits) at 6 months or 1 year.

The authors write that although their data are not inconsistent with a small absolute benefit at 30 days, outcome data at 90 days suggest that any benefits were not sustained. “As a consequence, given the per-patient costs of our intervention, it is highly unlikely that a virtual ward model of care structured similarly to ours would represent an efficient use of health care resources.”
(doi:10.1001/jama.2014.11492; 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: Managing Posthospital Care Transitions for Older Adults

“The rigorously conducted trial by Dhalla et al adds important data that contribute to advancing the understanding of determining optimal approaches to improve postdischarge transitions for high-risk patients,” writes Peter A. Boling, M.D., of Virginia Commonwealth University, Richmond, in an accompanying editorial.

“An important aspect of their report, however, was that the authors identified real-world obstacles including incompatible electronic health records, clinician discontinuity, difficulties integrating with primary care, and lack of contact with patients in hospital. These observations may be useful in the development of future trials designed to improve care transitions and reduce readmissions. Moreover, it is still likely that in this era of exponential development of technologically supported solutions to complex problems, elements of the ‘virtual ward’ may have a place, perhaps linked with more robust in-home care delivery.”
(doi:10.1001/jama.2014.12360; 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, SEPTEMBER 30, 2014
Media Advisory: To contact co-author Kim L. Bennell, Ph.D., email k.bennell@unimelb.edu.au.

Study Finds Acupuncture Does Not Improve Chronic Knee Pain

Among patients older than 50 years with moderate to severe chronic knee pain, neither laser nor needle acupuncture provided greater benefit on pain or function compared to sham laser acupuncture, according to a study in the October 1 issue of JAMA.

Chronic knee pain affects many people older than 50 years and is the most common pain concern among older people consulting family physicians. Nonpharmacological approaches are central to managing chronic knee pain, and patients with joint pain frequently use complementary and alternative medicine. Acupuncture is the most popular of alternative medical systems, with use increasing over time. Although traditionally administered with needles, laser acupuncture (low-intensity laser therapy to acupuncture points) is a noninvasive alternative with evidence of benefit in some pain conditions. There is debate about the benefit of acupuncture for knee pain, according to background information in the article.

Rana S. Hinman, Ph.D., of the University of Melbourne, Australia, and colleagues randomly assigned 282 patients (50 years or older) with chronic knee pain to no acupuncture (control group, n = 71) or needle (n = 70), laser (n = 71), or sham laser (n = 70) acupuncture. Treatments were delivered for 12 weeks. Participants and acupuncturists were blinded to laser and sham (inactive) laser acupuncture.

There were no significant differences in primary outcomes (measures of knee pain and physical function) between active and sham acupuncture at 12 weeks or 1 year. Both needle and laser acupuncture resulted in modest improvements in pain compared with control at 12 weeks that were not maintained at 1 year. Needle acupuncture improved physical function at 12 weeks compared with control but was not different from sham acupuncture and was not maintained at 1 year.

Most secondary outcomes (other pain and function measures, quality of life, global change, and 1-year follow-up) showed no difference. Needle acupuncture improved pain on walking at 12 weeks but was not maintained at 1 year.

The authors note that incidental factors such as treatment setting, patient expectations and attitudes (such as optimism), acupuncturist’s confidence in treatment, and patient and acupuncturist interaction may influence outcomes. “In our study, benefits of acupuncture were exclusively attributed to incidental effects, given the lack of significant differences between active acupuncture and sham treatment. Continuous subjective measures, such as pain and self-reported physical function, as used in our study, are particularly subject to placebo responses.”

“In patients older than 50 years with moderate or severe chronic knee pain, neither laser nor needle acupuncture conferred benefit over sham for pain or function. Our findings do not support acupuncture for these patients.”
(doi:10.1001/jama.2014.12660; 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: 6 A.M. (CT) MONDAY, SEPTEMBER 22, 2014
Media Advisory: To contact Jonathan A. Patz, M.D., M.P.H., call Kelly Tyrrell at 608-262-9772 or email ktyrrell2@wisc.edu. To contact editorial co-author Howard Bauchner, M.D., email the JAMA Network Media Relations department at mediarelations@jamanetwork.org.

To place an electronic embedded link to this study and editorial in your story This link to the study will be live at the embargo time: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2014.13186. This will be the link to the editorial: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2014.13094.

Study Examines Potential Adverse Health Effects of Climate Change

An examination of the evidence over the past 20 years indicates that climate change can be associated with adverse effects on various health conditions, including heat-related and respiratory disorders, and a projected increase in days with extreme heat could exacerbate various health issues, according to an article published in JAMA. The study is being released early to coincide with the UN Climate Summit 2014. The authors note that substantial health and economic benefits could be associated with reductions in fossil fuel combustion.

Although uncertainty remains regarding the extent of climate change, this uncertainty is diminishing. Consensus is substantial that human behavior contributes to climate change, caused by activities such as fossil fuel combustion and tropical deforestation. Health is inextricably linked to climate change. It is important for clinicians to understand this relationship in order to discuss associated health risks with their patients and to inform public policy, according to background information in the article.

Jonathan A. Patz, M.D., M.P.H., of the Global Health Institute, University of Wisconsin, Madison, and colleagues conducted a study to provide new U.S.-based temperature projections and to review recent studies on health risks related to climate change and the benefits of efforts to mitigate greenhouse gas emissions. The authors searched the medical literature for articles related to climate change and health, and identified 56 articles that met criteria for inclusion in the analysis. In addition, data were averaged over 13 climate models, and the researchers compared maximum daily 8-hour average ozone with air temperature data taken from the National Oceanic and Atmospheric Administration National Climate Data Center.

Analysis of the data indicated that by 2050, many U.S. cities may experience more frequent extreme heat days. For example, New York and Milwaukee may have 3 times their current average number of days hotter than 90°F, which may exacerbate heat-related disorders, including heat stress and economic consequences of reduced work capacity. In addition, adverse health aspects related to climate change may include:

• Respiratory disorders, including those made worse by fine particular pollutants, such as asthma, and allergic diseases;
• Infectious diseases, including vector-borne diseases (such as transmitted by mosquitos) and water-borne diseases, such as childhood gastrointestinal diseases;
• Food insecurity, including reduced crop yields and an increase in plant diseases;
• Mental health disorders, such as posttraumatic stress disorder and depression, that are associated with natural disasters.

The authors write that substantial health and economic benefits could be associated with reductions in fossil fuel combustion. “Accounting for co-benefits may document that reducing greenhouse emission yields net economic benefits, that labor productivity increases, and that health system costs are reduced. Co-benefits can provide policymakers with additional incentives, beyond those of curtailing climate change, to reduce the emissions of both carbon dioxide and short-lived climate pollutants.”

They add that health professionals have an important role in understanding and communicating potential health concerns related to climate change, as well as the benefits from burning less fossil fuels.

“Because climate change may have important implications for the health of the world’s population, high-quality research must be conducted, and responsible, informed debate needs to continue. However, given that evidence over the past 20 years suggests that climate change can be associated with adverse health outcomes, strategies to reduce climate change and avert the related adverse effects are necessary.”
(doi:10.1001/jama.2014.13186; 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: Climate Change – A Continuing Threat to the Health of the World’s Population

“Should physicians be concerned about climate change and its associated effects on health or is it outside the remit of medicine much like poverty and war,” write Howard Bauchner, M.D., Editor-in-Chief, JAMA, and Phil B. Fontanarosa, M.D., M.B.A., Executive Editor, JAMA, Chicago, in an accompanying editorial.

