EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, SEPTEMBER 27, 2016

Media Advisory: To contact Michael D. Hill, M.D., M.Sc., call Marta Cyperling at 403-210-3835 or email mcyperli@ucalgary.ca.

To place an electronic embedded link to this study in your story  This link will be live at the embargo time: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2016.13647

In an analysis that included nearly 1,300 patients with large-vessel ischemic stroke, earlier treatment with endovascular thrombectomy (intra-arterial use of a micro-catheter or other device to remove a blood clot) plus medical therapy (use of a clot dissolving agent) compared with medical therapy alone was associated with less disability at 3 months, according to a study appearing in the September 27 issue of JAMA.

Five randomized trials have demonstrated the benefit of second-generation endovascular recanalization therapies over medical therapy alone among patients with acute ischemic stroke due to large vessel occlusions (blockage). However, uncertainties remain about the benefit and risk of endovascular intervention when under taken more than 6 hours after symptom onset. Michael D. Hill, M.D., M.Sc., of the University of Calgary, Calgary, Canada, and colleagues conducted a meta-analysis of the data from these 5 randomized trials (1,287 patients enrolled at 89 international sites). Demographic, clinical, and brain imaging data as well as functional and radiologic outcomes were pooled.

The researchers found that compared with medical therapy alone, earlier treatment with endovascular thrombectomy plus medical therapy was associated with lower degrees of disability at 3 months. Benefit was greatest with time from symptom onset to arterial puncture for thrombectomy of less than 2 hours and became nonsignificant after 7.3 hours.

Among 390 patients who achieved substantial reperfusion with endovascular thrombectomy, each 1-hour delay to reperfusion was associated with a less favorable degree of disability and less functional independence, but no change in mortality.

The authors note that within 7.3 hours, “functional outcomes were better the sooner after symptom onset that endovascular reperfusion was achieved, emphasizing the importance of programs to enhance patient awareness, out-of-hospital care, and in-hospital management to shorten symptom onset-to-treatment times.”

“The results of this study reinforce guideline recommendations to pursue endovascular treatment when arterial puncture can be initiated within 6 hours of symptom onset, and provide evidence that potentially supports strengthening of recommendations for treatment from 6 through 7.3 hours after symptom onset.”

(doi:10.1001/jama.2016.13647; the study is available pre-embargo to the media at the For the Media website)

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: 11 A.M. (ET) TUESDAY, SEPTEMBER 27, 2016

Media Advisory: To contact Marc S. Sabatine, M.D., M.P.H., call Johanna Younghans at 617- 525-6373 or email jyounghans@partners.org.

To place an electronic embedded link to this study in your story  This link will be live at the embargo time: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2016.13985

In a study appearing in the September 27 issue of JAMA, Marc S. Sabatine, M.D., M.P.H., of Brigham and Women’s Hospital, Harvard Medical School, Boston, and colleagues evaluated the association between lowering low-density lipoprotein cholesterol (LDL-C) and relative cardiovascular risk reduction across different statin and nonstatin therapies.

Low-density lipoprotein cholesterol is a well-established risk factor for cardiovascular disease. The clinical benefit of lowering LDL-C with statins remains widely accepted. In contrast, the comparative clinical benefit of nonstatin therapies that reduce LDL-C remains uncertain. For this study, the authors conducted a review and meta-analysis of 49 trials that met criteria for inclusion. The study included a total of 312,175 participants with 39,645 major vascular events and 9 different interventions to lower LDL-C.

The interventions were divided into 4 groups: (1) statins; (2) nonstatin therapies that ultimately work predominantly through upregulation of LDL receptor expression (i.e., diet, bile acid sequestrants, ileal bypass, and ezetimibe); (3) interventions that do not reduce LDL-C levels primarily through upregulation of LDL receptor expression (i.e., fibrates, niacin, cholesteryl ester transfer protein [CETP] inhibitors); and (4) PCSK9 inhibitors, which upregulate LDL-C clearance through the LDL receptor, but for which dedicated cardiovascular outcome trials have not yet been completed (and were considered separately to evaluate how the data to date compare with established therapies that upregulate LDL receptor expression).

The authors found that there was a similar association between absolute reductions in LDL-C and lower relative risks for major vascular events (a composite of cardiovascular death, acute heart attack or other acute coronary syndrome, coronary revascularization, or stroke) across therapies that lead to upregulation of LDL receptor expression. Each 1-mmol/L (39 mg/dL) reduction in LDL-C was associated with a 23 percent relative reduction in the risk of major vascular events. There was also a significant linear association between achieved LDL-C and the rate of cardiovascular outcomes over the range of LDL-C studied.

“The implications of these results deserve careful consideration in light of the strength of the available trial evidence for different types of therapies. As per current guidelines, when tolerated, statins should be the first-line therapy given the large reductions observed for LDL-C, the excellent safety profile, the demonstrated clinical benefit, and low cost (now that most are generic). However, the data in the present meta-regression analysis raise the possibility that other interventions, especially those that ultimately act predominantly through upregulation of LDL receptor expression, may provide additional options and may potentially be associated with the same relative clinical benefit per each 1-mmol/L reduction in LDL-C,” the authors write.

(doi:10.1001/jama.2016.13985; the study is available pre-embargo to the media at the For the Media website)

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: 11 A.M. (ET) TUESDAY, SEPTEMBER 27, 2016

Media Advisory: To contact Kanu Okike, M.D., M.P.H., email okike@post.harvard.edu.

To place an electronic embedded link to this study in your story  This link will be live at the embargo time: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2016.11014

In a study appearing in the September 27 issue of JAMA, Kanu Okike, M.D., M.P.H., of the Kaiser Moanalua Medical Center, Honolulu, and colleagues examined if bias with single-blind peer review might be greatest in the setting of author or institutional prestige.

Most medical journals practice single-blind review (authors’ identities known to reviewers), but double-blind review (authors’ identities masked to reviewers) may improve the quality of reviews. This study was conducted at Clinical Orthopaedics and Related Research, an orthopedic journal that allows authors to select single-blind or double-blind peer review. Potential reviewers were informed that a study on peer review would occur in the coming year, and allowed to opt out.

Between June 2014 and August 2015, reviewers were randomly assigned to receive single-blind or double-blind versions of an otherwise identical fabricated manuscript, which was indicated as being written by 2 past presidents of the American Academy of Orthopaedic Surgeons from prominent institutions. Five subtle errors were included to determine differences in how critically the manuscript was examined. The primary outcome was recommendation of acceptance or rejection.

The authors found that reviewers (n = 119) were more likely to recommend acceptance when the prestigious authors’ names and institutions were visible (single-blind review) than when they were redacted (double-blind review) (87 percent vs 68 percent) and also gave higher ratings for the methods and other categories. There was no difference in the number of errors detected.

The researchers note that the study was conducted at a single orthopaedic journal; generalizability to other journals and other fields of medicine is unknown.

(doi:10.1001/jama.2016.11014; the study is available pre-embargo to the media at the For the Media website)

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: 11 A.M. (ET) THURSDAY, SEPTEMBER 22, 2016

Media Advisory: To contact Victor R. Fuchs, Ph.D., email Adam Gorlick at agorlick@stanford.edu.

To place an electronic embedded link to this study in your story  This link will be live at the embargo time: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2016.14398

In a Viewpoint published online by JAMA, Victor R. Fuchs, Ph.D., Henry J. Kaiser Professor Emeritus, Stanford University, Stanford, Calif., discusses the narrowing life-expectancy gap between the U.S. black and white populations and points out categories of disease and death that could further narrow the gap.

“In recent decades the U.S. black population has experienced substantial gains in life expectancy, now becoming closer to the life expectancy of the white population. Between 1995 and 2014, the increase in black life expectancy at birth was more than double the white increase: a gain of 6.0 years from 69.6 years to 75.6 years for black people compared with a gain of 2.5 years from 76.5 years to 79.0 for white people,” Dr. Fuchs writes.

In a study of changes in black-white differences in life expectancy from 1999 to 2013, Kochanek et al found that the gap in life-expectancy closed by 2.3 years, from 5.9 to 3.6 years, and that gains in just 5 causes (cardiovascular disease, cancer, human immunodeficiency virus (HIV), unintentional injuries, and perinatal conditions) accounted for almost 60 percent of the decrease in the black-white life expectancy gap.

Dr. Fuchs writes that to make a significant contribution to reducing the current gap between black and white life expectancy, a cause must have substantial number of deaths and a significantly higher age-adjusted death rate for blacks than for whites. Eleven causes of death meet those 2 criteria: HIV; homicide; essential hypertension & hypertensive renal disease; nephritis, nephrotic syndrome, and nephrosis; cancer of prostate; diabetes mellitus; septicemia; cancer of breast; cerebrovascular disease; cancer of colon, rectum, anus; and diseases of the heart. “With a goal of reducing the 17 percent differential in black-white all-cause deaths, it appears that progress in just a few causes probably will not be enough; progress in many causes will be required.”

“The very high black-white ratio for age-adjusted homicide deaths suggests another opportunity for reducing the racial gap in all-cause deaths, but realization of the opportunity depends more on public health measures such as gun control than on medical care. Essential hypertension, prostate cancer, kidney disease (nephritis, nephrotic syndrome, nephrosis), and septicemia all have high black-white age-adjusted mortality ratios and a substantial number of total deaths, posing a challenge to research, prevention, diagnosis, and therapeutic interventions. Continued progress in preventing and treating heart disease in black men could also make a substantial contribution because of the large number of these men who die young relative to white men and black women.”

“In 1944, Gunner Myrdahl, Nobel Prize winner in Economics, wrote that black-white differences were arguably the United States’ biggest problem. Major advances in life expectancy that bring blacks closer to whites is a significant contribution to its solution.”

(doi:10.1001/jama.2016.14398; the study is available pre-embargo to the media at the For the Media website)

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: 11 A.M. (ET) TUESDAY, SEPTEMBER 20, 2016

Media Advisory: To contact John M. Jakicic, Ph.D., email Anthony Moore at amm114@pitt.edu.

To place an electronic embedded link to this study in your story  This link will be live at the embargo time: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2016.12858

Among overweight or obese young adults, the addition of a wearable technology device (that provided feedback on physical activity) to a standard behavioral intervention resulted in less weight loss over 24 months, according to a study appearing in the September 20 issue of JAMA.

Effective long-term treatments are needed to address the obesity epidemic. There is wide availability of commercial technologies for physical activity and diet. These technologies include wearable devices to monitor physical activity, with many also including an interface to monitor diet. These technologies may provide a method to improve longer-term weight loss; however, there are limited data on the effectiveness of such technologies for modifying health behaviors long term.

John M. Jakicic, Ph.D., of the University of Pittsburgh, and colleagues randomly assigned study participants to a standard behavioral weight loss intervention (n = 233) or technology-enhanced weight loss intervention (n = 237). Participants (body mass index [BMI], 25 to <40; age range, 18-35 years; 29 percent nonwhite; 77 percent women) were placed on a low-calorie diet, prescribed increases in physical activity, and had group counseling sessions. At 6 months, the interventions added telephone counseling sessions, text message prompts, and access to study materials on a website. Also at 6 months, participants randomized to the standard intervention group initiated self-monitoring of diet and physical activity using a website, and those randomly assigned to the enhanced intervention group were provided with a wearable device and accompanying web interface to monitor diet and physical activity. The trial was conducted between October 2010 and October 2012.

Seventy-five percent of participants completed the study. The researchers found that weight change at 24 months differed significantly by intervention group. Estimated average weights for the enhanced intervention group were 212 lbs. at study entry and 205 lbs. at 24 months, resulting in an average weight loss of about 7.7 lbs. Corresponding values for the standard intervention group were 210 lbs. at baseline and 197 lbs. at 24 months, for an average loss of 13 lbs. At 24 months, weight loss was 5.3 lbs. lower in the enhanced intervention group compared with the standard intervention group.

Both groups had significant improvements in body composition, fitness, physical activity, and diet, with no significant difference between groups.

“Devices that monitor and provide feedback on physical activity may not offer an advantage over standard behavioral weight loss approaches,” the authors write.

The researchers add that the reason for the difference in weight loss between the groups warrants further investigation.

