EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, DECEMBER 15, 2015

Media Advisory: To contact Roger Stupp, M.D., email roger.stupp@usz.ch. To contact editorial author John H. Sampson, M.D., Ph.D., M.H.Sc., M.B.A., call Sarah Avery at 919-660-1306 or email sarah.avery@duke.edu.

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Early research indicates that the use of tumor-treating fields, a type of electromagnetic field therapy, along with chemotherapy in patients with a brain tumor who had completed standard chemoradiation resulted in prolonged progression-free and overall survival, according to a study in the December 15 issue of JAMA.

Glioblastoma is the most devastating primary malignancy of the central nervous system in adults. Most patients die within 1 to 2 years of diagnosis. During the last decade, all attempts to improve the outcome for patients with glioblastoma have failed when evaluated in large randomized trials. Tumor-treating fields (TTFields) are a treatment that selectively disrupts the division of cells by delivering low-intensity, intermediate-frequency alternating electric fields via transducer arrays applied to the shaved scalp. Preclinical data have demonstrated a synergistic antitumor effect with chemotherapy and TTFields, according to background information in the article.

Roger Stupp, M.D., of University Hospital Zurich and the University of Zurich, Switzerland, and colleagues randomly assigned 695 patients with glioblastoma who, after completion of chemoradiotherapy, received maintenance treatment with either TTFields plus the chemotherapy drug temozolomide (n = 466) or temozolomide alone (n = 229). Treatment with TTFields was delivered continuously (greater than 18 hours/day) via 4 transducer arrays placed on the shaved scalp and connected to a portable medical device. Temozolomide was given for 5 days of each 28-day cycle. The study was conducted at 83 centers in the United States, Canada, Europe, Israel, and South Korea.

The trial was terminated based on the results of a planned interim analysis, which included 210 patients randomized to TTFields plus temozolomide and 105 randomized to temozolomide alone. After a median follow-up of 38 months, the median progression-free survival was 7.1 months in the TTFields plus temozolomide group compared with 4 months in the temozolomide alone group. Median overall survival in the per-protocol population was 20.5 months in the TTFields plus temozolomide group (n = 196) and 15.6 months in the temozolomide alone group (n = 84).

The over-all incidence and severity of adverse events were similar between groups.

“In this interim analysis of 315 patients with glioblastoma who had completed standard chemoradiation therapy, adding TTFields to maintenance temozolomide chemotherapy significantly prolonged progression-free and overall survival,” the authors write.

(doi:10.1001/jama.2015.16669; Available pre-embargo to the media at http:/media.jamanetwork.com)

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

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Free for use but please credit with the following language:

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Editorial: Alternating Electric Fields for the Treatment of Glioblastoma

The mechanisms whereby the novel approach used in this study can treat tumors and leverage chemotherapy remain unclear, writes John H. Sampson, M.D., Ph.D., M.H.Sc., M.B.A., of Duke University, Durham, N.C.

“Given the survival benefit reported in this study, it should now be a priority to understand the scientific basis for the efficacy of TTFields; achieving this may require the development of robust and widely available large animal models for glioblastoma, which do not currently exist. Perhaps most concerning, because of the study design chosen, doubts may remain as to the true efficacy of this therapy. So, if TTFields therapy fails to be adopted, will this decision be attributed to professional parochialism or to data that are not trusted? The current study provides additional important data on a novel device for the treatment of glioblastoma, but it will not completely resolve that debate.”

(doi:10.1001/jama.2015.16701; Available pre-embargo to the media at http:/media.jamanetwork.com)

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

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EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, DECEMBER 15, 2015

Media Advisory: To contact Christopher J. Hawkey, F.Med.Sci., email cj.hawkey@nottingham.ac.uk.

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Among adults with difficult to treat Crohn disease not amenable to surgery, hematopoietic stem cell transplantation, compared with conventional therapy, did not result in significant improvement in sustained disease remission at l year and was associated with significant toxicity, according to a study in the December 15 issue of JAMA.

Crohn disease is a chronic relapsing inflammatory condition of the gastrointestinal tract that can result in life-long ill health, impaired quality of life, and reduced life expectancy. Immunosuppressive drugs are standard of care for Crohn disease, but some patients do not respond or lose response to treatment. Case reports and series suggest hematopoietic (blood) stem cell transplantation (HSCT) may benefit some patients with Crohn disease, according to background information in the article.