“As physicians have come to recognize that many aspects of daily living affect health, such as working conditions, pollution, education, mental health, and psychosocial aspects of disease, medicine has broadened its research, clinical and policy agendas. Many physicians are now involved in addressing these problems. But is climate change similar to poverty and war, best left to other scientists and politicians, or is it of such fundamental importance — like clean water, clean air and adequate sanitation— that physicians should strive to further clarify the effects of climate change on health, educate themselves and the public, and mount a campaign to ensure that climate change does not lead to an epidemic of eroding health?”

“The great gains in well-being in the 20th century occurred because of the concerted effort to improve the health of entire populations. Today, in the early part of the 21st century, it is critical to recognize that climate change poses the same threat to health as the lack of sanitation, clean water, and pollution did in the early 20th century. Understanding and characterizing this threat and educating the medical community, public, and policy makers are crucial if the health of the world’s population is to continue to improve during the latter half of the 21st century.”
(doi:10.1001/jama.2014.13094; 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, SEPTEMBER 23, 2014
Media Advisory: To contact corresponding author Eric L. Grogan, M.D., M.P.H., call Craig Boerner at 615-322-4747 or email craig.boerner@vanderbilt.edu.

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Lung Cancer Diagnosis Test May Be Less Effective in Areas Where Infectious Lung Disease is More Common

An analysis of 70 studies finds that use of the diagnostic imaging procedure of fludeoxyglucose F18 (FDG)-positron emission tomography (PET) combined with computed tomography (CT) may not reliably distinguish benign disease from lung cancer in populations with endemic (high prevalence) infectious lung disease compared with nonendemic regions, according to a study in the September 24 issue of JAMA.

Depending on the risk for cancer, diagnostic guidelines suggest or recommend FDG combined with PET as a noninvasive test to assess the risk of cancer or benign disease, according to background information in the article.

Stephen A. Deppen, Ph.D., of the Tennessee Valley Healthcare System and Vanderbilt University Medical Center, Nashville, and colleagues conducted a meta-analysis to examine the accuracy of FDG-PET to diagnose lung lesions in regions with locally endemic infectious lung diseases. The researchers identified 70 studies that met criteria for inclusion in the analysis. Studies reported on a total of 8,511 nodules; 5,105 (60 percent) were malignant.

Pooled sensitivity of FDG-PET for diagnosing lung cancer was 89 percent and pooled specificity was 75 percent. There was a 16 percentage points difference in specificity in regions with endemic infectious lung disease (61 percent) compared with nonendemic regions (77 percent). Lower specificity was observed when the analysis was limited to rigorously conducted and well-controlled studies.

“FDG-PET for the diagnosis of lung cancer in patients who reside in a region with significant endemic infectious lung disease should be recognized as having lower specificity than previously reported. Knowledge of this reduction in specificity should limit the use of FDG-PET to diagnose lung cancer unless substantial institutional expertise in FDG-PET interpretation has been proven. Should low-dose CT screening for lung cancer become the diagnostic standard, knowledge of FDG-PET/CT performance is even more critical because the vast majority of indeterminate lung nodules detected through screening are benign,” the authors write.
(doi:10.1001/jama.2014.11488; 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, SEPTEMBER 23, 2014
Media Advisory: To contact Miriam Kuppermann, Ph.D., M.P.H., call Elizabeth Fernandez at 415-514-1592 or email Elizabeth.Fernandez@UCSF.edu. To contact editorial co-author Siobhan M. Dolan, M.D., M.P.H., call Deirdre Branley at 718-430-2923 or email dbranley@einstein.yu.edu.

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Use of Decision-Support Guide for Prenatal Genetic Testing and Removing Costs For Testing Results in Less Prenatal Test Use

An intervention for pregnant women that included a computerized, interactive decision-support guide regarding prenatal genetic testing, and no cost for testing, resulted in less prenatal test use and more informed choices, according to a study in the September 24 issue of JAMA.

Since the introduction of amniocentesis, prenatal genetic testing guidelines have focused on identifying women at increased risk of giving birth to an infant with Down syndrome or other chromosomal abnormalities, for whom invasive diagnostic testing should be recommended. Prenatal genetic testing guidelines recommend providing patients with detailed information to allow informed, preference-based screening and diagnostic testing decisions. The effect of implementing these guidelines is not well understood, according to background information in the article.

Miriam Kuppermann, Ph.D., M.P.H., of the University of California, San Francisco, and colleagues randomly assigned 710 pregnant women to receive either a computerized, interactive decision-support guide and access to prenatal testing with no out-of-pocket expense (n = 357) or usual care as per current guidelines (n = 353). The trial was conducted from 2010-2013 at prenatal clinics and practices from throughout the San Francisco Bay area.

The researchers found that significantly fewer women who were assigned to the intervention group underwent invasive diagnostic testing compared with women randomized to the control group (5.9 percent vs 12.3 percent). The overall prenatal testing strategy used by the 2 groups also differed: women randomized to the intervention group were more likely to have no testing (25.6 percent vs 20.4 percent) or screening alone (68.5 percent vs 67.3 percent).

Also, women assigned to the intervention group had significantly higher genetic testing knowledge scores, were more likely to correctly report both the miscarriage risk of amniocentesis and their likelihood of carrying a fetus with the congenital disorder trisomy 21.

“This study’s finding that women who were randomized to the intervention group were less likely to undergo testing than those who received usual care adds support to the contention that women may not be receiving adequate counseling about their options. This underscores the need for clinicians to be clear that prenatal testing is not appropriate for everyone, and to present forgoing testing as a reasonable choice,” the authors write.

“If validated in additional populations, this approach may result in more informed and preference-based prenatal testing decision making and fewer women undergoing testing.”
(doi:10.1001/jama.2014.11479; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: This study was funded by grants from the National Institutes of Health and the March of Dimes Foundation. 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, September 23 at this link.

Editorial: Personalized Genomic Medicine and Prenatal Genetic Testing

In an accompanying editorial, Siobhan M. Dolan, M.D., M.P.H., of the Albert Einstein College of Medicine/Montefiore Medical Center, Bronx, New York, writes that the finding from this study that women with better understanding of the information about various prenatal testing options were less likely to undertake invasive prenatal testing is important, and it contradicts the notion that more information is always desired.

“It is possible that the nature of prenatal testing is different than other health care decisions, but the public may be increasingly aware that the numerous medical advances of the last decade have also created greater complexity in decision making. This finding also suggests that prenatal genetic testing decisions require a complex calculus that considers the timing of the testing, the certainty of the results, and the risks related to undergoing invasive genetic testing during pregnancy.”
(doi:10.1001/jama.2014.12205; 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, SEPTEMBER 23, 2014
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Rate of Diabetes in U.S. May Be Leveling Off
Although Increase in Prevalence Continues for Certain Subgroups

Following a doubling of the incidence and prevalence of diabetes in the U.S. from 1990-2008, new data suggest a plateauing of the rate between 2008 and 2012 for adults, however the incidence continued to increase in Hispanic and non-Hispanic black adults, according to a study in the September 24 issue of JAMA.

Although there has been an increase in the prevalence and incidence of diabetes in the United States in recent decades, no studies have systematically examined long-term, national trends of this disease, according to background information in the article.

Linda S. Geiss, M.A., of the Centers for Disease Control and Prevention, Atlanta, and colleagues analyzed 1980-2012 data for 664,969 adults ages 20 to 79 years from the National Health Interview Survey and determined the annual percentage change in rates of the prevalence and incidence of diagnosed diabetes (type 1 and type 2 combined).

During 1980-2012, the trends in age-adjusted prevalence of diagnosed diabetes in the overall population were similar to those for age-adjusted incidence. The prevalence per 100 persons was 3.5 in 1990, 7.9 in 2008, and 8.3 in 2012. The incidence per 1,000 persons was 3.2 in 1990, 8.8 in 2008, and 7.1 in 2012. Both prevalence and incidence increased sharply during 1990-2008 (for prevalence, 4.5 percent, for incidence, 4.7 percent) before leveling off with no significant change during 2008-2012 (for prevalence, 0.6 percent, for incidence, -5-4 percent).