(doi:10.1001/jama.2016.12858; the study is available pre-embargo to the media at the For the Media website)

Editor’s Note: This study was supported by a grant from the National Institutes of Health and the National Heart, Lung, and Blood 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: 11 A.M. (ET) TUESDAY, SEPTEMBER 20, 2016

Media Advisory: To contact Robert J. Boyle, M.D., Ph.D., email r.boyle@nhs.net. To contact editorial author Matthew Greenhawt, M.D., M.B.A., M.Sc., email Hollon Kohtz at Hollon.Kohtz@childrenscolorado.org.

To place an electronic embedded link to this study in your story  This link will be live at the embargo time: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2016.12623

In a study appearing in the September 20 issue of JAMA, Robert J. Boyle, M.D., Ph.D., of Imperial College London, and colleagues examined the evidence that timing of allergenic food introduction during infancy influences risk of allergic or autoimmune disease.

Infant feeding guidelines have moved away from advising parents to delay the introduction of allergenic food, but most guidelines do not yet advise early feeding of such foods. Timing of introduction of allergenic foods to the infant diet may influence the risk of allergic or autoimmune disease, but the evidence for this has not been comprehensively examined.

For this study, the researchers conducted a systematic review and meta-analysis of intervention trials and observational studies that evaluated timing of allergenic food introduction during the first year of life and reported allergic or autoimmune disease or allergic sensitization. Of 16,289 original titles screened, data were extracted from 204 titles reporting 146 studies.

The authors found evidence that timing of introduction of certain allergenic foods to the infant diet was associated with risk of allergic disease but not risk of autoimmune disease. There was moderate-certainty evidence that introduction of egg to the infant diet at age 4 to 6 months was associated with reduced egg allergy and introduction of peanut at age 4 to 11 months was associated with reduced peanut allergy compared with later introduction of these foods. Absolute risk reduction for a population with 5.4 percent incidence of egg allergy was 24 cases per 1,000 population. Absolute risk reduction for a population with 2.5 percent incidence of peanut allergy was 18 cases per 1,000 population.

There was low-certainty evidence that fish introduction before age 6 to 12 months was associated with reduced allergic rhinitis and very low-certainty evidence that fish introduction before age 6 to 9 months was associated with reduced allergic sensitization. There was high-certainty evidence that timing of gluten introduction was not associated with celiac disease risk, and timing of allergenic food introduction was not associated with other outcomes.

The authors note that these systematic review findings should not automatically lead to new recommendations to feed egg and peanut to all infants. “The imprecise effect estimates, issues regarding indirectness, and inconclusive trial sequential analysis findings all need to be considered, together with a careful assessment of the safety and acceptability of early egg and peanut introduction in different populations.”

(doi:10.1001/jama.2016.12623; the study is available pre-embargo to the media at the For the Media website)

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

Editorial: Early Allergen Introduction for Preventing Development of Food Allergy

“The rigorous, comprehensive meta-analysis by Ierodiakonou and colleagues is an important addition to the evidence regarding food allergy prevention,” writes Matthew Greenhawt, M.D., M.B.A., M.Sc., of Children’s Hospital Colorado, Aurora, in an accompanying editorial.

“Their conclusions highlight that the 2008 guidelines to not delay introduction were correct. Delay of introduction of these foods may be associated with some degree of potential harm, and early introduction of selected foods appears to have a well-defined benefit. These important points should resonate with allergy specialists, primary care physicians, and other health care professionals who care for infants, as well as obstetricians caring for pregnant mothers, all of whom are important stakeholders in effectively conveying the message that guidance to delay allergen introduction is outdated.”

(doi:10.1001/jama.2016.12715; the study is available pre-embargo to the media at the For the Media website)

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

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EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, SEPTEMBER 20, 2016

Media Advisory: To contact Hilary D. Marston, M.D., M.P.H., email niaidnews@niaid.nih.gov.

To place an electronic embedded link to this study in your story  This link will be live at the embargo time: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2016.11764

Antimicrobial resistance poses significant challenges for current clinical care, and the modified use of antimicrobial agents and public health interventions, coupled with new antimicrobial strategies, may help reduce the effect of multidrug-resistant organisms in the future, according to a study appearing in the September 20 issue of JAMA.

Antibiotics have revolutionized the practice of medicine by enabling breakthroughs across the spectrum of clinical medicine, including safer childbirth, surgical procedures and organ transplantation. However, antimicrobial resistance (AMR) threatens to impede and even reverse some of this progress. In the United States, AMR organisms cause more than 2 million infections and are associated with approximately 23,000 deaths each year. In Europe, AMR is associated with approximately 25,000 deaths annually.

Anthony S. Fauci, M.D., Hilary D. Marston, M.D., M.P.H., of the National Institutes of Health, Bethesda, Md., and colleagues conducted a study to identify factors associated with AMR, the current epidemiology of important resistant organisms, and possible solutions to the AMR problem. Databases were searched for articles and entries related to AMR, focusing on epidemiology, clinical effects of AMR, discovery of novel agents to treat AMR bacterial infections, and nonpharmacological strategies to eliminate or modify AMR bacteria. In addition, selected health policy reports and public health guidance documents were reviewed. Of 217 articles, databases, and reports identified, 103 were selected for review.

The authors summarize that the increase in AMR has been driven by a diverse set of factors, including inappropriate antibiotic prescribing and sales, use of antibiotics outside of the health care sector, and genetic factors intrinsic to bacteria. The problem has been exacerbated by inadequate economic incentives for pharmaceutical development of new antimicrobial agents. A range of specific AMR concerns, including carbapenem- and colistin-resistant gram-negative organisms, pose a clinical challenge. Alternative approaches to address the AMR threat include new methods of antibacterial drug identification and strategies that neutralize virulence factors.

“Since bacterial resistance to antibiotics is inevitable, researchers must respond with innovative strategies to identify and develop new drug candidates, vaccines, and other prophylactic immune interventions and create novel treatment methods that are less likely than typical antibiotics to result in resistance,” the researchers write.

“Although advances in biomedical research hold promise for efforts to prevent and treat AMR, many of these technologies are in the earliest stages of discovery. Meanwhile, effective action can slow the spread and mitigate the negative effects of resistant bacteria today. Medical professionals and facilities have an important role to play, through implementation of antimicrobial stewardship programs, reduction in inappropriate prescribing, immunization against bacterial and viral pathogens, and robust infection control measures including enhanced surveillance for resistant organisms.”

“National plans, such as the President’s National Strategy for Combating Antibiotic Resistant Bacteria, lay out more comprehensive approaches, drawing on contributions from health care practitioners, biomedical researchers, and the pharmaceutical and agricultural sectors (among others). Analogous international efforts, overseen by the World Health Organization, are also under way. These programs require committed and concerted implementation to realize their promise. Without a coordinated response, the postantibiotic age presaged by so many is a distinct and unwelcome possibility,” the authors conclude.

(doi:10.1001/jama.2016.11764; the study is available pre-embargo to the media at the For the Media website)

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: 11 A.M. (ET) TUESDAY, SEPTEMBER 20, 2016

Media Advisory: To contact Bradley D. Stein, M.D., Ph.D., email Warren Robak at robak@rand.org.

To place an electronic embedded link to this study in your story  This link will be live at the embargo time: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2016.10542

In a study appearing in the September 20 issue of JAMA, Bradley D. Stein, M.D., Ph.D., of RAND Corporation, Pittsburgh, and colleagues examined patient censuses of buprenorphine prescribers to determine whether patient limits have been a barrier to buprenorphine treatment.

Buprenorphine, a medication effective in treating individuals with opioid use disorders, can be prescribed in the United States by addiction specialists or by physicians who complete an 8-hour course and obtain a U.S. Drug Enforcement Administration waiver. Waivered prescribers have been restricted to treating up to 30 patients with an opioid use disorder concurrently; after a year, physicians could request that the limit be increased to 100 patients. Policy makers have prioritized increasing capacity to provide buprenorphine to fight the opioid epidemic but lack adequate information about how to do so effectively.

The researchers used a database that contains pharmacy retail transactions from more than 80 percent of pharmacies nationwide, including high-volume national chain pharmacies, resulting in information on approximately 90 percent of prescriptions filled at retail pharmacies in the United States. Data from 7 states with the most buprenorphine-waivered physicians (California, Florida, Massachusetts, Michigan, New York, Pennsylvania, Texas) were analyzed.

The study included 3,234 buprenorphine prescribers with 245,016 patients receiving a new prescription of buprenorphine from 2010-2013. The authors found that the monthly patient censuses for buprenorphine-prescribing physicians were substantially below patient limits; more than 20 percent treated 3 or fewer patients, and fewer than 10 percent treated more than 75 patients. The median treatment duration (53 days) was lower than expected given clinical recommendations of maintenance treatment for up to 12 months and evidence linking longer treatment to better outcomes.

“Novice prescribers cite insufficient access to more experienced prescribers and insufficient access to substance abuse counseling for patients as barriers to treating more patients. Such barriers might be addressed by web-based or tele-counseling for patients and by programs providing mentoring and telephone consultation from more experienced prescribers. Strategies to help current prescribers treat more patients safely and effectively could complement policy initiatives designed to increase access to treatment by increasing patient limits and number of waivered prescribers,” the authors write.

(doi:10.1001/jama.2016.10542; the study is available pre-embargo to the media at the For the Media website)

Editor’s Note: The work was supported by a grant from the National Institute on Drug Abuse of the National Institutes 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: 11 A.M. (ET) TUESDAY, SEPTEMBER 20, 2016

Media Advisory: To contact Jacques-Eric Gottenberg, M.D., Ph.D., email jacques-eric.gottenberg@chru-strasbourg.fr.

To place an electronic embedded link to this study in your story  This link will be live at the embargo time: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2016.13512

Among patients with rheumatoid arthritis previously treated with anti-tumor necrosis factor (TNF) drugs but with insufficient response, a non-TNF biologic agent was more effective in achieving a good or moderate disease activity response at 24 weeks than was a second anti-TNF medication, according to a study appearing in the September 20 issue of JAMA.

Tumor necrosis factor α (TNF-α) inhibitors have improved the quality of life for patients with rheumatoid arthritis who show insufficient response to the agent methotrexate. However, as many as one-third of patients have persistent disease activity and insufficient response to anti-TNF agents, and there is little guidance on choosing the next treatment.

Jacques-Eric Gottenberg, M.D., Ph.D., of the Universite de Strasbourg, Strasbourg, France, and colleagues randomly assigned 300 patients with rheumatoid arthritis with persistent disease activity and an insufficient response to anti-TNF therapy to receive a non-TNF-targeted biologic agent or an anti-TNF that differed from their previous treatment. The choice of the biologic prescribed within each randomized group was left to the treating clinician.

Of the 300 randomized patients, 269 (90 percent) completed the study. At week 24, 101 of 146 patients (69 percent) in the non-TNF group and 76 (52 percent) in the second anti-TNF group achieved a good or moderate response. A measure of disease activity was lower in the non-TNF group than in the second anti-TNF group. At weeks 24 and 52, more patients in the non-TNF group vs the second anti-TNF group showed low disease activity (45 percent vs 28 percent at week 24; and 41 percent vs 23 percent at week 52).

“Among patients with rheumatoid arthritis previously treated with anti-TNF drugs but considered for a second medication due to inadequate primary response, a non-TNF biologic agent was more effective in achieving a good or moderate disease activity response at 24 weeks. However, a second anti-TNF drug to treat these patients was often effective in producing a clinical improvement,” the authors conclude.

(doi:10.1001/jama.2016.13512; the study is available pre-embargo to the media at the For the Media website)

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: 11 A.M. (ET) MONDAY, SEPTEMBER 19, 2016

Media Advisory:  For media inquiries, email press@cms.hhs.gov.

To place an electronic embedded link to this study in your story  This link will be live at the embargo time: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2016.12717

In a study published online by JAMA, Laura A. Dummit, M.S.P.H., of The Lewin Group, Falls Church, Va., and colleagues evaluated whether Bundled Payments for Care Improvement (BPCI) was associated with a greater reduction in Medicare payments without loss of quality of care for lower extremity joint (primarily hip and knee) replacement episodes initiated in BPCI-participating hospitals that are accountable for total episode payments (for the hospitalization and Medicare-covered services during the 90 days after discharge).

The Centers for Medicare & Medicaid Services (CMS) launched the BPCI initiative in 2013 to test whether linking payments for services provided during an episode of care can reduce Medicare payments, while maintaining or improving quality. Hospitals, physician group practices, postacute care providers such as skilled nursing facilities and home health agencies, and other entities were invited to participate in BPCI, which holds them accountable for Medicare payments for services provided during an episode of care triggered by a hospitalization. As with other alternative payment models, BPCI is designed to reward clinicians and facilities that deliver care more efficiently and effectively.