Christopher J. Hawkey, F.Med.Sci., of Queens Medical Centre, Nottingham, United Kingdom, and colleagues randomly assigned 45 patients with impaired quality of life from refractory (not responsive to treatment) Crohn disease not amenable to surgery to autologous (the use of one’s own cells) HSCT (n = 23) or control treatment (HSCT deferred for 1 year [n = 22]). All were given standard Crohn disease treatment as needed. The trial was conducted in 11 European transplant units from July 2007 to September 2011, with follow-up through March 2013. Patients were ages 18 to 50 years.

The researchers found that there was no statistically significant between-group difference in the proportion of patients who met the study definition of sustained disease remission (2 [8.7 percent] in the HSCT group vs l [4.5 percent] in the control group); or on a certain measure on the Crohn Disease Activity Index in the last 3 months; or freedom from active disease. There was a statistically significant difference among patients able to discontinue active treatment in the last 3 months (HSCT group, 61 percent; control group, 23 percent).

There were 76 serious adverse events in patients undergoing HSCT vs 38 in controls; 1 patient undergoing HSCT died.

“Because very few patients achieved sustained disease remission, we conclude that HSCT is unlikely to alter the natural history of Crohn disease, and our findings argue against extension of HSCT to a wider group of patients outside of future additional trials,” the authors write.

The researchers add that based on these findings, further study of HSCT in patients with refractory Crohn disease may be warranted. “It is possible that optimal sustained remission after HSCT may require maintenance immunosuppressive therapy. It is also possible that patients will regain responsiveness to treatments to which they were previously refractory. Therefore, future trials should assess the benefit of maintenance therapy. Toxicity will remain the most significant barrier to HSCT in patients with Crohn disease. Therefore, identification of factors that predict either the risk of adverse effects or response to treatment will enhance the utility of this treatment in clinical practice.”

(doi:10.1001/jama.2015.16700; Available pre-embargo to the media at http:/media.jamanetwork.com)

Editor’s Note: This study was sponsored by the European Group for Blood and Marrow Transplantation Autoimmune Diseases Working Party and the European Crohn and Colitis Organisation. 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, DECEMBER 15, 2015

Media Advisory: To contact Stephan Ehrhardt, M.D., M.P.H., call Stephanie Desmon at 410-955-7619 or email sdesmon1@jhu.edu.

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From 2006 through 2014, there was a decrease in newly registered NIH-funded trials, whereas industry-funded trials increased substantially, based on trials registered in ClinicalTrials.gov. The study appears in the December 15 issue of JAMA.

The National Institutes of Health (NIH) and the pharmaceutical industry have been major funders of clinical trials. In general, the pharmaceutical industry funds trials that test their own products, whereas the NIH’s funding strategies are not commercially motivated. In 2005, registration of trials became required for publication in major journals. Stephan Ehrhardt, M.D., M.P.H., of Johns Hopkins Bloomberg School of Public Health, Baltimore, and colleagues investigated trends in funding of trials using the NIH-built database, ClinicalTrials.gov, with a focus on NIH and industry funding. The researchers downloaded data from ClinicalTrials.gov, searched for “interventional study” and obtained counts of newly registered trials by funder type: “NIH,” “industry,” “other U.S. federal agency,” or “all others (individuals, universities, organizations).”

Examining data according to the first received date, the number of newly registered trials doubled from 9,321 in 2006 to 18,400 in 2014. The number of industry-funded trials increased by 1,965 (43 percent). Concurrently, the number of NIH-funded trials decreased by 328 (24 percent). During this period of relatively few trials being funded by other U.S. federal agencies, funding from the all others category increased by 7,357 (227 percent). In a random sample of 500 trials in this category, a majority (353; 71 percent) did not have U.S.­ based funders. From 2006 through 2014, the total number of newly registered trials increased by 5,410 (59 percent) and that of industry-funded trials increased by 758 (17 percent). The number of NIH-funded trials declined by 316 (27 percent).

The authors write that the decrease in NIH-funded trials may have resulted from a decline in discretionary spending by the U.S. federal government. “The 2014 NIH budget is 14 percent less than the 2006 budget (when adjusted for inflation). An expanding portfolio of NIH research with a flat budget may also have contributed to the decline in NIH-funded trials.”

(doi:10.1001/jama.2015.12206; Available pre-embargo to the media at http:/media.jamanetwork.com)

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

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EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, DECEMBER 8, 2015

Media Advisory: To contact Douglas A. Mata, M.D., M.P.H., call Elaine St. Peter at 617-525-6375 or email estpeter@partners.org. To contact editorial author Thomas L. Schwenk, M.D., call Susan Hill at 775-784-6006 or email susanhill@medicine.nevada.edu.