The researchers speculate that reasons for the potential slowing of the increase in diabetes may include a slowing in the rate of obesity, a major risk factor for type 2 diabetes.

Incidence and prevalence of diabetes ceased growing or leveled off in many population subgroups. However, incidence continued to increase in Hispanic and non-Hispanic black adults and prevalence continued to grow among those with a high school education or less. “This threatens to exacerbate racial/ethnic and socioeconomic disparities in diabetes prevalence and incidence. Furthermore, in light of the well-known excess risk of amputation, blindness, end-stage renal disease, disability, mortality, and health care costs associated with diabetes, the doubling of diabetes incidence and prevalence ensures that diabetes will remain a major public health problem that demands effective prevention and management programs,” the authors write.
(doi:10.1001/jama.2014.11494; 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, SEPTEMBER 16, 2014
Media Advisory: To contact corresponding author Marc Carrier, M.D., M.Sc., email Paddy Moore at padmoore@ohri.ca or Kina Leclair at kleclair@uOttawa.ca.

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Study Compares Effectiveness of Treatments for Blood Clots

In an analysis of the results of nearly 50 randomized trials that examined treatments of venous thromboembolisms (blood clot in a vein), there were no significant differences in clinical and safety outcomes associated with most treatment strategies when compared with the low-molecular-weight heparin-vitamin K antagonist combination, according to a study in the September 17 issue of JAMA.

Venous thromboembolism, manifested as deep vein thrombosis or pulmonary embolism (blood clot in a lung), is a common medical condition and is the third leading cause of cardiovascular death. Clinicians have many potential treatment options regarding management of this condition, although little guidance exists about which treatment is most effective yet safe, according to background information in the study.

Lana A. Castellucci, M.D., of the Ottawa Hospital Research Institute, University of Ottawa, Ontario, Canada, and colleagues conducted a network meta-analysis to summarize and compare the efficacy and safety outcomes for the treatment of venous thromboembolism associated with 8 anticoagulation options (unfractionated heparin [UFH], low-molecular-weight heparin [LMWH], or fondaparinux in combination with vitamin K antagonists); LMWH with dabigatran or edoxaban; rivaroxaban; apixaban; and LMWH alone). The researchers conducted a search of the medical literature and identified 45 randomized trials (44,989 patients) for inclusion in the analyses.

The UFH-vitamin K antagonist combination was associated with a higher percentage of patients experiencing recurrent venous thromboembolism during 3 months of treatment (1.84 percent) than patients taking the LMWH-vitamin K antagonist combination (1.30 percent). Rivaroxaban and apixaban were associated with the lowest bleeding risk compared with the LMWH-vitamin K antagonist combination, with a lower proportion of patients experiencing a major bleeding event during 3 months of anticoagulation: 0.49 percent for rivaroxaban, 0.28 percent for apixaban, and 0.89 percent for the LMWH-vitamin K antagonist combination.

All other treatment regimens were associated with bleeding risks that did not differ significantly from the LMWH-vitamin K antagonist combination.

“To our knowledge, this network meta-analysis is the largest review, including nearly 45,000 patients, assessing the clinical outcomes and safety associated with different anticoagulation strategies for the treatment of acute venous thromboembolism. We provide estimates on symptomatic recurrent venous thromboembolism and major bleeding outcomes (both patient-important outcomes), which are clinically relevant and are what clinical practice guideline recommendations are based on,” the authors write.

“All management options, with the exception of the UFH-vitamin K antagonist combination, were associated with similar clinical outcomes compared with a management strategy using the LMWH­ vitamin K antagonist combination. Treatment using the UFH-vitamin K antagonist combination was associated with a higher risk of recurrent venous thromboembolism during the follow-up period.”
(doi:10.1001/jama.2014.10538; 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, SEPTEMBER 16, 2014
Media Advisory: To contact Lex W. Doyle, M.D., M.Sc., email lwd@unimelb.edu.au.

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Magnesium Sulfate During Pregnancy Does Not Show Long-Term Benefit on Various Outcomes for Very Preterm Infants

Magnesium sulfate given intravenously to pregnant women at risk of very preterm birth was not associated with benefit on neurological, behavioral, growth, or functional outcomes in their children at school age, according to a study in the September 17 issue of JAMA.

Rates of adverse long-term neurodevelopmental outcomes for infants born at less than 28 weeks’ gestation remain high relative to full-term infants. Among the multiple uses for magnesium sulfate in obstetrics is as a neuroprotectant for preterm fetuses. Antenatal (before birth) magnesium sulfate given to pregnant women at imminent risk of very preterm delivery reduces the risk of cerebral palsy in early childhood, although its effects into school age have not been reported from randomized trials, according to background information in the article.

Lex W. Doyle, M.D., M.Sc., of the University of Melbourne, Australia, and colleagues randomly assigned magnesium sulfate or placebo to pregnant women (n = 535 magnesium; n = 527 placebo) for whom imminent birth was planned or expected before 30 weeks’ gestation. The trial was conducted in 16 centers in Australia and New Zealand.

There were 1,255 fetuses known to be alive at randomization. Of 867 survivors available for follow-up, outcomes at school age (6 to 11 years) were determined for 669 (77 percent). The researchers found that receipt of antenatal magnesium sulfate was not associated with any long-term benefits or harms compared with placebo on measures of neurological, cognitive, behavioral, growth, and functional outcomes. There was a nonsignificant reduction in the risk of death in the magnesium sulfate group.

The authors note that the absence of benefit does not negate the proven value of magnesium sulfate in reducing cerebral palsy, based on the collective evidence from all of the randomized clinical trials.

They add that the lack of long-term benefit requires confirmation in additional studies.
(doi:10.1001/jama.2014.11189; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: This study was funded by a project grant from the National Health and Medical Research Council Australia and the Victorian Government’s Operational Infrastructure Support Program. 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, SEPTEMBER 16, 2014
Media Advisory: To contact Andrea S. Gershon, M.D., M.Sc., call Deborah Creatura at 416-480-4780 or email deborah.creatura@ices.on.ca. To contact editorial author Peter M. A. Calverley, M.B.Ch.B., D.Sc., email pmacal@liverpool.ac.uk.

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Combination Therapy for COPD Associated With Better Outcomes

Among older adults with chronic obstructive pulmonary disease (COPD), particularly those with asthma, newly prescribed long-acting beta-agonists (LABAs) and inhaled corticosteroid combination therapy, compared with newly prescribed LABAs alone, was associated with a lower risk of death or COPD hospitalization, according to a study in the September 17 issue of JAMA.

Chronic obstructive pulmonary disease is the third leading cause of death worldwide. Medications are a mainstay of COPD management, and knowing which are most effective in real-world practice is essential. Combination therapy consisting of LABAs and inhaled corticosteroids (ICSs) has been shown to decrease exacerbations and possibly decrease the risk of death compared with placebo. However, there are still gaps in what is known about its effectiveness compared with LABAs alone, according to background information in the article.

Andrea S. Gershon, M.D., M.Sc., of the Sunnybrook Health Sciences Centre and Institute for Clinical Evaluative Sciences, Toronto, and colleagues examined the outcomes of LABA-ICS combination therapy compared with LABAs alone in older COPD patients with other illnesses, including asthma. The study, which included data from 2003 to 2011 in Ontario, included individuals ages 66 years or older who met a validated case definition of COPD; there were 8,712 new users of LABA-inhaled corticosteroid combination therapy and 3,160 new users of LABAs alone who were followed up for a median of 2.7 years and 2.5 years, respectively.