For this study, the researchers estimated the change in outcomes for Medicare fee-for-service beneficiaries who had a lower extremity joint replacement at a BPCI-participating hospital between the baseline (October 2011 through September 2012) and intervention (October 2013 through June 2015) periods and beneficiaries with the same surgical procedure at matched comparison hospitals.

There were 29,441 lower extremity joint replacement episodes in the baseline period and 31,700 in the intervention period at 176 BPCI-participating hospitals, compared with 29,440 episodes in the baseline period (768 hospitals) and 31,696 episodes in the intervention period (841 hospitals) at matched comparison hospitals. The authors found that average Medicare payments for a lower extremity joint replacement hospitalization and the 90-day postdischarge period declined $1,166 more for Medicare beneficiaries with episodes initiated in a BPCI-participating hospital than for beneficiaries in a comparison hospital. The lower Medicare payments were primarily due to reduced use of institutional postacute care. Claims-based quality measures, including unplanned readmissions, emergency department visits, and mortality, were not statistically different between the BPCI and comparison populations.

“This analysis of lower extremity joint replacement episodes, which account for more than 450,000 Medicare hospitalizations per year, significantly extends the evidence on the use of payment incentives to reduce spending for episodes of care, while maintaining or improving quality,” the researchers write.

“Further studies are needed to assess longer-term follow-up as well as patterns for other types of clinical care.”

(doi:10.1001/jama.2016.12717; the study is available pre-embargo to the media at the For the Media website)

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: 11 A.M. (ET) TUESDAY, SEPTEMBER 13, 2016

Media Advisory: To contact Vivian S. Lee, M.D., Ph.D., M.B.A., email Julie Kiefer at julie.kiefer@hsc.utah.edu. To contact editorial co-author Thomas H. Lee, M.D., M.Sc., email Jon Siegal at PressGaney@mslgroup.com.

To place an electronic embedded link to this study and editorial in your story  These links will be live at the embargo time: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2016.12226  https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2016.11698

Implementing an analytic tool that allocates clinical care costs and quality measures to individual patient encounters was associated with significant improvements in value of care for 3 designated outcomes—total joint replacement, laboratory testing among medical inpatients, and sepsis management, according to a study appearing in the September 13 issue of JAMA.

Fee-for-service payment models reward care volume over value. Under fee-for-service models, health care costs are increasing at a rate of 5.3 percent annually, accounted for 17.7 percent of the U.S. gross domestic product in 2014, and are projected to increase to 19.6 percent of the gross domestic product by 2024. Value-based payment models and alternative payment models incentivize the provision of efficient, high-quality, patient-centered care through financial penalties and rewards. Under alternative payment models, clinicians will theoretically deliver higher-quality care that results in better outcomes, fewer complications, and reduced health care spending. To implement alternative payment models effectively, physicians must understand actual care costs (not charges) and outcomes achieved for individual patients with defined clinical conditions—the level at which they can most directly influence change.

Vivian S. Lee, M.D., Ph.D., M.B.A., of the University of Utah, Salt Lake City, and colleagues measured quality and outcomes relative to cost from 2012 to 2016 at University of Utah Health Care. Clinical improvement projects included total hip and knee joint replacement, hospitalist (physicians who practice in the inpatient setting) laboratory utilization, and management of sepsis. Physicians were given access to a tool with information about outcomes, costs (not charges), and variation and partnered with process improvement experts.

From July 1, 2014 to June 30, 2015, there were 1.7 million total patient visits, including 34,000 inpatient discharges. For total joint replacement, a composite quality index was 54 percent at baseline (n = 233 encounters) and 80 percent 1 year into the implementation (n = 188 encounters). Compared with the baseline year, average direct costs were 7 percent lower in the implementation year and 11 percent lower in the post-implementation year.

The initiative to reduce hospitalist laboratory testing was associated with 11 percent lower costs, with no significant change in length of stay and a lower 30-day readmission rate. A sepsis intervention was associated with reduced average times to anti-infective administration following fulfillment of systemic inflammatory response syndrome criteria in patients with infection (7.8 hours to 3.6 hours).

“Implementation of a multifaceted value-driven outcomes tool to identify high variability in costs and outcomes in a large single health care system was associated with reduced costs and improved quality for 3 selected clinical projects. There may be benefit for individual physicians to understand actual care costs (not charges) and outcomes achieved for individual patients with defined clinical conditions,” the authors write.

(doi:10.1001/jama.2016.12226; the study is available pre-embargo to the media at the For the Media website)

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

Editorial: From Volume to Value in Health Care

Michael E. Porter, Ph.D., of Harvard Business School, Boston, and Thomas H. Lee, M.D., M.Sc., of Press Ganey, Wakefield, Mass., comment on the findings of this study in an accompanying editorial.

“The study by Lee and colleagues in this issue of JAMA is an impressive and important step forward, not just for the University of Utah Health Care system but for the rest of U.S. health care and other health care systems around the world that are focused on value. The findings offer proof of concept that improving value by patient condition can lead to lower costs and better quality—at the same time. There is much to be done and the road is long, but the report by Lee and colleagues points out how the path begins.”

(doi:10.1001/jama.2016.11698; the editorial is available pre-embargo to the media at the For the Media website)

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

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EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, SEPTEMBER 13, 2016

Media Advisory: To contact Gillian D. Sanders, Ph.D., call Ellen de Graffenreid at 919-660-1922 or email ellen.degraffenreid@duke.edu. To contact editorial author Mark S. Roberts, M.D., M.P.P., email Allison Hydzik at hydzikam@upmc.edu.

To place an electronic embedded link to this study and editorial in your story  These links will be live at the embargo time: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2016.12195  https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2016.12844

The Second Panel on Cost-Effectiveness in Health and Medicine reviewed the current status of the field of cost-effectiveness analysis and developed a new set of recommendations, with major changes including the recommendation to perform analyses from 2 reference case perspectives and to provide an impact inventory to clarify included consequences, according to an article appearing in the September 13 issue of JAMA.

In 1993, the U.S. Public Health Service convened a panel of 13 nongovernment scientists and scholars with expertise in economics, clinical medicine, ethics, and statistics to review the state of cost-effectiveness analysis and to develop recommendations for its conduct and use in health and medicine. The primary goals were to improve the quality of cost-effectiveness analyses and promote comparability across studies. In 1996, the original Panel on Cost-Effectiveness in Health and Medicine published its findings in a series of articles in JAMA and in a book. The panel emphasized that the growing field of cost-effectiveness analysis provided an opportunity to rationalize health policy if the technique and its application were well understood and implemented. Since publication of the report, researchers have advanced the methods of cost-effectiveness analysis, and policy makers have experimented with its application. The need to deliver health care efficiently and the importance of using analytic techniques to understand the clinical and economic consequences of strategies to improve health have increased in recent years.

Gillian D. Sanders, Ph.D., of the Duke Clinical Research Institute, Durham, N.C., Peter J. Neumann, Sc.D., of the Center for the Evaluation of Value and Risk in Health, Tufts Medical Center, Boston, and colleagues representing the Second Panel on Cost-Effectiveness in Health and Medicine, reviewed the state of the field and provided recommendations to improve the quality of cost-effectiveness analyses. The panel developed recommendations by consensus. These recommendations were then reviewed by invited external reviewers and through a public posting process.

Among the Key Recommendations:

— The concept of a “reference case” and a set of standard methodological practices that all cost-effectiveness analyses should follow to improve quality and comparability;

— All cost-effectiveness analyses should report two reference case analyses: one based on a health care sector perspective and another based on a societal perspective;

— Use of an “impact inventory,” which is a structured table that contains consequences (both inside and outside the formal health care sector), intended to clarify the scope and boundaries of the two reference case analyses.

“The goal of the Second Panel was to promote the continued evolution of cost-effectiveness analysis and its use to support judicious, efficient, and fair decisions regarding the use of health care resources,” the authors write.

“Cost-effectiveness analysis can help inform decisions about how to apply new or existing tests, therapies, and preventive and public health interventions so that they represent a judicious use of resources. It also can help to fill gaps in the evidence about the estimated population-level public health effect of such interventions, and can support decisions to disinvest in older interventions for which there are more cost-effective alternatives. Cost-effectiveness analysis provides a framework for comparing the relative value of different interventions, along with information that can help decision makers sort through alternatives and decide which ones best serve their programmatic and financial needs.”

(doi:10.1001/jama.2016.12195; the study is available pre-embargo to the media at the For the Media website)

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

Editorial: The Next Chapter in Cost-effectiveness Analysis

“This chapter in the development of a solid methodological foundation for the use of cost-effectiveness analysis [CEA] is an informative, rigorous, and welcome addition. The Second Panel has updated the specific recommendations to incorporate a significant amount of important advances that have resolved many methodological questions posed by the first panel,” writes Mark S. Roberts, M.D., M.P.P., of the University of Pittsburgh Graduate School of Public Health, in an accompanying editorial.

“Although this work represents an important step along the way to enhancing the applicability and acceptance of CEA as a tool that can inform policy decisions, it is not sufficient. Hopefully the next chapter will include expanded use of CEA as 1 of many inputs for decisions about health care resources. An important task toward that goal will be the education of decision makers, including politicians, that the amount of resources to spend on health care is not unlimited, and that CEA can be an important tool in making resource allocation decisions more transparent and explicit, rather than hidden and ad hoc.”

(doi:10.1001/jama.2016.12844; the editorial is available pre-embargo to the media at the For the Media website)

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: 11 A.M. (ET) TUESDAY, SEPTEMBER 13, 2016

Media Advisory: To contact Jouke T. Annema, M.D., Ph.D., email j.t.annema@amc.uva.nl

To place an electronic embedded link to this study in your story  This link will be live at the embargo time: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2016.10349

In a study appearing in the September 13 issue of JAMA, Jouke T. Annema, M.D., Ph.D., of the Academic Medical Center, Amsterdam, and colleagues examined five-year survival after endosonography vs mediastinoscopy for mediastinal nodal staging of lung cancer.

Accurate mediastinal nodal staging is crucial in the management of non-small cell lung cancer (NSCLC) because it directs therapy and has prognostic value. The Assessment of Surgical Staging vs Endosonographic Ultrasound in Lung Cancer (ASTER) trial compared mediastinoscopy (surgical staging) with an endosonographic staging strategy (which combined the use of endobronchial and transesophageal ultrasound followed by mediastinoscopy if negative). The endosonographic strategy was significantly more sensitive for diagnosing mediastinal nodal metastases than surgical staging (94 percent endosonographic strategy vs 79 percent surgical strategy). If mediastinal staging is improved, more patients should receive optimal treatment and might survive longer.

This analysis evaluated survival in ASTER. Of 241 patients with potentially resectable NSCLC, 123 were randomized to endosonographic staging and 118 to surgical staging in 4 tertiary referral centers. Survival data were obtained through patient records, death registers, or contact with general practitioners. Survival data at 5 years were obtained for 237 of 241 patients. The prevalence of mediastinal nodal metastases was 54 percent in the endosonographic strategy group and 44 percent in the surgical strategy group. Survival at 5 years was 35 percent for the endosonographic strategy vs 35 percent for the surgical strategy. The estimated median survival was 31 months for the endosonographic strategy vs 33 months for the surgical strategy.

“Why did improved mediastinal staging not lead to improved survival? Missing data occurred in less than 2 percent and therefore are an unlikely source of bias. However, ASTER was powered to detect a difference in diagnostic sensitivity, not survival, as reflected by the wide confidence intervals. If a survival difference between the strategies exists, it is likely to be small and a larger sample size may be needed to detect it. However, randomized trials to detect a survival difference based on staging strategy are not likely to be conducted as the endosonographic strategy is now advised in clinical guidelines,” the authors write.

(doi:10.1001/jama.2016.10349; the study is available pre-embargo to the media at the For the Media website)

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: 11 A.M. (ET) TUESDAY, SEPTEMBER 13, 2016

Media Advisory: To contact Josep Rodes-Cabau, M.D., call Jean-François Huppé at 418-656-7785 or email Jean-Francois.Huppe@dc.ulaval.ca.

To place an electronic embedded link to this study in your story  This link will be live at the embargo time: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2016.12347

Among patients undergoing transcatheter aortic valve replacement, younger age, male sex, history of diabetes mellitus, and moderate to severe residual aortic regurgitation were significantly associated with an increased risk of infective endocarditis, and patients who developed endocarditis had high rates of in-hospital mortality and 2-year mortality, according to a study appearing in the September 13 issue of JAMA.

Infective endocarditis (an infection caused by bacteria that enter the bloodstream and settle in the heart valve or heart lining) following surgical valve replacement occurs in 1 percent to 6 percent of patients and is associated with a high risk of illness and death. Transcatheter aortic valve replacement (TAVR) has emerged as a therapeutic option for patients with aortic stenosis (narrowing) who are considered to be at high or prohibitive surgical risk. Limited data exist on clinical characteristics and outcomes of patients who had infective endocarditis after undergoing TAVR.

Josep Rodes-Cabau, M.D., of Quebec Heart and Lung Institute, Laval University, Quebec City, Quebec, Canada and colleagues analyzed data from the Infectious Endocarditis after TAVR International Registry, which included patients with definite infective endocarditis after TAVR from 47 centers from Europe, North America, and South America between June 2005 and October 2015. A total of 250 cases of infective endocarditis occurred in 20,006 patients after TAVR (incidence, 1.1 percent per person-year; median age, 80 years; 64 percent men). Median time from TAVR to infective endocarditis was 5.3 months.

The characteristics associated with higher risk of progressing to infective endocarditis after TAVR was younger age (78.9 years vs 81.8 years), male sex (62 percent vs 50 percent), diabetes mellitus (42 percent vs 30 percent), and moderate to severe aortic regurgitation (22 percent vs 15 percent). Health care-associated infective endocarditis was present in 53 percent of patients. Enterococci species and Staphylococcus aureus were the most frequently isolated microorganisms (25 percent and 23 percent, respectively). The in-hospital mortality rate was 36 percent, and surgery was performed in 15 percent of patients during the infective endocarditis episode. In-hospital mortality was associated with heart failure and acute kidney injury. The 2-year mortality rate was 67 percent.

“The rate of infective endocarditis after TAVR observed in the present study is similar to that reported for surgical prosthetic valve endocarditis, therefore, supports the lack of reduction in the rate of prosthetic valve infective endocarditis after TAVR despite less invasive nature of TAVR compared with surgical valve replacement. This study confirms the high rate of morbidity and mortality of infective endocarditis after TAVR and provides novel information about the timing, causative organisms, and predictive factors of infective endocarditis in this particular population. This information may help the clinicians identify patients at higher risk and aid in implementing appropriate preventive measures,” the authors write.

(doi:10.1001/jama.2016.12347; the study is available pre-embargo to the media at the For the Media website)

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: 11 A.M. (ET) TUESDAY, SEPTEMBER 6, 2016

Media Advisory: To contact Joel G. Ray, M.D., M.Sc., F.R.C.P.C., call Maria Feldman at 416-864-5047 or email feldmanm@smh.ca.

To place an electronic embedded link to this study and editorial in your story  These links will be live at the embargo time: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2016.12126

In an analysis that included more than 1.4 million births, exposure to magnetic resonance imaging (MRI) during the first trimester of pregnancy compared with nonexposure was not associated with increased risk of harm to the fetus or in early childhood, although gadolinium MRI at any time during pregnancy was associated with an increased risk of a broad set of rheumatological, inflammatory, or skin conditions and, possibly, for stillbirth or neonatal death, according to a study appearing in the September 6 issue of JAMA.

Concern has been expressed about the safety of MRI exposure in the first trimester of pregnancy due to the heating of sensitive tissues by radiofrequency fields and exposure to the loud acoustic environment. When indicated, MRI’s diagnostic accuracy is improved with gadolinium, an intravenous contrast medium. Fetal safety of MRI during the first trimester of pregnancy or with gadolinium enhancement at any time of pregnancy is unknown.

With the use of universal health care databases in the province of Ontario, Joel G. Ray, M.D., M.Sc., F.R.C.P.C., of St. Michael’s Hospital and the Institute for Clinical Evaluative Sciences, Toronto, and colleagues identified all births of more than 20 weeks from 2003-2015 to evaluate the long-term safety after exposure to MRI in the first trimester of pregnancy or to gadolinium at any time during pregnancy.

The study included 1,424,105 deliveries. In pregnancies that lasted a minimum of 21 gestational weeks, 1 in 250 had an MRI in pregnancy, including 1 in 1,200 in the first trimester and 1 in 3,000 with gadolinium contrast. Maternal MRI in the first trimester was not associated with a higher risk of stillbirth or neonatal death, congenital anomalies, neoplasm, or hearing loss.

Exposure to gadolinium-enhanced MRI at any gestation was not associated with a greater risk of congenital anomalies. Although a nephrogenic systemic fibrosis-like outcome was extremely rare, gadolinium-enhanced MRI was associated with an increased risk for a non-specific outcome of any rheumatological, inflammatory or infiltrative skin condition up to age 4 years, and for stillbirth or neonatal death, although there were just 7 events in the gadolinium MRI group.

“The current findings inform published recommendations about the safety of MRI in the first trimester of pregnancy,” the authors write. “Until further studies are done, these findings suggest that gadolinium contrast should be avoided during pregnancy.”

(doi:10.1001/jama.2016. 12126; the study is available pre-embargo to the media at the For the Media website)

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: 11 A.M. (ET) TUESDAY, SEPTEMBER 6, 2016

Media Advisory: To contact the U.S. Preventive Services Task Force, email the Media Coordinator at Newsroom@USPSTF.net or call 202-572-2044.

To place an electronic embedded link to this report in your story  This link will be live at the embargo time: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2016.11046

The U.S. Preventive Services Task Force (USPSTF) recommends screening for latent tuberculosis infection in populations at increased risk. People who are considered at increased risk include people who were born in or have lived in countries where tuberculosis is highly prevalent, or who have lived in group settings where exposure to tuberculosis is more likely, such as homeless shelters or correctional facilities. The report appears in the September 6 issue of JAMA.

This is a B recommendation, indicating that there is high certainty that the net benefit is moderate, or there is moderate certainty that the net benefit is moderate to substantial.

In the United States, tuberculosis remains an important preventable disease, including active tuberculosis infection, which may be infectious, and latent infection (LTBI), which is asymptomatic and not infectious but can later reactivate and progress to active disease. The precise prevalence rate of LTBI in the United States is difficult to determine; however, based on 2011-2012 National Health and Nutrition Examination Survey data, estimated prevalence is 4.7 percent to 5.0 percent. An effective strategy for reducing the transmission, illness and death of active disease is the identification and treatment of LTBI to prevent progression to active disease. To issue a current recommendation on screening for LTBI, the USPSTF reviewed the evidence on screening for LTBI in asymptomatic adults seen in primary care, including evidence dating from the inception of searched databases.

The USPSTF is an independent, volunteer panel of experts that makes recommendations about the effectiveness of specific preventive care services such as screenings, counseling services, and preventive medications.

Detection

The USPSTF found adequate evidence that accurate screening tests are available to detect LTBI. Screening tests include the Mantoux tuberculin skin test (TST) and interferon-gamma release assays (IGRAs); both are moderately sensitive and highly specific.

Benefits of Early Detection and Treatment

The USPSTF found no studies that evaluated the direct benefits of screening for LTBI. The USPSTF found adequate evidence that treatment of LTBI with regimens recommended by the Centers for Disease Control and Prevention (CDC) decreases progression to active tuberculosis; the magnitude of this benefit is moderate.

Harms of Early Detection and Treatment

The USPSTF found no direct evidence on the harms of screening for LTBI. The USPSTF found adequate evidence that the magnitude of harms of treatment of LTBI with CDC-recommended regimens is small. The primary harm of treatment is hepatotoxicity.

Summary

The USPSTF found adequate evidence that accurate screening tests for LTBI are available, treatment of LTBI provides a moderate health benefit in preventing progression to active disease, and the harms of screening and treatment are small. The USPSTF has moderate certainty that screening for LTBI in persons at increased risk for infection provides a moderate net benefit.

(doi:10.1001/jama.2016.11046; the full report is available pre-embargo to the media at the For the Media website)

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

Note: More information about the U.S. Preventive Services Task Force, its process, and its recommendations can be found on the newsroom page of its website.

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EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, SEPTEMBER 6, 2016

Media Advisory: To contact Craig G. Crandall, Ph.D., call Cathy Frisinger at 214-648-7228 or email Cathy.Frisinger@UTSouthwestern.edu.

To place an electronic embedded link to this study in your story  This link will be live at the embargo time: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2016.10550

In a study appearing in the September 6 issue of JAMA, Craig G. Crandall, Ph.D., of the University of Texas Southwestern Medical Center, Dallas, and colleagues examined whether electric fan use would delay elevations in heart rate and core temperature of elderly adults exposed to extreme heat and humidity.

Research has indicated that electric fan use delays elevations in heart rate and core temperature of young adults exposed to 108°F. However, it remains unknown if fans are effective in vulnerable populations, such as the elderly who display altered cardiovascular and thermoregulatory responses during heat exposure. This study included 3 men and 6 women volunteers (average age, 68 years). Wearing shorts (men) or shorts and a sports bra (women), participants sat in a chamber maintained at 108°F. After 30 minutes at a relative humidity of 30 percent, relative humidity was increased 2 percent every 5 minutes to 70 percent (100 minutes total). On separate randomly assigned days, participants performed the protocol with or without a 16-in fan facing them from about 3 feet. No fluid intake was allowed during the protocol. Measurements taken included heart rate, core temperature and sweat loss.

The researchers found that fan use resulted in greater heart rate and core temperature. “Although differences were small, their cumulative effect may become clinically important with fan use during more prolonged heat exposure. Fan use elevates sweat loss in young adults. This was not observed in elderly adults, suggesting that age-related impairments in sweating capacity possibly limit the effectiveness of electric fans. Overall, this preliminary study indicates that electric fans may be detrimental for attenuating cardiovascular and thermal strain of elderly adults during heat waves.”

(doi:10.1001/jama.2016.10550; the study is available pre-embargo to the media at the For the Media website)

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: 11 A.M. (ET) TUESDAY, SEPTEMBER 6, 2016

Media Advisory: To contact Sophie Dupuis-Girod, M.D., Ph.D., email sophie.dupuis-girod@chu-lyon.fr. To contact Kevin J. Whitehead, M.D., email Julie Kiefer at julie.kiefer@hsc.utah.edu.

To place an electronic embedded link to these studies in your story  These links will be live at the embargo time: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2016.11387  https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2016.11724

Two studies appearing in the September 6 issue of JAMA examine the effectiveness of nasal sprays to reduce the frequency and duration of nosebleeds caused by hereditary hemorrhagic telangiectasia (HHT), an inherited condition characterized by abnormal blood vessels which are delicate and prone to bleeding.

Epistaxis (nosebleed) are the most frequent and disabling manifestation of HHT. These epistaxis episodes can be severe and life threatening. There is currently no medical or surgical treatment available to cure the nosebleeds definitively. Sophie Dupuis-Girod, M.D., Ph.D., of the Hopital Femme-Mere-Enfants, Bron, France and colleagues evaluated the efficacy of 3 different doses of the drug bevacizumab administered as a nasal spray. Bevacizumab is a monoclonal antibody that slows the growth of new bloods vessels. In this phase 2/3 clinical trial, 80 patients with HHT and a history of nosebleeds were randomly assigned to received placebo or one of three doses of bevacizumab nasal spray (3 doses 14 days apart for a total treatment duration of 4 weeks).

The researchers found that average monthly epistaxis duration measured at 3 months was not significantly different in the patients receiving bevacizumab in comparison with the placebo group or between the bevacizumab groups. Toxicity was low and no severe adverse events were reported. Treatment with bevacizumab had no measurable effect on secondary outcomes including number of epistaxis episodes, quality of life, number of red blood cell transfusions, or hemoglobin and ferritin levels.

The study was terminated prior to phase 3 for treatment futility after interim analysis on the recommendations of an independent data monitoring committee.

(doi:10.1001/jama.2016.11387; the study is available pre-embargo to the media at the For the Media website)

Editor’s Note: This work was financed by the Hospices Civils de Lyon grant supported by the National Research Program and by the patients’ association (Association Pour la Maladie de Rendu-Osler). All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were re­ported.