The primary outcome (the composite of death and COPD hospitalizations) was observed among 2,129 new users of LABAs (1,179 deaths [37.3 percent]); 950 COPD hospitalizations [30.1 percent]) and 5,594 new users of LABAs and ICSs (3,174 deaths [36.4 percent]; 2,420 COPD hospitalizations [27.8 percent]). There was a modest but significantly lower risk of the composite outcome among new users of LABAs and ICSs compared with new users of LABAs alone.

The greatest difference was among COPD patients with a codiagnosis of asthma (difference in composite at 5 years, -6.5 percent) and those who were not receiving inhaled long-acting anticholinergic medication (a different class of COPD medication that works by inhibiting the transmission of certain nerve impulses to help reverse airway resistance; difference in composite at 5 years, -8.4 percent).

“Our finding of an association between LABAs and ICSs and outcomes helps clarify the management of patients with COPD and asthma, as many studies of COPD medications have excluded people with asthma and vice versa,” the authors write. “In addition, practice guidelines for COPD recommend that LABAs be considered first-line treatment while asthma guidelines warn against use of LABAs without ICSs. Our findings also offer insight into the optimal treatment of COPD patients without asthma—those who would not be considered especially corticosteroid responsive.”

The researchers add that these findings should be confirmed in randomized clinical trials.
(doi:10.1001/jama.2014.11432; 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: Treating COPD in the Real World

Peter M. A. Calverley, M.B.Ch.B., D.Sc., of the University of Liverpool, England, comments on the findings of this study in an accompanying editorial.

“Perhaps the most noteworthy feature of the new data reported by Gershon et al is the difference in the characteristics of the patients who use these treatments from those in whom therapy was validated in randomized clinical trials (RCTs). The outcomes of treatment in these ‘real-world’ patients were somewhat better than might have been expected from RCTs, but the patients were also much more diverse and often sicker. The study by Gershon et al shows that findings from appropriately conducted database analyses complement data from RCTs and should be considered when determining treatment algorithms.”
(doi:10.1001/jama.2014.11322; 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, SEPTEMBER 16, 2014
Media Advisory: To contact Earl S. Ford, M.D., M.P.H., call 404-639-3286 or email Brittany Behm at jiz9@cdc.gov.

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Waistlines of U.S. Adults Continue to Increase

The prevalence of abdominal obesity and average waist circumference increased among U.S. adults from 1999 to 2012, according to a study in the September 17 issue of JAMA.

Waist circumference is a simple measure of total and intra-abdominal body fat. Although the prevalence of abdominal obesity has increased in the United States through 2008, its trend in recent years has not been known, according to background information in the article.

Earl S. Ford, M.D., M.P.H., of the U.S. Centers for Disease Control and Prevention, Atlanta, and colleagues used data from seven 2-year cycles of the National Health and Nutrition Examination Survey (NHANES) starting with 1999-2000 and concluding with 2011-2012 to determine trends in average waist circumference and prevalence of abdominal obesity among adults in the United States. Abdominal obesity was defined as a waist circumference greater than 40.2 inches (102 cm) in men and greater than 34.6 inches (88 cm) in women.

Data from 32,816 men and nonpregnant women ages 20 years or older were analyzed. The overall age-adjusted average waist circumference increased progressively and significantly, from 37.6 inches in 1999-2000 to 38.8 inches in 2011-2012. Significant increases occurred in men (0.8 inch), women (1.5 inch), non-Hispanic whites (1.2 inch), non­Hispanic blacks (1.6 inch), and Mexican Americans (1.8 inch).

The overall age-adjusted prevalence of abdominal obesity increased significantly from 46.4 percent in 1999-2000 to 54.2 percent in 2011-2012. Significant increases were present in men (37.1 percent to 43.5 percent), women (55.4 percent to 64.7 percent), non-Hispanic whites (45.8 percent to 53.8 percent), non-Hispanic blacks (52.4 percent to 60.9 percent), and Mexican Americans (48.1 percent to 57.4 percent).

The authors write that previous analyses of data from NHANES show that the prevalence of obesity calculated from body mass index (BMI) did not change significantly from 2003-2004 to 2011-2012. “In contrast, our analyses using data from the same surveys indicate that the prevalence of abdominal obesity is still increasing. The reasons for increases in waist circumference in excess of what would be expected from changes in BMI remain speculative, but several factors, including sleep deprivation, endocrine disruptors, and certain medications, have been proposed as potential explanations.”

“Our results support the routine measurement of waist circumference in clinical care consistent with current recommendations as a key step in initiating the prevention, control, and management of obesity among patients.”
(doi:10.1001/jama.2014.8362; 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, SEPTEMBER 9, 2014
Media Advisory: To contact corresponding author John P. A. Ioannidis, M.D., D.Sc., email Krista Conger at kristac@stanford.edu. To contact editorial co-author Eric D. Peterson, M.D., M.P.H., call Sarah Avery at 919-660-1306 or email sarah.avery@duke.edu.

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Reanalyses of Data From RCTs Can Lead to Different Conclusions

Although only a small number of reanalyses of data from randomized clinical trials (RCTs) have been published, an examination of those that have been conducted finds that about one-third led to changes in findings that implied conclusions different from those of the original article regarding the types and number of patients who should be treated, according to a study in the September 10 issue of JAMA.

Some authors have argued that a standard of RCT data sharing and reanalysis should be more widely adopted and could have major consequences for individual and public health, and that paying consumers (the public) should have access to complete information about drugs and devices. Arguments against accessibility to raw data and reanalyses include potential risk to trial patient confidentiality; inappropriate use of data sets, resulting in spurious findings; release of commercially sensitive information; and “rogue” reanalysis by nonexperts or by analysts who have conflicts of interest, according to background information in the article.

Shanil Ebrahim, Ph.D., of Stanford University, Stanford, Calif., and colleagues conducted an electronic search of MEDLINE to identify all published studies (through March 9, 2014) that completed a reanalysis of individual patient data from previously published RCTs addressing the same hypothesis as the original RCT. The primary outcomes examined were changes in direction and magnitude of treatment effect, statistical significance, and interpretation about the types or numbers of patients who should be treated.

The researchers identified 37 reanalyses of patient-level data from previously published RCTs (reported in 36 articles). Most of the reanalyses were completed by authors involved in the original trial; five were performed by entirely independent authors. Reanalyses differed most commonly in statistical or analytical approaches (n = 18) and in definitions or measurements of the outcome of interest (n = 12). Four reanalyses changed the direction and two changed the magnitude of treatment effect; four led to changes in statistical significance of findings.

Approximately a third (35 percent) of the reanalyses led to interpretations different from that of the original article, 3 (8 percent) showing that different patients should be treated; 1 (3 percent) that fewer patients should be treated; and 9 (24 percent) that more patients should be treated.

“It is difficult to assess whether these changes in trial conclusions led eventually to major changes in clinical practice and, if so, how large these changes were. Clinical practice choices depend only partly on trial evidence, and sometimes multiple additional trials exist that inform the same question. Nevertheless, when contradicting messages exist, it is unclear which of the 2 discrepant articles will have more influence: the original is usually published in more influential journals, but the subsequent reanalysis may be viewed as a more correct appraisal of the data,” the authors write.
(doi:10.1001/jama.2014.9646; 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: Open Access to Clinical Trials Data

Harlan M. Krumholz, M.D., S.M., of the Yale University School of Medicine, New Haven, Conn., and Eric D. Peterson, M.D., M.P.H., of the Duke University Medical Center, Durham, N.C., and Associate Editor, JAMA, comment on this study in an accompanying editorial.

“Replication is a vital part of the scientific method. Fields outside of medicine have already embraced sharing experimental data, as have the basic biological sciences within medicine. The culture of clinical research in medicine will need to evolve for open science to succeed. The recognition that one trial can potentially lead to different findings and conclusions depending on many discretionary decisions that are made about the data and reanalyses almost mandates that those choices are transparent and described in detail—and that others have the chance to replicate them. Rather than the rare exception, open science and replication should become the standard for all trials and especially those that have high potential to influence practice.”
(doi:10.1001/jama.2014.9647; 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, SEPTEMBER 9, 2014
Media Advisory: To contact corresponding author Barbara A. Hutten, Ph.D., M.Sc., email b.a.hutten@amc.uva.nl.