In another study, Kevin J. Whitehead, M.D., of the University of Utah, Salt Lake City, and colleagues examined whether therapy with any of 3 drugs would be effective in reducing HHT-related epistaxis.

Based on published data and anecdotal experience, 3 agents with theoretically differing mechanisms of action were selected: bevacizumab, estriol, or tranexamic acid. The study included 121 patients with HHT who had experienced HHT-related epistaxis. Patients were randomly assigned to receive twice-daily nose sprays for 12 weeks with either of the agents or placebo.

The researchers found that drug therapy did not significantly reduce epistaxis frequency. After 12 weeks of treatment, the median weekly number of bleeding episodes was 7 for patients in the bevacizumab group, 8 for the estriol group, 7.5 for the tranexamic acid group, and 8 for the placebo group. No drug treatment was significantly different from placebo for epistaxis duration. There were no significant differences between groups for hemoglobin level, ferritin level, treatment failure, need for transfusion, or emergency department visits.

No serious adverse effects were seen in the study.

(doi:10.1001/jama.2016.11724; the study is available pre-embargo to the media at the For the Media website)

Editor’s Note: The North American Study of Epistaxis in HHT trial was funded by Cure HHT, a nonprofit patient organization supporting the HHT community. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, etc.

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EMBARGOED FOR RELEASE: 2:30 A.M. (ET) TUESDAY, AUGUST 30, 2016

Media Advisory: To contact Marlous Hall, Ph.D., email m.s.hall@leeds.ac.uk.

To place an electronic embedded link to this study in your story  This link will be live at the embargo time: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2016.10766

Among nearly 400,000 patients hospitalized with a certain type of heart attack in England and Wales between 2003 and 2013, improvement in survival was significantly associated with use of an invasive coronary strategy (such as coronary angiography) and not entirely related to a decline in baseline clinical risk or increased use of pharmacological therapies, according to a study published online by JAMA. The study is being released to coincide with its presentation at the European Society of Cardiology Congress 2016.

There has been a global decline in the rates of death following acute coronary syndrome (conditions such as heart attack or unstable angina); however, the extent to which this is due to use of guideline-indicated treatments for management of non-ST-elevation myocardial infarction (NSTEMI; a type of heart attack with certain findings on an electrocardiogram) is not known. Marlous Hall, Ph.D., of the University of Leeds, Leeds, England, and colleagues analyzed data on 389,057 patients with NSTEMI in 247 hospitals in England and Wales. Among these patients, there were 113,586 deaths (29 percent). From 2003-2004 to 2012-2013, proportions with intermediate to high clinical risk (patient factors such as cardiac arrest, elevated enzyme levels, systolic blood pressure, heart rate) decreased (87 percent vs 82 percent); proportions with lowest risk increased (4.2 percent vs 7.6 percent). The prevalence of diabetes, hypertension, cerebrovascular disease, chronic obstructive pulmonary disease, chronic renal failure, previous invasive coronary strategy, and current or ex-smoking status increased. Unadjusted all-cause mortality rates at 180 days decreased from 10.8 percent to 7.6 percent.

Analysis indicated that improvements in survival were associated with use of an invasive coronary strategy (defined as coronary angiography, percutaneous coronary intervention [procedure such as stent placement], coronary artery bypass graft surgery), which was associated with a relative decrease in mortality of 46 percent. A reduction in baseline acute coronary syndrome risk, increase in comorbidities, and use of guideline-indicated pharmacological therapies did not fully explain improvement in survival.

The authors note that these findings should not be interpreted to indicate that medical therapies have no role in management of NSTEMI. In this study group, aspirin, P2Y₁₂ inhibitors, beta-blockers, angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, and statins each had a significant association with improved survival.

(doi:10.1001/jama.2016.10766; the study is available pre-embargo to the media at the For the Media website)

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

Note: Available pre-embargo at the For The Media website is an accompanying editorial, “Management of Non-ST-Elevation Myocardial Infarction,” by Erin A. Bohula, M.D., D.Phil., and Elliott M. Antman, M.D., of Brigham and Women’s Hospital, Harvard Medical School, Boston.

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For more information, contact JAMA Network Media Relations at 312-464-JAMA (5262) or email mediarelations@jamanetwork.org.

EMBARGOED FOR RELEASE: 3 A.M. (ET) MONDAY, AUGUST 29, 2016

Media Advisory: To contact John P. Greenwood, Ph.D., email j.greenwood@leeds.ac.uk.

To place an electronic embedded link to this study in your story  This link will be live at the embargo time: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2016.12680

In a study published online by JAMA, John P. Greenwood, Ph.D., of the University of Leeds, Leeds, United Kingdom, and colleagues examined whether among patients with suspected coronary heart disease (CHD), cardiovascular magnetic resonance (CMR)-guided care is superior to National Institute for Health and Care Excellence (NICE) guidelines-directed care and myocardial perfusion scintigraphy (MPS)-guided care in reducing unnecessary angiography. The study is being released to coincide with its presentation at the European Society of Cardiology Congress 2016.

Coronary heart disease is a leading cause of death and disability worldwide. Several methods are available to diagnose CHD, risk-stratify patients, and determine the need for revascularization. Despite the widespread availability and recommendations for noninvasive imaging in international guidelines, invasive coronary angiography is commonly used in patients with suspected CHD. Evidence from large populations presenting with chest pain has confirmed that the majority will not have significant obstructive coronary disease. Avoiding unnecessary angiography should reduce patient risk and provide significant financial savings.

In this study, 1,202 symptomatic patients from 6 UK hospitals with suspected CHD were randomly assigned to management according to UK NICE guidelines (n = 240) or to guided care based on the results of CMR (n = 481) or MPS (n = 481) testing. Among the patients, the number with invasive coronary angiography after 12 months was 102 in the NICE guidelines group (43 percent), 85 in the CMR group (18 percent); and 78 in the MPS group (16 percent). The researchers found that a CMR-guided strategy significantly reduced study-defined unnecessary angiography compared with NICE guidelines-guided care, but was not significantly different from an MPS-guided strategy.

Between the 3 strategies, there was no difference in major adverse cardiovascular event rates at 12 months or disease detection (positive angiography) rates.

(doi:10.1001/jama.2016.12680; the study is available pre-embargo to the media at the For the Media website)

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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For more information, contact JAMA Network Media Relations at 312-464-JAMA (5262) or email mediarelations@jamanetwork.org.

EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, AUGUST 23, 2016

Media Advisory: To contact Aaron S. Kesselheim, M.D., J.D., M.P.H., call Elaine St. Peter at 617-525-6375 or email estpeter@partners.org.

To place an electronic embedded link to this study and editorial in your story  These links will be live at the embargo time: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2016.11237

High prescription drug prices are attributable to several causes, including the approach the U.S. has taken to granting government-protected monopolies to drug manufacturers, and the restriction of price negotiation at a level not observed in other industrialized nations, according to a study appearing in the August 23/30 issue of JAMA.

The increasing cost of prescription drugs in the United States has become a source of growing concern for patients, prescribers, payers, and policy makers. Aaron S. Kesselheim, M.D., J.D., M.P.H., of Brigham and Women’s Hospital and Harvard Medical School, Boston, and colleagues reviewed the peer-reviewed medical and health policy literature from January 2005 to July 2016 for articles addressing the sources of drug prices in the United States, the justifications and consequences of high prices, and possible solutions.

The authors write that per capita prescription drug spending in the United States exceeds that in all other countries, largely driven by brand-name drug prices that have been increasing in recent years at rates far beyond the consumer price index. In 2013, per capita spending on prescription drugs was $858 compared with an average of $400 for 19 other industrialized nations. In the United States, prescription medications now comprise an estimated 17 percent of overall personal health care services.

Drug prices are higher in the United States than in the rest of the industrialized world because, unlike that in nearly every other advanced nation, the U.S. health care system allows manufacturers to set their own price for a given product. In contrast, in countries with national health insurance systems, a delegated body negotiates drug prices or rejects coverage of products if the price demanded by the manufacturer is excessive in light of the benefit provided; manufacturers may then decide to offer the drug at a lower price.

The most important factor that allows manufacturers to set high drug prices is market exclusivity, protected by monopoly rights awarded upon Food and Drug Administration approval and by patents. The availability of generic drugs after this exclusivity period is the main means of reducing prices in the United States, but access to them may be delayed by numerous business and legal strategies. The primary counterweight against excessive pricing during market exclusivity is the negotiating power of the payer, which is currently constrained by several factors, including the requirement that most government drug payment plans cover nearly all products. Another key contributor to drug spending is physician prescribing choices when comparable alternatives are available at different costs. Although prices are often justified by the high cost of drug development, there is no evidence of an association between research and development costs and prices; rather, prescription drugs are priced in the United States primarily on the basis of what the market will bear.

The researchers write that the most realistic short-term strategies to address high prices include enforcing more stringent requirements for the award and extension of exclusivity rights; enhancing competition by ensuring timely generic drug availability; providing greater opportunities for meaningful price negotiation by governmental payers; generating more evidence about comparative cost-effectiveness of therapeutic alternatives; and more effectively educating patients, prescribers, payers, and policy makers about these choices.

“There is little evidence that such policies would hamper innovation, and they could even drive the development of more valuable new therapies rather than rewarding the persistence of older ones. Medications are the most common health care intervention and can have a major benefit on the health of individuals, as well as of populations, but unnecessarily high prices limit the ability of patients and health care systems to benefit fully from these vital products.”

(doi:10.1001/jama.2016.11237; the study is available pre-embargo to the media at the For the Media website)

Editor’s Note: This work was funded by a grant from the Laura and John Arnold Foundation. Additional support was provided by the Engelberg 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: 11 A.M. (ET) TUESDAY, AUGUST 23, 2016

Media Advisory: To contact Brenda Reiss-Brennan, Ph.D., A.P.R.N., email Daron Cowley at daron.cowley@imail.org. To contact editorial author Thomas L. Schwenk, M.D., call Anne McMillin at 775-682-9254 or email amcmillin@med.unr.edu.

To place an electronic embedded link to this study and editorial in your story  These links will be live at the embargo time: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2016.11232  https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2016.11031

Among adults enrolled in an integrated health care system, receipt of primary care at integrated team-based care practices compared with traditional practice management practices was associated with higher rates of some measures of quality of care, lower rates for some measures of acute care utilization, and lower actual payments received by the delivery system, according to a study appearing in the August 23/30 issue of JAMA.

Limited evidence is available to support the utility of medical home and accountable care integration with mental health and primary care teams. Brenda Reiss-Brennan, Ph.D., A.P.R.N., of Intermountain Healthcare, Salt Lake City, and colleagues assessed the association of integrating physical and mental health over time in team-based care (TBC) practices with patient outcomes and costs. The study included adult patients who received primary care at 113 Intermountain Healthcare Medical Group primary care practices from 2003 through 2005 and had yearly encounters with Intermountain Healthcare through 2013, including some patients who received care in both TBC and traditional practice management (TPM) practices.

Of the 113 practices observed over the study period (2010- 2013), 102 practices were classified annually as TBC (n = 27) or TPM (n = 75). The analysis included 113,452 patients (average age, 56 years; women, 59 percent). The researchers found that patients treated in TBC practices compared with those treated in TPM practices had higher rates of active depression screening (46 percent for TBC vs 24 percent for TPM), adherence to a diabetes care bundle (25 percent for TBC vs 20 percent for TPM), and documentation of self-care plans (48 percent for TBC vs 8.7 percent for TPM), lower proportion of patients with controlled hypertension (85 percent for TBC vs 98 percent for TPM), and no significant differences in documentation of advanced directives (9.6 percent for TBC vs 9.9 percent for TPM).

Rates of health care utilization were lower for TBC patients compared with TPM patients for emergency department visits, hospital admissions, ambulatory care sensitive visits and admissions, and primary care physician encounters, with no significant difference in visits to urgent care facilities and visits to specialty care physicians.

Payments to the delivery system were lower in the TBC group vs the TPM group ($3,401 for TBC vs $3,516 for TPM) and were less than investment costs of the TBC program.

“The study suggests the value of coordinated team relationships within a delivery system emphasizing the integration of physical and mental health care,” the authors write.

(doi:10.1001/jama.2016.11232; the study is available pre-embargo to the media at the For the Media website)

Editor’s Note: This research was supported by Intermountain Healthcare’s Medical Group, Primary Care Clinical Program, Institute for Healthcare Leadership, Office of Research, and Office of Population Health. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, etc.

Editorial: Integrated Behavioral and Primary Care – What Is the Real Cost?

“This study has several important implications. Integrated TBC is clearly superior to TPM for patients with complex mental illness and chronic medical disease, consistent with the increasing recognition that this type of care is best applied to higher-risk patients with substantial disease burden,” writes Thomas L. Schwenk, M.D., of the University of Nevada, Reno, in an accompanying editorial.

“However, practicing in an integrated, value- and outcomes­ based model but continuing to be reimbursed in a traditional, volume-based system is costly. The investigators note that the investment cost of the program was lower than the reduction in reimbursement, but both are, in fact, a reduction in the bottom line for practices large and small, and therein lies the most important implication of this study.”

“The results of the study by Reiss-Brennan et al document the value of an integrated model of mental health and chronic disease care that likely can only be provided to patients who receive their care in large, integrated health systems. The most significant consequence, however unintended, of outcomes-based medical care and value-based reimbursement may be a profound change in the fundamental structure of the U.S. health care delivery system.”

(doi:10.1001/jama.2016.11031; the study is available pre-embargo to the media at the For the Media website)

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: 11 A.M. (ET) TUESDAY, AUGUST 23, 2016

Media Advisory: To contact Michael Levin, F.R.C.P.C.H., email m.levin@imperial.ac.uk. To contact Octavio Ramilo, M.D., call Gina Bericchia at 614-355-0495 or email MediaRelations@NationwideChildrens.org. To contact Howard Bauchner, M.D., email mediarelations@jamanetwork.org.

To place an electronic embedded link to these studies and editorial in your story  These links will be live at the embargo time: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2016.11236

https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2016.9207  https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2016.11137

Two studies appearing in the August 23/30 issue of JAMA examine the use of genetic tests to help rule out a serious bacterial infection in infants with fever, and also to determine if an infection is bacterial or viral in children with fever.

In one study, Michael Levin, F.R.C.P.C.H., of Imperial College London, and colleagues investigated whether bacterial infection can be distinguished from other causes of fever in children by the pattern of host genes activated or suppressed in blood in response to the infection and whether a subset of these genes could be identified as the basis for a diagnostic test.

The majority of febrile (with fever) children have self-resolving viral infection, but a small proportion have life-threatening bacterial infections. Because clinical features do not reliably distinguish bacterial from viral infection, many children worldwide receive unnecessary antibiotic treatment, while bacterial infection is missed in others. A number of studies have suggested that specific infections can be identified by the pattern of host genes activated during the inflammatory response.

This study included febrile children presenting to participating hospitals in the United Kingdom, Spain, the Netherlands, and the United States between 2009-2013, and placed in a discovery group or validation group. Each group was classified after microbiological investigation as having definite bacterial infection, definite viral infection, or indeterminate infection. RNA expression signatures (determined with a blood sample) distinguishing definite bacterial from viral infection were identified in the discovery group and diagnostic performance assessed in the validation group. Additional validation was undertaken in separate studies of children with meningococcal disease (n = 24) and inflammatory diseases (n = 48) and on published gene expression datasets.

The discovery group of 240 children (median age, 19 months) included 52 with definite bacterial infection, of whom 36 (69 percent) required intensive care, and 92 with definite viral infection, of whom 32 (35 percent) required intensive care. Ninety-six children had indeterminate infection. The researchers identified a host whole blood RNA transcriptomic signature that distinguished bacterial from viral infection with 2 gene transcripts. The signature also distinguished bacterial infection from childhood inflammatory diseases, systemic lupus erythematosus, juvenile idiopathic arthritis, and discriminated bacterial from viral infection in published adult studies. Of the children in the indeterminate groups, 46 percent were classified as having bacterial infection, although 95 percent received antibiotic treatment.

The authors write that a major challenge in using transcriptomic signatures for diagnosis is the translation of multitranscript signatures into clinical tests suitable for use in hospital laboratories or at the bedside. “The disease risk score signature, distinguishing viral from bacterial infections with only 2 transcripts, has potential to be translated into a clinically applicable test using current technology such as polymerase chain reaction. Furthermore, new methods for rapid detection of nucleic acids … have potential for low­ cost, rapid analysis of multitranscript signatures.”

“This study provides preliminary data regarding test accuracy of a 2-transcript host RNA signature discriminating bacterial from viral infection in febrile children. Further studies are needed in diverse groups of patients to assess accuracy and clinical utility of this test in different clinical settings.”

(doi:10.1001/jama.2016.11236; the study is available pre-embargo to the media at the For the Media website)

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, Octavio Ramilo, M.D., of Nationwide Children’s Hospital, Columbus, Ohio, and colleagues examined whether RNA biosignatures can distinguish febrile infants age 60 days or younger with and without serious bacterial infections.

Young febrile infants are at substantial risk of serious bacterial infections; however, the current culture-based diagnosis has limitations. The lack of an optimal management strategy has led to substantial variation in the care for this vulnerable population, unnecessarily exposing many infants to potential harm. A genomic approach based on analysis of the host response to infection has been investigated as an alternative. Microbial pathogens induce specific host responses or “RNA biosignatures” that can be identified using microarray analyses of blood leukocytes (white cells).

This study involved a sample of febrile infants 60 days or younger evaluated for fever in 22 emergency departments from December 2008 to December 2010 who underwent laboratory evaluations including blood cultures. A random sample of infants with and without bacterial infections was selected for RNA biosignature analysis. Afebrile healthy infants served as controls. Blood samples were collected for cultures and RNA biosignatures. Bioinformatics tools were applied to define RNA biosignatures to classify febrile infants by infection type.

Of 1,883 febrile infants (median age, 37 days), RNA biosignatures were measured in 279 randomly selected infants (89 with bacterial infections—including 32 with bacteremia and 15 with urinary tract infections—and 190 without bacterial infections), and 19 afebrile healthy infants. Sixty-six classifier genes were identified that distinguished infants with and without bacterial infections in the test set. Ten classifier genes distinguished infants with bacteremia from those without bacterial infections in the test set.

“In this preliminary study, RNA biosignatures were defined to distinguish febrile infants aged 60 days or younger with vs without bacterial infections. Further research with larger populations is needed to refine and validate the estimates of test accuracy and to assess the clinical utility of RNA biosignatures in practice,” the authors write.

“As technology advances, RNA biosignatures may prove to be an alternative and accurate method to identify infants with bacterial infections. This would help clinicians target evaluation and therapy when they are needed and avoid invasive procedures, antibiotics, and hospitalizations when they are not.”

(doi:10.1001/jama.2016.9207; the study is available pre-embargo to the media at the For the Media website)

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

Editorial: Genetics and the Evaluation of the Febrile Child

“The results of these 2 preliminary studies represent promissory notes. Clearly, RNA sequencing and other techniques for RNA quantitation are in the early days of development and evaluation for clinical applications,” writes Howard Bauchner, M.D., Editor in Chief, JAMA, Chicago, in an accompanying editorial.

“The substantial decline in the prevalence of serious bacterial infection, following the introduction of conjugate vaccines, has made clinical decision making more difficult—the needle has become much smaller, and the haystack much larger, particularly in young infants. However, if the promises of findings reported in the studies by Mahajan and colleagues and Herberg and colleagues are fulfilled by replication and refinement in other rigorous investigations, it may be possible that such advances will further reduce morbidity, mortality, and costs associated with caring for febrile children. The day when a parent of a febrile child may do a laboratory test at home, call a physician, and mutually decide if that child should be seen for evaluation may soon be here.”

(doi:10.1001/jama.2016.11137; the editorial is available pre-embargo to the media at the For the Media website)

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: 11 A.M. (ET) TUESDAY, AUGUST 23, 2016

Media Advisory: To contact Jason D. Wright, M.D., email Karin Eskenazi at ket2116@cumc.columbia.edu.

To place an electronic embedded link to this study in your story  This link will be live at the embargo time: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2016.9432

In a study appearing in the August 23/30 issue of JAMA, Jason D. Wright, M.D., of the Columbia University College of Physicians and Surgeons, New York, and colleagues examined trends in the route of hysterectomy (abdominal, minimally invasive, or vaginal), use of electric power morcellators (a procedure in which the uterus is fragmented into smaller pieces, and may result in the spread of undetected malignancies), and prevalence of abnormal pathology before and after a Food and Drug Administration (FDA) warning.

Concern about the safety of electric power morcellation for gynecologic surgery led the FDA to issue a safety communication in April 2014 discouraging use of the devices and, in November 2014, to recommend against use of morcellation in perimenopausal and postmenopausal women. Concern has been raised that these actions may result in performance of a greater number of hysterectomies via laparotomy (surgical incision into the abdominal wall), with an increased risk of complications.

The study included women age 18 to 95 years who underwent hysterectomy from 2013 to the first quarter of 2015 recorded in the Perspective database, which includes more than 500 hospitals across the United States and approximately 15 percent of hospitalized patients. Outcomes were compared before and after the FDA’s alert in April 2014.

The researchers identified 203,520 women, including 117,653 women (58 percent) who underwent minimally invasive hysterectomy. Among women who underwent minimally invasive hysterectomy, power morcellation was used in 13.5 percent in Q1 2013, peaked at 13.7 percent by Q4 2013, and declined to 2.8 percent by Q1 2015. The overall complication rate was unchanged over time. Complications declined for abdominal hysterectomy, attributable to a decline in intraoperative complications, but were stable for minimally invasive hysterectomy and vaginal hysterectomy. The prevalence of uterine cancer, endometrial hyperplasia, other gynecologic cancers, and uterine tumors of indeterminate behavior in women who underwent morcellation were unchanged.

“The FDA warnings might result in a lower prevalence of cancer among women who underwent morcellation due to greater scrutiny on patient selection. However, the high rate of abnormal pathology after the warnings highlights the difficulty in the preoperative detection of uterine pathology. Continued caution is needed to limit the inadvertent morcellation of uterine pathology,” the authors write.

(doi:10.1001/jama.2016.9432; the study is available pre-embargo to the media at the For the Media website)

Editor’s Note: This article was funded by grants from the National Cancer Institute. 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: 11 A.M. (ET) TUESDAY, AUGUST 16, 2016

Media Advisory: To contact Paul D. Miller, M.D., call 303-925-4514 or email millerccbr@aol.com. To contact editorial co-author Anne R. Cappola, M.D., Sc.M., email Abbey Anderson at Abbey.Anderson@uphs.upenn.edu.

To place an electronic embedded link to this study and editorial in your story  These links will be live at the embargo time: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2016.11136  https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2016.11032

Among postmenopausal women with osteoporosis at risk of fracture, daily injection of the drug abaloparatide for 18 months significantly reduced the risk of new vertebral and nonvertebral fractures compared with placebo, according to a study appearing in the August 16 issue of JAMA.

Osteoporosis is associated with substantial social, economic, and public health burdens. Based on 2010 U.S. Census data, a study estimated the prevalence of osteoporosis among women 50 to 69 years of age at 3.4 million. It has been estimated that the lifetime risk of osteoporotic fracture for a 60-year-old woman is 44 percent. Additional therapies are needed for prevention of osteoporotic fractures. As a result of its mechanism of action, it has been hypothesized that the drug abaloparatide, a synthetic peptide, would have a more pronounced anabolic (i.e., bone growing) action on bone compared with the osteoporosis drug teriparatide.

Paul D. Miller, M.D., of the Colorado Center for Bone Research, Lakewood, Colo., and colleagues randomly assigned postmenopausal women with osteoporosis to receive daily injections for 18 months of placebo (n = 821); abaloparatide (n = 824); or teriparatide (n = 818). The trial was conducted at 28 sites in 10 countries.

Among 2,463 women (average age, 69 years), 1,901 completed the study. New vertebral fractures occurred less frequently in the active treatment groups vs placebo: in 0.58 percent (n = 4) of participants in the abaloparatide group; in 0.84 percent (n = 6) of participants in the teriparatide group; and in 4.22 percent (n = 30) of those in the placebo group. The estimated event rate for nonvertebral fracture was lower with abaloparatide vs placebo: 2.7 percent in the abaloparatide group; 3.3 percent in the teriparatide group; and 4.7 percent in the placebo group.

Bone mineral density (BMD) increases were greater with abaloparatide than placebo. Incidence of hypercalcemia (the presence of abnormally high levels of calcium in the blood) was lower with abaloparatide (3.4 percent) vs teriparatide (6.4 percent). Overall, there were no differences in serious adverse events between the treatment groups.