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Long-Term Follow-up Shows Benefit of Statin Therapy for Children With Inherited Cholesterol Disorder

Ten-year follow-up of children who have been taking statin therapy for an inherited cholesterol disorder showed benefit on a measure of atherosclerosis, although levels of low-density lipoprotein suggested that stronger or earlier initiation of statin therapy may be warranted, according to a study in the September 10 issue of JAMA.

Familial hypercholesterolemia (FH) is a prevalent (1:500 individuals) inherited disorder that strongly predisposes to premature atherosclerosis and subsequent cardiovascular disease. In children with FH, atherosclerosis progression is observed before puberty. Consequently, guidelines for FH treatment advocate initiation of statins in children as young as 8 years. However, long­term efficacy and safety data for statin therapy initiated during childhood do not exist, according to background information in the article.

D. Meeike Kusters, M.D., of the Academic Medical Center, Amsterdam, the Netherlands and colleagues followed up a group of children with FH receiving statin therapy until adulthood. The study included 214 children heterozygous (possessing two different forms of a particular gene, one inherited from each parent) for FH, living in the Netherlands, ages 8 to 18 years, who were randomly assigned between 1997 and 1999 into a 2-year, placebo-controlled trial of pravastatin. After the trial, all children received pravastatin and were followed up until March 2011 along with 95 unaffected siblings. After 10 years, all participants underwent a physical examination, fasted blood sample, assessment of family and medical history, including the occurrence of adverse events, and measurement of carotid intima-media thickness (IMT; thickness of a wall of an artery), a validated marker of atherosclerosis.

Ten-year follow-up was achieved in 194 (91 percent) patients with FH and 83 (87 percent) siblings, all ages 18 to 30 years. The researchers found that statin treatment initiated during childhood in patients with FH was associated with normalization of carotid IMT progression. Moreover, earlier statin initiation was associated with thinner carotid IMT at follow-up. No serious adverse events were reported during follow-up.

The low-density lipoprotein levels of patients with FH at follow-up did not meet current treatment standards and carotid IMT was thicker than in unaffected siblings.

“More robust lipid-lowering therapy or earlier initiation of statins may be required to completely restore arterial wall morphology and avert cardiovascular events later in life in this high-risk population,” the authors write.
(doi:10.1001/jama.2014.8892; 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, SEPTEMBER 9, 2014
Media Advisory: To contact Barbara P. Yawn, M.D., M.Sc., M.S.P.H., call 507-287-2758 or email byawn@olmmed.org. To contact editorial author Michael R. DeBaun, M.D., M.P.H., call Craig Boerner at 615-322-4747 or email craig.boerner@vanderbilt.edu.

To place an electronic embedded link to this study and editorial in your story This link to the study will be live at the embargo time: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2014.10517. This will be the link to the editorial: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2014.11103.

New Guideline Created for Managing Sickle Cell Disease

An expert panel has created a new evidence-based guideline for managing sickle cell disease (SCD), with a strong recommendation for the use of the drug hydroxyurea and transfusion therapy for many individuals with SCD, although high-quality evidence is limited, with few randomized clinical trials conducted for this disease, according to an article in the September 10 issue of JAMA.

Sickle cell disease is a life-threatening genetic disorder affecting nearly 100,000 individuals in the United States; most of those affected are of African ancestry or self-identify as black. This disease is associated with many acute and chronic complications requiring immediate medical attention. Care for persons with SCD often lacks continuity. Primary care and emergency care health professionals need up-to-date clinical guidance regarding care of persons with this disease, according to background information in the article.

In 2009, the National Heart, Lung, and Blood Institute convened an expert panel that developed the Evidence-Based Management of Sickle Cell Disease: Expert Panel Report 2014. Barbara P. Yawn, M.D., M.Sc., M.S.P.H., of the Olmsted Medical Center, Rochester, Minn., and colleagues produced a summary of this report and conducted a search of the medical literature to examine the strength of the quality of evidence for the recommendations.

Among the Strong Recommendations

• For prevention: daily oral prophylactic penicillin up to the age of 5 years, annual transcranial Doppler examinations from the ages of 2 to 16 years in those with sickle cell anemia, and long-term transfusion therapy to prevent stroke in those children with abnormal transcranial Doppler velocity (elevated speed of blood flow in the cerebral arteries).

• To address acute complications: rapid initiation of opioids for treatment of severe pain associated with a vasoocclusive crisis (blockage of blood flow due to the abnormal “sickled” red blood cells getting stuck in the blood vessels) and use of incentive spirometry (a method of encouraging deep breathing with the use of an instrument to provide feedback) in patients hospitalized for a vasoocclusive crisis.

• For chronic complications: use of analgesics and physical therapy for treatment of avascular necrosis (a condition in which poor blood supply to an area of bone leads to bone death) and use of angiotensin-converting enzyme inhibitor therapy for microalbuminuria (a subtle increase in the urinary excretion of the protein albumin that cannot be detected by a conventional urinalysis) in adults with SCD.

• For children and adults with proliferative sickle cell retinopathy: referral to expert specialists for consideration of laser photocoagulation and for echocardiography to evaluate signs of pulmonary hypertension.

• Hydroxyurea therapy is strongly recommended for adults with 3 or more severe vasoocclusive crises during any 12-month period, with SCD pain or chronic anemia interfering with daily activities, or with severe or recurrent episodes of acute chest syndrome (an SCD syndrome associated with one or more symptoms that may include fever, cough, sputum production or difficulty breathing.

A recommendation of moderate strength suggests offering treatment with hydroxyurea without regard to the presence of symptoms for infants, children, and adolescents.

The authors note that some of the strong recommendations appearing in this guideline are supported by low- or very low-quality evidence, and that evidence is lacking in many areas important to care for individuals with SCD.

“The process of developing guidelines for the management of children, adolescents, and adults with SCD has been challenging because high-quality evidence is limited in virtually every area related to SCD management. The systematic review of the literature identified a very small number of randomized clinical trials in individuals with SCD, demonstrating the extensive knowledge gaps in SCD and care of affected individuals. The expert panel realizes that this summary report and the guidelines leave many uncertainties for health professionals caring for individuals with SCD and highlight the importance of collaboration between primary care health professionals and SCD experts. However, we hope that this summary report and the SCD guideline begins to facilitate improved and more accessible care for all affected individuals, and that the discrepancies in the existing data will trigger new research programs and processes to facilitate future guidelines,” the authors conclude.
(doi:10.1001/jama.2014.10517; 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, September 9 at this link.

Editorial: The Challenge of Creating an Evidence-Based Guideline for Sickle Cell Disease

Michael R. DeBaun, M.D., M.P.H., of the Vanderbilt University School of Medicine, Nashville, Tenn., comments on this guideline in an accompanying editorial.

“Yawn and colleagues have undertaken a monumental effort to produce a practical, evidence-based guideline for SCD. Many aspects of this guideline will help both individuals with the disease and clinicians. As would be expected, when the guideline is based on recommendations from randomized clinical trials, such as penicillin prophylaxis, transcranial Doppler screening, blood transfusion therapy prior to surgery, or hydroxyurea therapy for severe disease, these strong recommendations will be embraced by the SCD community. However, when recommendations are based on consensus panel expertise, practice variation will justifiably continue.”
(doi:10.1001/jama.2014.11103; 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, SEPTEMBER 2, 2014
Media Advisory: To contact corresponding author Charles J. Billington, M.D., call Matt DePoint at 612-625-4110 or email mdepoint@umn.edu. To contact editorial co-author David E. Arterburn, M.D., M.P.H., call Rebecca Hughes at 206-287-2055 or email hughes.r@ghc.org.