“Further research is needed to understand the clinical importance of risk difference, the risks and benefits of abaloparatide treatment, and the efficacy of abaloparatide vs other osteoporosis treatments,” the authors write.

(doi:10.1001/jama.2016.11136; the study is available pre-embargo to the media at the For the Media website)

Editor’s Note: This study was funded by Radius Health. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, etc.

Editorial: Osteoporosis Therapy in Postmenopausal Women With High Risk of Fracture

“Ultimately, which therapy is selected for osteoporosis treatment may be less important than identifying and initiating an approved treatment,” write Anne R. Cappola, M.D., Sc.M., of the Perelman School of Medicine at the University of Pennsylvania, Philadelphia, and Associate Editor, JAMA, and Dolores M. Shoback, M.D., of the University of California, San Francisco, in an accompanying editorial.

“The bar is high for any preventive treatment—in the efforts to prevent a fracture that may or may not ever occur, prescribers do not want to prescribe a therapy that causes a new problem. The way forward for fracture prevention involves not only the development of better therapies to prevent fracture and easier delivery systems but also improved adoption of existing osteoporosis therapies for patients with prior fractures and minimization of adverse effects, particularly those associated with long-term use.”

(doi:10.1001/jama.2016.11032; the editorial is available pre-embargo to the media at the For the Media website)

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

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EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, AUGUST 16, 2016

Media Advisory: To contact Imran S. Haque, Ph.D., call Andrew Padgett at 415-318-4301 or email Press@counsyl.com. To contact editorial author Wayne W. Grody, M.D., Ph.D., call Elaine Schmidt at 310- 267-8323 or email eschmidt@mednet.ucla.edu.

To place an electronic embedded link to this study and editorial in your story  These links will be live at the embargo time: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2016.11139  https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2016.10888

In an analysis that included nearly 350,000 adults of diverse racial and ethnic background, expanded carrier screening for up to 94 severe or profound conditions may increase the detection of carrier status for a variety of potentially serious genetic conditions compared with current recommendations from professional societies, according to a study appearing in the August 16 issue of JAMA.

Genetic testing of prospective parents to detect carriers of specific inherited recessive diseases is part of routine obstetrical practice. Current recommendations by professional organizations are to test for a limited number of individual diseases in part based on self-reported racial/ethnic background. Advances in genetic testing now allow for rapid expanded carrier screening for a large number of conditions. These advances could facilitate screening for an expanded number of conditions independent of racial/ethnic background.

Imran S. Haque, Ph.D., of Counsyl, South San Francisco, and colleagues analyzed results from expanded carrier screening in reproductive-aged individuals without known indication for specific genetic testing, primarily from the United States. Tests were offered by clinicians providing reproductive care. Individuals were tested for carrier status for up to 94 conditions. Risk was defined as the probability that a hypothetical fetus created from a random pairing of individuals (within or across 15 self-reported racial/ethnic categories) would be homozygous (possessing two identical forms of a particular gene, one inherited from each parent) or compound heterozygous (the presence of two different mutant alleles at a particular gene locus) for 2 mutations presumed to cause severe or profound disease. Severe conditions were defined as those that if left untreated cause intellectual disability or a substantially shortened lifespan; profound conditions were those causing both.

The study included 346,790 individuals. Among major U.S. racial/ethnic categories, the calculated frequency of fetuses potentially affected by a profound or severe condition ranged from 95 per 100,000 for Hispanic couples to 392 per 100,000 for Ashkenazi Jewish couples. In most racial/ethnic categories, expanded carrier screening modeled more hypothetical fetuses at risk for severe or profound conditions than did screening based on current professional guidelines. For Northern European couples, the 2 professional guidelines-based screening panels (American College of Medical Genetics and Genomics [ACMG], the American Congress of Obstetricians and Gynecologists [ACOG]), modeled 55 hypothetical fetuses affected per 100,000 and the expanded carrier screening modeled 159 fetuses per 100,000.

Overall, relative to expanded carrier screening, guideline-based screening ranged from identification of 6 percent of hypothetical fetuses affected for East Asian couples to 87 percent for African or African American couples.

“The findings showed that an expanded testing panel identified more hypothetical fetuses at risk for severe or profound phenotypes than did testing based on current screening guidelines. This was not only because expanded carrier screening included additional disorders but also because guideline-based testing was based in part on self-identified racial/ethnic categories. The data further suggested that the guidelines recommended by the ACOG and the ACMG at the time of the study did not perform equally between racial/ethnic categories, resulting in differing residual risk among different racial/ethnic categories,” the authors write.

“Even though current guidelines target a number of diseases prevalent in those of European descent (such as cystic fibrosis), they do not identify risk for other conditions that may be important to diverse populations. Expanded carrier screening revealed that many non-European racial/ethnic categories have a risk of a profound or severe genetic disease that may not be detected by the guidelines in place at the time of this analysis.”

The researchers write that “before assertions regarding the clinical utility of broadly testing for these variants can be made with certainty, additional data are needed from unselected diverse populations on the phenotypic spectrum and for the health consequences of pathogenic variants associated with rare conditions.”

(doi:10.1001/jama.2016.11139; the study is available pre-embargo to the media at the For the Media website)

Editor’s Note: This study was funded by Counsyl, a laboratory providing expanded carrier screening. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, etc.

Editorial: Where to Draw the Boundaries for Prenatal Carrier Screening

“The study by Haque and colleagues is an important contribution in the evolving field of prenatal testing. It provides a wealth of data on the frequency of genetic variants that can be detected in individuals of childbearing age from a diversity of racial/ethnic backgrounds,” writes Wayne W. Grody, M.D., Ph.D., of the UCLA Medical Center, Los Angeles, in an accompanying editorial.

“The large number of silent but potentially damaging sequence variants in every human genome went unnoticed until the last few years when high-throughput DNA sequencing technology became widely available. However, just because these variants can now be detected, there needs to be convincing evidence before they all are tested for and possibly acted upon. Pregnant couples have many other concerns (genetic, obstetric, and psychosocial) of substantially higher and more certain risk to occupy their attention.”

(doi:10.1001/jama.2016.10888; the editorial is available pre-embargo to the media at the For the Media website)

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: 11 A.M. (ET) TUESDAY, AUGUST 16, 2016

Media Advisory: To contact Kirsten Bibbins-Domingo, Ph.D., M.D., M.A.S., email Scott Maier at Scott.Maier@ucsf.edu.

To place an electronic embedded link to this study in your story  This link will be live at the embargo time: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2016.11004

Although the recently FDA approved cholesterol-lowering drugs, PCSK9 inhibitors, could substantially reduce heart attacks, strokes, and cardiovascular deaths, they would not be cost-effective for use in patients with heterozygous familial hypercholesterolemia or atherosclerotic cardiovascular disease, with annual drug prices needing to be reduced by more than two-thirds to meet a generally acceptable threshold for cost-effectiveness, according to a study appearing in the August 16 issue of JAMA.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors were approved by the U.S. Food and Drug Administration (FDA) for use in patients with heterozygous familial hypercholesterolemia (FH; a disorder caused primarily by mutations in the low-density lipoprotein [LDL] receptor gene that causes severe elevations in levels of LDL-cholesterol [C], resulting in early atherosclerotic lesions) or pre-existing atherosclerotic cardiovascular disease (ASCVD) who require additional lowering of LDL-C despite maximally tolerated doses of statins. If clinical benefits seen in short-term trials are sustained in the longer term, PCSK9 inhibitors could become an important option for patients at high risk of ASCVD, potentially lowering health care costs through preventing ASCVD events. However, with an average U.S. price in 2015 of more than $14,000 per patient per year, their cost-effectiveness and effect on national health care spending are uncertain.

Kirsten Bibbins-Domingo, Ph.D., M.D., M.A.S., of the University of California, San Francisco, and colleagues used the Cardiovascular Disease Policy Model, an established simulation model of ASCVD in the U.S. population, to evaluate cost-effectiveness of PCSK9 inhibitors or the cholesterol drug ezetimibe in heterozygous FH or ASCVD. The model incorporated 2015 annual PCSK9 inhibitor costs of $14,350 (based on average wholesale acquisition costs of evolocumab and alirocumab).

Adding PCSK9 inhibitors to statins in heterozygous FH was estimated to prevent 316,300 major adverse cardiovascular events (MACE; cardiovascular death, nonfatal heart attack, or stroke) at a cost of $503,000 per quality-adjusted life-year (QALY) gained compared with adding ezetimibe to statins. In ASCVD, adding PCSK9 inhibitors to statins was estimated to prevent 4.3 million MACE compared with adding ezetimibe at $414,000 per QALY. Reducing annual drug costs to $4,536 per patient or less would be needed for PCSK9 inhibitors to be cost-effective at less than $100,000 per QALY.

At 2015 prices, PCSK9 inhibitor use in all eligible patients was estimated to reduce cardiovascular care costs by $29 billion over 5 years, but drug costs increased by an estimated $592 billion (a 38 percent increase over 2015 prescription drug expenditures), and was estimated to increase annual U.S. health care expenditures by about $120 billion (a 4 percent increase from the $2.8 trillion dollars in total U.S. health care spending in 2015).

The authors write that the high cost of PCSK9 inhibitors is uniquely challenging. “This is because PCSK9 inhibitors are meant to be lifelong therapy not only for the relatively small number of patients with FH but also for a large and growing population with ASCVD. As a result, the potential increase in health care expenditures at current or even moderately discounted prices could be staggering, despite cost savings from averted ASCVD events.”

“In the face of limited health care resources, payers must consider the potential trade-off between paying for new drug treatments like PCSK9 inhibitors and investing in interventions known to improve access, physician prescription rates, and patient adherence to statin therapy among those at high ASCVD risk.”

(doi:10.1001/jama.2016.11004; the study is available pre-embargo to the media at the For the Media website)

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: 11 A.M. (ET) TUESDAY, AUGUST 16, 2016

Media Advisory: To contact Susan L. Mitchell, M.D., M.P.H., call Courtney Howe at 617-363-8267 or email CourtneyHowe@hsl.harvard.edu.

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In a study appearing in the August 16 issue of JAMA, Susan L. Mitchell, M.D., M.P.H., of Hebrew SeniorLife Institute for Aging Research, Harvard Medical School, Boston, and colleagues examined feeding tube insertion rates from 2000-2014 among U.S. nursing home residents with advanced dementia.

Over the last 2 decades, research has failed to demonstrate benefits of tube feeding in patients with advanced dementia. Expert opinion and position statements by national organizations increasingly advocate against this practice. For this study, data were derived from federally mandated Minimum Data Set assessments completed quarterly, as required, on all residents in U.S. nursing homes between January 1, 2000, and October 31, 2015. Residents who met certain study criteria were included in the analysis.

Between 2000 and 2014, 71,251 residents with advanced dementia and recent dependence for eating were identified with the following characteristics: average age, 84 years; women, 76 percent; white, 86 percent; black, 9.5 percent; and prior stroke, 14 percent. These characteristics were similar across years. The proportion of residents receiving feeding tubes over the next 12 months declined from 12 percent in 2000 to 6 percent in 2014. Insertion rates declined between 2000 and 2014 among white residents (8.6 percent to 3.1 percent) and black residents (38 percent to 18 percent). However, black residents were more likely to get tube fed in 2000 and 2014 than white residents.

“The proportion of U.S. nursing home residents with advanced dementia and eating dependency receiving feeding tubes decreased by approximately 50 percent between 2000 and 2014,” the authors write. “Feeding tube use decreased across racial groups, but remained relatively higher among black residents, consistent with prior research.”

“To ensure the message from existing evidence and expert recommendations is disseminated and disparities are reduced, fiscal and regulatory policies are needed that discourage tube feeding and promote a palliative approach to feeding problems in patients with advanced dementia.”

(doi:10.1001/jama.2016.9374; the study is available pre-embargo to the media at the For the Media website)

Editor’s Note: This work was supported by grants from the National Institutes of Health. 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: 11 A.M. (ET) TUESDAY, AUGUST 9, 2016

Media Advisory: To contact the U.S. Preventive Services Task Force, email the Media Coordinator at Newsroom@USPSTF.net or call 202-572-2044.

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The U.S. Preventive Services Task Force (USPSTF) has concluded that the current evidence is insufficient to assess the balance of benefits and harms of screening for lipid disorders in children and adolescents 20 years or younger. The report appears in the August 9 issue of JAMA.

This is an I statement, indicating that the evidence is lacking, of poor quality, or conflicting, and the balance of benefits and harms cannot be determined.

Elevations in levels of total, low-density lipoprotein (LDL), and non-high-density lipoprotein cholesterol (non-HDL-C); lower levels of high-density lipoprotein cholesterol; and, to a lesser extent, elevated triglyceride levels are associated with risk of cardiovascular disease in adults. Recent estimates from the National Health and Nutrition Examination Survey (NHANES) indicate that 7.8 percent of children age 8 to 17 years have elevated levels of total cholesterol (TC) and 7.4 percent of adolescents age 12 to 19 years have elevated LDL-C. The rationale for screening for lipid disorders in children and adolescents is that early identification and treatment of elevated levels of LDL-C could delay the atherosclerotic process and thereby reduce the incidence of premature ischemic cardiovascular events in adults.

To update its 2007 recommendation, the USPSTF reviewed the evidence on screening for lipid disorders in children and adolescents 20 years or younger—1 review focused on screening for heterozygous familial hypercholesterolemia (a disorder caused primarily by mutations in the LDL receptor gene that causes severe elevations in levels of LDL-C, resulting in early atherosclerotic lesions), and 1 review focused on screening for multifactorial dyslipidemia (defined by elevated levels of LDL-C or TC that are not attributable to familial hypercholesterolemia).

The USPSTF is an independent, volunteer panel of experts that makes recommendations about the effectiveness of specific preventive care services such as screenings, counseling services, and preventive medications.

Detection

The USPSTF found inadequate evidence on the quantitative difference in diagnostic yield between universal and selective screening for familial hypercholesterolemia or multifactorial dyslipidemia.

Benefits of Early Detection and Treatment

The USPSTF found inadequate direct evidence on the benefits of screening for familial hypercholesterolemia or multifactorial dyslipidemia.

— Familial Hypercholesterolemia: The USPSTF found adequate evidence from short-term trials (2 years or less) that pharmacotherapy interventions result in substantial reductions in levels of LDL-C and TC in children with familial hypercholesterolemia. The USPSTF found inadequate evidence to address whether treatment with short-term pharmacotherapy leads directly to a reduced incidence of premature cardiovascular disease (e.g., heart attack or stroke). The USPSTF found inadequate evidence on the association between changes in intermediate lipid outcomes or noninvasive measures of atherosclerosis in children and adolescents and incidence of or mortality from relevant adult health outcomes.

— Multifactorial Dyslipidemia: The USPSTF found inadequate evidence on the benefits of lifestyle modification or pharmacotherapy interventions in children and adolescents with multifactorial dyslipidemia to improve intermediate lipid outcomes or atherosclerosis markers or to reduce incidence of premature cardiovascular disease.

Harms of Early Detection and Treatment

The USPSTF found inadequate evidence to assess the harms of screening for familial hypercholesterolemia or multifactorial dyslipidemia. The USPSTF found inadequate evidence to assess the long-term harms of treatment of familial hypercholesterolemia in children or adolescents. Long-term evidence on the treatment of familial hypercholesterolemia was limited to 1 study of statins. Short-term statin use was generally well tolerated in children and adolescents with familial hypercholesterolemia, with transient adverse effects (such as elevated liver enzyme levels). The USPSTF also found inadequate evidence to assess the harms of treatment of multifactorial dyslipidemia in children or adolescents.

Summary

Evidence on the quantitative difference in diagnostic yield between universal and selective screening approaches, the effectiveness and harms of long-term treatment and the harms of screening, and the association between changes in intermediate outcomes and improvements in adult cardiovascular health outcomes are limited. Therefore, the USPSTF concludes that the balance of benefits and harms cannot be determined.

(doi:10.1001/jama.2016.9852; the full report is available pre-embargo to the media at the For the Media website)

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

Note: More information about the U.S. Preventive Services Task Force, its process, and its recommendations can be found on the newsroom page of its website.

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EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, AUGUST 9, 2016

Media Advisory: To contact Axel Linke, M.D., email Axel.Linke@medizin.uni-leipzig.de. To contact editorial co-author Steven R. Messe, M.D., email Lee-Ann Donegan at Leeann.Donegan@uphs.upenn.edu.

To place an electronic embedded link to this study and editorial in your story  These links will be live at the embargo time: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2016.10302  https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2016.10316

Among patients with severe aortic stenosis (narrowing of the aortic valve) undergoing transcatheter aortic valve implantation, the use of a cerebral protection device (a filter that captures debris [tissue and plaque] dislodged during the procedure) reduced the number and volume of brain lesions, according to a study appearing in the August 9 issue of JAMA.

Although the clinical outcomes of transcatheter aortic valve implantation (TAVI; replacement of the aortic valve, delivered via a blood vessel with a catheter) have improved considerably during the last decade, stroke, which is associated with a 3-fold increase in mortality following TAVI, remains an important concern. Adding to this concern is the observation that ischemic lesions are found in as many as 80 percent of TAVI patients. Numerous devices have been developed to protect the brain from injury caused by embolic debris during TAVI, although clear evidence of the efficacy of any embolic protection device in TAVI is still missing.

Axel Linke, M.D., of the University of Leipzig, Germany, and colleagues randomly assigned 100 higher-risk patients with severe aortic stenosis to undergo TAVI with a cerebral protection device (n = 50; filter group) or without a cerebral protection device (n = 50; control group). Brain magnetic resonance imaging (MRI) was performed at study entry, 2 days, and 7 days after TAVI.

The researchers found that the number of new brain lesions 2 days after TAVI was lower in the filter group (4) than in the control group (10). New lesion volume after TAVI was lower in the filter group (242 mm³) vs in the control group (527 mm³).

Regarding adverse events, 1 patient in the control group died prior to the 30-day visit. Life-threatening hemorrhages occurred in 1 patient in the filter group and 1 in the control group. Major vascular complications occurred in 5 patients in the filter group and 6 patients in the control group. One patient in the filter group and 5 in the control group had acute kidney injury, and 3 patients in the filter group had a thoracotomy (surgical incision into the chest wall).

“Larger studies are needed to assess the effect of cerebral protection device use on neurological and cognitive function after TAVI and to devise methods that will provide more complete coverage of the brain to prevent new lesions,” the authors write.

(doi:10.1001/jama.2016.10302; the study is available pre-embargo to the media at the For the Media website)

Editor’s Note: The Leipzig Heart Center received a grant from Claret Medical and Medtronic. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, etc.

Editorial: Improving Outcomes From Transcatheter Aortic Valve Implantation

The results from this trial demonstrates 2 important points, write Steven R. Messe, M.D., of the University of Pennsylvania, Philadelphia, and Michael J. Mack, M.D., of the Heart Hospital Baylor Plano, Plano, Texas, in an accompanying editorial.

“First, as other studies have noted, emboli to the brain that cause infarction detected on MRI are very common with TAVI. In this trial, acute lesions on MRI were present in virtually all patients enrolled, although the vast majority of these lesions were quite small. Second, use of an embolic protection device can successfully reduce cerebral infarct number and volume. Whether that reduction translates to a meaningful improvement in clinical outcomes will require more study, but the findings represent a compelling and encouraging start.”

(doi:10.1001/jama.2016.10316; the editorial is available pre-embargo to the media at the For the Media website)

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

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EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, AUGUST 9, 2016

Media Advisory: To contact Ian H. de Boer, M.D., M.S., call Bobbi Nodell at 206-543-7129 or email bnodell@uw.edu.

To place an electronic embedded link to this study in your story  This link will be live at the embargo time: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2016.10924

Among U.S. adults with diabetes from 1988 to 2014, the overall prevalence of diabetic kidney disease did not change significantly, while the prevalence of albuminuria declined and the prevalence of reduced estimated glomerular filtration rate increased, according to a study appearing in the August 9 issue of JAMA.

Diabetes mellitus is the most common cause of chronic kidney disease in the world, leading to multiple complications including end-stage renal disease, cardiovascular disease, infection, and death. Chronic kidney disease in the setting of diabetes or diabetic kidney disease (DKD), manifests clinically as albuminuria (the presence of excessive protein in the urine), reduced glomerular filtration rate (GFR; a measure of kidney function), or both. Changes in demographics and treatments may affect the prevalence and clinical manifestations of diabetic kidney disease.

Ian H. de Boer, M.D., M.S., of the University of Washington, Seattle, and colleagues analyzed data of 6,251 adults with diabetes mellitus participating in National Health and Nutrition Examination Surveys from 1988 through 2014.

The researchers found that the prevalence of any diabetic kidney disease, defined as persistent albuminuria, persistent reduced estimated (e) GFR, or both, did not significantly change over time from 28 percent in 1988-1994 to 26 percent in 2009-2014. However, the prevalence of albuminuria decreased progressively over time from 21 percent in 1988-1994 to 16 percent in 2009-2014. In contrast, the prevalence of reduced eGFR increased from 9 percent in 1988-1994 to 14 percent in 2009-2014, with a similar pattern for severely reduced eGFR.

Significant heterogeneity in the trend for albuminuria was noted by age and race/ethnicity, with a decreasing prevalence of albuminuria observed only among adults younger than 65 years and non-Hispanic whites, whereas the prevalence of reduced GFR increased without significant differences by age or race/ethnicity. In 2009-2014, approximately 8.2 million adults with diabetes had albuminuria, reduced eGFR, or both.

The authors write that the lower prevalence of albuminuria observed over time may be attributable to a higher rate of prescribed diabetes therapies (glucose-lowering medications, renin-angiotensin-aldosterone system [RAAS] inhibitors, and statins). And that while reasons for the increasing prevalence of reduced eGFR cannot be conclusively discerned from these data, it is possible that hemodynamic effects of RAAS inhibitors and improved blood pressure control could contribute to lower eGFR. Alternatively, an increasing duration of diabetes may be contributing to kidney damage.

(doi:10.1001/jama.2016.10924; the study is available pre-embargo to the media at the For the Media website)

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: 11 A.M. (ET) TUESDAY, AUGUST 9, 2016

Media Advisory: To contact Eric D. Peterson, M.D., M.P.H., call Sarah Avery at 919-660-1306 or email sarah.avery@duke.edu.

To place an electronic embedded link to this study in your story  This link will be live at the embargo time: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2016.9356

In a study appearing in the August 9 issue of JAMA, Sean D. Pokorney, M.D., M.B.A., Eric D. Peterson, M.D., M.P.H., of Duke University Medical Center, Durham, N.C., and colleagues examined whether patients receiving warfarin who have stable international normalized ratio (INR) values remain stable over time.

Warfarin substantially decreases stroke risk among patients with atrial fibrillation yet has a narrow therapeutic window (INR values of 2.0-3.0) and is associated with multiple drug and food interactions. Non-vitamin K oral anticoagulants do not require drug monitoring and have similar or improved safety and efficacy relative to warfarin but are more costly. Whether patients previously stable on warfarin should be switched to non-vitamin K oral anticoagulants remains controversial.

Data for this study were obtained from a prospective registry of patients with atrial fibrillation from 176 clinics who were enrolled June 2010 through August 2011 and followed up for 3 years through November 2014. Patients receiving warfarin at study entry with 3 or more INR values in the first 6 months and 6 or more in the subsequent year were included. Stability was defined as 80 percent or more INRs in therapeutic range (2.0-3.0).

Of 10,132 registry patients, 6,383 were not taking warfarin or had insufficient INR values and were excluded. Among 3,749 patients taking warfarin (average age, 75 years), 968 (26 percent) had 80 percent or more of INR values in 2.0-3.0 range during the first 6 months. Of patients with stable INRs during the first 6 months, 34 percent remained stable over the subsequent year. Stability during the baseline period had limited predictive ability of stability over the subsequent year. Among patients with 80 percent or more INRs in range at baseline, 36 percent had 1 or more well-out-of-range INR in the following year, demonstrating limited predictive ability of stability on well-out-of-range INRs.

“A common belief has been that patients with stable INRs while taking warfarin would continue to be stable and derive less benefit from switching to non-vitamin K oral anticoagulants. This analysis suggests warfarin stability is difficult to predict and challenges the notion that patients who have done well taking warfarin should maintain taking warfarin,” the authors write.

(doi:10.1001/jama.2016.9356; the study is available pre-embargo to the media at the For the Media website)

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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