To place an electronic embedded link to this study and editorial in your story This link to the study will be live at the embargo time: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2014.10540. This will be the link to the editorial: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2014.10940.

Researchers Examine Effectiveness of Blocking Nerve to Help With Weight Loss

Among patients with morbid obesity, blocking the vagus nerve, which plays a role with appetite and metabolism, did not meet pre-specified efficacy objectives compared to a control group, although the intervention did result in greater weight loss, according to a study in the September 3 issue of JAMA.

Bariatric surgery can produce significant weight loss and improvement in health but is associated with several potential adverse effects. There is interest in the development of a device that could be as effective or nearly as effective as bariatric surgery but has fewer risks and is less invasive. One such possibility is blockade of the vagus nerve using electrodes implanted through minimally invasive laparoscopic surgery, according to background information in the article.

Sayeed Ikramuddin, M.D., of the University of Minnesota, Minneapolis, and colleagues randomly assigned 239 participants who had a body mass index of 40 to 45 or 35 to 40 and 1 or more obesity-related condition to receive an implanted active vagal nerve block device (n = 162) or an implanted sham (inactive) device (n = 77). All participants received weight management education. The study was conducted at 10 sites in the United States and Australia between May and December 2011.

At 12 months in the intent-to-treat population, the average percentages of excess weight loss was 24.4 percent (9.2 percent of their initial body weight loss) in the vagal nerve block group and 15.9 percent (6.0 percent initial body weight loss) in the sham group, with an average difference of 8.5 percentage points, which did not meet the primary efficacy objective of achieving superiority with a 10 percentage-point margin. Weight loss was statistically greater in the vagal nerve block group.

At 12 months, 52 percent of participants in the vagal nerve block group achieved at least 20 percent; and 38 percent, at least 25 percent of excess weight loss, which did not meet the primary efficacy objective performance goals of at least 55 percent of participants achieving a 20 percent excess weight loss and 45 percent achieving a 25 percent excess weight loss.

The device, procedure, or therapy-related serious adverse event rate in the vagal nerve block group was 3.7 percent, significantly lower than the 15 percent primary safety objective goal. The adverse events more frequent in the vagal nerve block group were heartburn, indigestion and abdominal pain attributed to therapy; all were reported as mild or moderate in severity.

“Additional studies are needed to compare effectiveness of vagal nerve block with other obesity treatments and to assess long­term durability of weight loss and safety,” the authors conclude.
(doi:10.1001/jama.2014.10540; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: This study was supported by EnteroMedics Inc., St. Paul, Minn. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, etc.

Editorial: The Current State of the Evidence for Bariatric Surgery

David E. Arterburn, M.D., M.P.H., of the Group Health Research Institute, Seattle, and David P. Fisher, M.D., of the Permanente Medical Group, Richmond, Calif., write in an accompanying editorial that several conclusions can be drawn from this study.

“First, vagal nerve blockade plus moderately intensive lifestyle counseling does not appear to be much more effective than an intensive lifestyle program. Second, based on comparisons with other studies, procedures for adjustable gastric banding, which reported a 50 percent excess weight loss; Roux-en-Y gastric bypass, a 68 percent excess weight loss; and vertical sleeve gastrectomy, a 65 percent excess weight loss, are clearly more effective for initial weight loss than vagal nerve blockade. Third, the rate of serious adverse events with vagal nerve blockade (8.6 percent) is clinically important. Fourth, the long-term rates of weight regain and reoperation with vagal nerve blockade are currently unknown. Fifth, the report by Ikramuddin et al does not include a discussion of how vagal nerve blockade compares with other obesity treatments in terms of costs. Although vagal nerve blockade therapy is an innovative approach, it does not appear to be a sustained, effective treatment for severe obesity.”
(doi:10.1001/jama.2014.10940; 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, SEPTEMBER 2, 2014
Media Advisory: To contact Bradley N. Reames, M.D., M.S., call Nicole Fawcett at 734-764-2220 or email nfawcett@umich.edu.

To place an electronic embedded link to this study in your story This link for the study will be live at the embargo time: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2014.7651.

Study Finds Change in Type of Procedure Most Commonly Used for Bariatric Surgery

In an analysis of the type of bariatric surgery procedures used in Michigan in recent years, sleeve gastrectomy (SG) surpassed Roux-en-Y gastric bypass (RYGB) in 2012 as the most common procedure performed for patients seeking this type of surgery, and SG became the predominant bariatric surgery procedure for patients with type 2 diabetes, according to a study in the September 3 issue of JAMA.

Bariatric surgery is the most effective therapy available for significant and sustainable weight loss in patients with morbid obesity, and its use has increased during the last decade. Changes in procedure use over time reflect emerging evidence regarding the comparative safety and effectiveness of available procedures. An understanding of current trends in bariatric procedure use can inform primary care physicians counseling patients with morbid obesity who are considering surgical intervention, according to background information in the article.

Bradley N. Reames, M.D., M.S., of the University of Michigan, Ann Arbor, and colleagues analyzed data on 43,732 adults who underwent primary inpatient and outpatient bariatric surgery within the 39-hospital Michigan Bariatric Surgery Collaborative between June 2006 and December 2013.

The researchers found that relative use of SG increased from 6.0 percent of all procedures in 2008 to 67.3 percent of all procedures in 2013, an increase of 61 percent. During the same period, use of RYGB decreased from 58.0 percent to 27.4 percent, and use of laparoscopic adjustable gastric banding decreased from 34.5 percent to 4.6 percent.

Even though SG was the most common procedure across all subgroups in 2012 and 2013, SG rates were relatively lower in patients 65 years or older, in patients with gastroesophageal reflux disease, and in patients with type 2 diabetes.

“Although long-term outcomes of SG are still unclear, these changes may reflect the favorable perioperative safety profile and emerging evidence of successful weight loss at 2 to 3 years after SG. These findings are important to inform primary care physicians of the predominant bariatric procedure currently used, regardless of pre-existing comorbidity, and may assist in the preoperative counseling of patients considering surgical therapy for morbid obesity,” the authors write.
(doi:10.1001/jama.2014.7651; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: Dr. Reames is supported by a grant from the National Cancer Institute. 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, SEPTEMBER 2, 2014
Media Advisory: To contact corresponding author Scarlett L. Gomez, Ph.D., call Jana Cuiper at 510-608-5160 or email Jana.Cuiper@cpic.org. To contact editorial author Lisa A. Newman, M.D., M.P.H., call Nicole Fawcett at 734-764-2220 or email nfawcett@umich.edu.

To place an electronic embedded link to this study and editorial in your story This link to the study will be live at the embargo time: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2014.10707. This will be the link to the editorial: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2014.11308.

Increase Seen in Use of Double Mastectomy, Although Procedure Not Associated With Reducing Risk of Death

Among women diagnosed with early-stage breast cancer in California, the percentage undergoing a double mastectomy increased substantially between 1998 and 2011, although this procedure was not associated with a lower risk of death than breast-conserving surgery plus radiation, according to a study in the September 3 issue of JAMA. The authors did find that surgery for the removal of one breast was associated with a higher risk of death than the other options examined in the study.

Randomized trials have demonstrated similar survival for patients with early-stage breast cancer treated with breast-conserving surgery and radiation or with mastectomy. However, previous data show increasing use of mastectomy, and particularly bilateral mastectomy (removal of both breasts) among U.S. patients with breast cancer. Evidence for a survival benefit with this procedure appears limited to rare patient subgroups. “Because bilateral mastectomy is an elective procedure for unilateral breast cancer [in one breast] and may have detrimental effects in terms of complications and associated costs as well as body image and sexual function, a better understanding of its use and outcomes is crucial to improving cancer care,” according to background information in the article.

Allison W. Kurian, M.D., M.Sc., of the Stanford University School of Medicine, Stanford, Calif., and colleagues used data from the California Cancer Registry from 1998 through 2011 to compare the use of and rate of death after bilateral mastectomy, breast-conserving therapy with radiation, and unilateral mastectomy (removal of one breast).

The analyses included 189,734 patients. The researchers found that the rate of bilateral mastectomy increased from 2.0 percent in 1998 to 12.3 percent in 2011, an annual increase of 14.3 percent. The increase in bilateral mastectomy rate was greatest among women younger than 40 years: the rate increased from 3.6 percent in 1998 to 33.0 percent in 2011, increasing by 17.6 percent annually. Use of unilateral mastectomy declined in all age groups

Bilateral mastectomy was more often used by non-Hispanic white women, those with private insurance, and those who received care at a National Cancer Institute-designated cancer center; in contrast, unilateral mastectomy was more often used by racial/ethnic minorities and those with public/Medicaid insurance.

Compared with breast-conserving surgery with radiation, bilateral mastectomy was not associated with a mortality difference, whereas unilateral mastectomy was associated with higher mortality.

“In a time of increasing concern about overtreatment, the risk-benefit ratio of bilateral mastectomy warrants careful consideration and raises the larger question of how physicians and society should respond to a patient’s preference for a morbid, costly intervention of dubious effectiveness,” the authors write.

“These results may inform decision-making about the surgical treatment of breast cancer.”

(doi:10.1001/jama.2014.10707; 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: Contralateral Prophylactic Mastectomy
Is It a Reasonable Option?

In an accompanying editorial, Lisa A. Newman, M.D., M.P.H., of the University of Michigan, Ann Arbor, discusses the issues involved with the use of contralateral prophylactic mastectomy (risk-reducing mastectomy for the unaffected breast).

“The need for patients to be accurately informed regarding safe and oncologically acceptable treatment options is indisputable. The dense fog of complex emotions that accompanies a new cancer diagnosis can impair the ability to process this information. Patients should be encouraged to allow the intensity of these immediate reactions to subside before committing to mastectomy prematurely. Physicians should not permit excessive treatment delays to compromise outcomes, but the initial few weeks surrounding the diagnosis are more effectively utilized by time invested in patient education and procedures that contribute to comprehensive treatment planning as opposed to hastily coordinating impulsive, irreversible surgical plans.”
(doi:10.1001/jama.2014.11308; 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, SEPTEMBER 2, 2014
Media Advisory: To contact Bradley C. Johnston, Ph.D., email Veronica McGuire at vmcguir@mcmaster.ca. To contact editorial author Linda Van Horn, Ph.D., R.D., call Marla Paul at 312-503-8928 or email marla-paul@northwestern.edu.

To place an electronic embedded link to this study and editorial in your story This link to the study will be live at the embargo time: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2014.10397. This will be the link to the editorial: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2014.10837.

Comparison of Named Diet Programs Finds Little Difference in Weight Loss Outcomes

In an analysis of data from nearly 50 trials including about 7,300 individuals, significant weight loss was observed with any low-carbohydrate or low-fat diet, with weight loss differences between diet programs small, findings that support the practice of recommending any diet that a patient will adhere to in order to lose weight, according to a study in the September 3 issue of JAMA.

Named or branded (trade-marked) weight loss programs provide structured dietary and lifestyle recommendations via popular books and in-person or online behavioral support and represent a multibillion dollar industry. Debate regarding the relative merit of the diets is accompanied by advertising claiming which macronutrient composition is superior, such as a low-carbohydrate or low-fat diet. Establishing which of the major named diets is most effective is important because overweight patients often want to know which diet results in the most effective weight loss, according to background information in the article.

Bradley C. Johnston, Ph.D., of the Hospital for Sick Children Research Institute, Toronto, and McMaster University, Hamilton, Ontario, and colleagues conducted a meta-analysis to assess the relative effectiveness of different popular diets in improving weight loss. The researchers conducted a search of the medical literature to identify studies in which overweight or obese adults (body mass index 25 or greater) were randomized to a popular self-administered named diet and reported weight or body mass index data at 3-month follow-up or longer.

The meta-analysis included 59 articles that reported 48 randomized clinical trials (7,286 individuals; median age, 46 years; median weight, 207.5 lbs.). In the diet-class analysis adjusted for exercise and behavioral support, all treatments were superior to no diet at 6-month follow-up. Compared with no diet, low-carbohydrate diets had a median difference in weight loss of 19.2 lbs. and low-fat diets had similar estimated effects (17.6 lbs.).

At 12-month follow-up, the estimated average weight losses of all diet classes compared with no diet were approximately 2.2 to 4.4 lbs. less than after 6-month follow-up. The diet classes of low fat (16 lbs.) and low carbohydrate (16 lbs.) continued to have the largest estimated treatment effects.

Weight loss differences between individual diets were minimal. For example, the Atkins diet resulted in a 3.8 lbs. greater weight loss than the Zone diet at 6-month follow-up. “Although statistical differences existed among several of the diets, the differences were small and unlikely to be important to those seeking weight loss,” the authors write.

“Our findings should be reassuring to clinicians and the public that there is no need for a one-size-fits­all approach to dieting because many different diets appear to offer considerable weight loss benefits. This is important because many patients have difficulties adhering to strict diets that may be particularly associated with cravings or be culturally challenging (such as low-carbohydrate diets). Our findings suggest that patients may choose, among those associated with the largest weight loss, the diet that gives them the least challenges with adherence. Although our study did not examine switching between diets, such a strategy may offer patients greater choices as they attempt to adhere to diet and lifestyle changes.”
(doi:10.1001/jama.2014.10397; 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: A Diet by Any Other Name Is Still About Energy

Linda Van Horn, Ph.D., R.D., of the Northwestern University Feinberg School of Medicine, Chicago, comments on the findings of this study in an accompanying editorial.

“Overall, the findings from the study by Johnston et al, along with other recent data, underscore the importance of effective diet and lifestyle interventions that promote behavioral changes to support adherence to a calorie-restricted, nutrient-dense diet that ultimately accomplishes weight loss. Choosing the best diet suited to an individual’s food preferences may help foster adherence, but beyond weight loss, diet quality including micronutrient composition may further benefit longevity.”
(doi:10.1001/jama.2014.10837; 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 EARLY RELEASE: 2 A.M. (CT) SUNDAY, AUGUST 31, 2014
Media Advisory: To contact Michelle L. O’Donoghue, M.D., M.P.H., call Jessica Maki at 617-525-6373 or email jmaki3@partners.org.

Inhibiting Inflammatory Enzyme After Heart Attack Does Not Reduce Risk of Subsequent Event

In patients who experienced an acute coronary syndrome (ACS) event (such as heart attack or unstable angina), use of the drug darapladib to inhibit the enzyme lipoprotein-associated phospholipase A2 (believed to play a role in the development of atherosclerosis) did not reduce the risk of recurrent major coronary events, according to a study published by JAMA. The study is being released early online to coincide with its presentation at the European Society of Cardiology Congress.

A number of epidemiologic studies have shown that higher circulating levels of lipoprotein-associated phospholipase A2 (Lp-PLA2) activity or mass are associated with an increased risk of coronary events. Darapladib is a Lp-PLA2 inhibitor that reduces Lp-PLA2 activity in plasma and in atherosclerotic plaques, according to background information in the article.

Michelle L. O’Donoghue, M.D., M.P.H., of Brigham and Women’s Hospital, Boston, and colleagues randomly assigned 13,026 participants within 30 days of hospitalization with an ACS to either once-daily darapladib or placebo along with guideline-recommended therapy. The study was conducted at 868 sites in 36 countries.

Patients were followed up for a median of 2.5 years. At the end of follow-up, the primary end point of the study, major coronary events (composite of coronary heart disease death, heart attack, or urgent coronary revascularization for myocardial ischemia) had occurred in 903 of 6,504 participants in the darapladib group and 910 of 6,522 participants in the placebo group (16.3 percent vs 15.6 percent at 3 years). Cardiovascular death, heart attack, or stroke occurred in 824 darapladib-assigned participants and 838 placebo¬treated patients (15.0 percent vs 15.0 percent at 3 years). There were no significant differences between treatment groups in the incidence and number of events for the individual components of the primary end point.

The rate of all-cause mortality at 3 years was similar between the groups (darapladib, 7.3 percent; placebo, 7.1 percent).

The incidence of any serious adverse event was similar between treatment groups.

The authors conclude that their findings “do not support a strategy of targeted Lp-PLA2 inhibition with darapladib in patients stabilized after an ACS event who are similar to those enrolled into this trial.”
(doi:10.1001/jama.2014.11061; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: This trial was funded by GlaxoSmithKline. 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: 6 A.M. (CT) SATURDAY, AUGUST 30, 2014
Media Advisory: To contact Massimo Imazio, M.D., email massimo_imazio@yahoo.it.

Medication Shows Mixed Results in Reducing Complications From Cardiac Surgery

Administration of colchicine, a plant-based medication commonly used to treat gout, before and after cardiac surgery showed mixed results in reducing potential complications from this type of surgery, but it did increase the risk of gastrointestinal adverse effects, according to a study published by JAMA. The study is being released early online to coincide with its presentation at the European Society of Cardiology Congress.

Common complications after cardiac surgery include postpericardiotomy syndrome (the occurrence of the symptoms of pericarditis, including chest pain), postoperative atrial fibrillation (AF), and postoperative pericardial/pleural effusions (excess fluid around the heart and lungs), affecting more than one-third of patients. These complications may lead to prolonged hospital stay, readmissions, and need for invasive interventions. Postoperative use of colchicine helped prevent these complications in a single trial, according to background information in the article.

Massimo Imazio, M.D., of Maria Vittoria Hospital, Torino, Italy, and colleagues randomly assigned 360 cardiac surgery patients from 11 centers in Italy to receive placebo (n=180) or colchicine (n=l80) starting between 48 and 72 hours before surgery and continued for 1 month after surgery.

The primary measured outcome for the study, postpericardiotomy syndrome within 3 months, occurred in 35 patients (19.4 percent) assigned to colchicine and in 53 (29.4 percent) assigned to placebo. There were no significant differences between the colchicine and placebo groups for postoperative AF (colchicine, 33.9 percent; placebo, 41.7 percent) or postoperative pericardial/pleural effusion (colchicine, 57.2 percent; placebo, 58.9 percent).

Adverse event rates occurred in 21 patients (11.7 percent) in the placebo group and 36 (20.0 percent) in the colchicine group, primarily because of an increased incidence of gastrointestinal intolerance (6.7 percent in the placebo group; 14.4 percent in the colchicine group). Discontinuation rates were similar in both groups.

“In this multicenter trial, perioperative administration of colchicine significantly reduced the incidence of postpericardiotomy syndrome after cardiac surgery but did not reduce the risk of postoperative AF and postoperative pericardial/pleural effusions by intention-to-treat analysis,” the authors write. “About 20 percent of all patients enrolled in the trial discontinued study drug; this relatively high rate may have affected the overall efficacy of the drug, especially for postoperative AF prevention.”

“The high rate of adverse effects is a reason for concern and suggests that colchicine should be considered only in well­selected patients.”
(doi:10.1001/jama.2014.11026; 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, AUGUST 26, 2014
Media Advisory: To contact Jacob A. Udell, M.D., M.P.H., call Heidi Singer at 416-978-5811 or email Heidi.Singer@utoronto.ca.

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Study Questions Generalizability of Findings of Cardiovascular Trials for Heart Attack Patients

An analysis of a cardiovascular registry finds that of clinical trials that included heart attack patients, participation among eligible patients was infrequent and has been declining, and trial participants had a lower risk profile and a more favorable prognosis compared with the broader population of patients who have had a heart attack, according to a study in the August 27 issue of JAMA.

Jacob A. Udell, M.D., M.P.H., of the University of Toronto, and colleagues evaluated whether participants in cardiovascular trials are representative of contemporary patients with myocardial infarction (MI; heart attack). The researchers used data from the National Cardiovascular Data Registry Acute Coronary Treatment and Intervention Outcomes Network Registry-Get With The Guidelines, an ongoing, voluntary, quality improvement registry of patients with MI treated at participating centers across the United States.

Among 141,135 registry participants at 466 centers, 4,008 (2.8 percent) were trial participants; among the 137,127 nonparticipants, 93,274 were eligible (68.0 percent) and 43,853 were ineligible (32.0 percent). Overall, 255 sites (54.7 percent) enrolled at least 1 patient; and trial participation (as a proportion of eligible patients) declined each year during the study period (2008: 5.2 percent; 2009: 4.4 percent; 2010: 3.8 percent; and 2011: 3.4 percent). Trial participants were younger, with less previous cardiovascular disease, lower predicted risk of mortality, shorter hospital stays, and more frequent treatment with evidence­based therapy than nonparticipants.

Common reasons for trial ineligibility included uncontrolled hypertension, elevated INR (abnormal clotting), severe anemia, and cardiogenic shock. In-hospital mortality was lowest for trial participants, intermediate among eligible nonparticipants, and highest among ineligible patients.

“Efforts to improve trial participation are needed to enhance generalizability of results,” the authors write.
(doi:10.1001/jama.2014.6217; 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, AUGUST 26, 2014
Media Advisory: To contact corresponding author Petra Susan Huppi, M.D., email petra.huppi@hcuge.ch.

To place an electronic embedded link to this study in your story This link for the study will be live at the embargo time: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2014.9645.

EPO May Help Reduce Risk of Brain Abnormalities in Preterm Infants

High-dose erythropoietin (EPO; a hormone) administered within 42 hours of birth to preterm infants was associated with a reduced risk of brain injury, as indicated by magnetic resonance imaging, according to a study in the August 27 issue of JAMA.

Survival of premature infants has improved over the past decades, but at the expense of an increase in the number of infants affected by long-term developmental disabilities. Premature infants are at risk of developing encephalopathy of prematurity, which includes structural changes of brain white and gray matter and is associated with long-term neurodevelopmental delay. Erythropoietin has shown beneficial effects on neurodevelopmental outcomes in observational and retrospective studies, according to background information in the article.

Russia Ha-Vinh Leuchter, M.D., of the University Hospital of Geneva, Switzerland, and colleagues conducted a study in which 495 infants (born from 26 weeks to 31 weeks and 6 days of gestation) were randomly assigned to receive recombinant human erythropoietin (n=256) or placebo (n=239) intravenously before 3 hours, at 12 to18 hours, and at 36 to 42 hours after birth. In a nonrandomized subset of 165 of the 495 infants (n=77 erythropoietin; n=88 placebo), brain abnormalities were evaluated on magnetic resonance imaging (MRI) acquired at term-equivalent age.

The researchers found that at term-equivalent age, compared with untreated controls, fewer infants treated with recombinant human erythropoietin had abnormal scores for white matter injury (22 percent vs 36 percent); white matter signal intensity (3 percent vs 11 percent); periventricular white matter loss (18 percent vs 33 percent); and gray matter injury (7 percent vs 19 percent).

“These findings require assessment in a randomized trial designed primarily to assess this outcome, as well as investigation of the association with neurodevelopmental outcomes,” the authors conclude.
(doi:10.1001/jama.2014.9645; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: This trial was sponsored by the Swiss National Science Foundation. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, etc.

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