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An analysis that included more than 17,000 physicians in training finds that nearly one-third screened positive for depression or depressive symptoms during residency, according to a study in the December 8 issue of JAMA, a theme issue on medical education.

Studies have suggested that resident physicians experience higher rates of depression than the general public. Beyond the effects of depression on individuals, resident depression has been linked to poor-quality patient care and increased medical errors. However, the estimated prevalence of this disorder varies substantially between studies. A reliable estimate of depression prevalence during medical training is important for informing efforts to prevent, treat, and identify causes of depression among residents, according to background information in the article.

Douglas A. Mata, M.D., M.P.H., of Brigham and Women’s Hospital and Harvard Medical School, Boston, and colleagues conducted a systematic review and meta-analysis of 54 studies involving 17,560 physicians. Studies were included that had information on the prevalence of depression or depressive symptoms among resident physicians, and were published between January 1963 and September 2015. Studies were eligible for inclusion if they used a validated method to assess for depression or depressive symptoms. Three studies used clinical interviews and 51 used self-report instruments.

The researchers found that the overall pooled prevalence of depression or depressive symptoms was 29 percent (4,969/17,560 individuals). Prevalence estimates ranged from 21 percent to 43 percent, depending on how the prevalence was measured. There was an increased prevalence with increasing calendar year. In a secondary analysis of 7 longitudinal studies, the median absolute increase in depressive symptoms with the onset of residency training was 16 percent. No statistically significant differences were observed between studies of only interns vs only upper-level residents, or studies of nonsurgical vs both nonsurgical and surgical residents.

“Because the development of depression has been linked to a higher risk of future depressive episodes and greater long-term morbidity, these findings may affect the long-term health of resident doctors. Depression among residents may also affect patients, given established associations between physician depression and lower-quality care. These findings highlight an important issue in graduate medical education,” the authors write.

“Further research is needed to identify effective strategies for preventing and treating depression among physicians in training.”

(doi:10.1001/jama.2015.15845; Available pre-embargo to the media at http:/media.jamanetwork.com)

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

Editorial: Resident Depression

Thomas L. Schwenk, M.D., of the University of Nevada School of Medicine, Reno, comments on the findings of this study in an accompanying editorial.

“The solutions to this endemic can be classified into 3 categories: provide more and better mental health care to depressed physicians and those in training, limit the trainees’ exposure to the training environment and system that are thought to contribute at least in part to poorer mental health and wellness, and consider the possibility that the medical training system needs more fundamental change.”

“The prevalence of depressive symptomatology and disease in physicians in training reported by Mata et al is a significant and important marker for deeper and more profound problems in the graduate medical education system that is in need of equally profound change.”

(doi:10.1001/jama.2015.15408; Available pre-embargo to the media at http:/media.jamanetwork.com)

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

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EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, DECEMBER 8, 2015

Media Advisory: To contact Lars E. Peterson, M.D., Ph.D., email lpeterson@theabfm.org.

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Graduating family medicine residents have indicated they intend to provide a broader scope of practice than that reported by current family physicians, including for prenatal care, inpatient care, nursing home care, home visits, and women’s health procedures, according to a study in the December 8 issue of JAMA, a theme issue on medical education.

Family physicians are trained broadly to provide comprehensive continuing health care, yet despite its known benefits, research has documented narrowing in the scope of practice of family physicians. Proposed reasons include changing practice patterns as physicians age, employer restrictions, or generational choices. Determining components of care that remain integral to the practice of family medicine may be informed by assessing gaps between the intended scope of practice of residents and actual scope of practice of family physicians, according to background information in the article.

Lars E. Peterson, M.D., Ph.D., of the American Board of Family Medicine, Lexington, Ky., and colleagues collected data from a practice demographic questionnaire completed by all individuals applying to take the American Board of Family Medicine (ABFM) Maintenance of Certification for Family Physicians examination. Initial board certifiers reported intentions for scope of practice and recertifying family physicians reported actual provision of specific clinical activities. All physicians who registered for the 2014 ABFM Maintenance of Certification for Family Physicians examination were included: 3,038 initial certifiers and 10,846 recertifiers. The Scope of Practice for Primary Care score (scope score) was calculated for each physician and ranged from 0 to 30, with higher numbers equating to broader scope of practice.

The final sample included 13,884 family physicians. The researchers found that the average scope score was significantly higher for initial certifier intended practice compared with recertifying physicians’ reported actual practices (18 vs l6). Compared with recertifiers, initial certifiers were more likely to report intending to provide all clinical services asked except pain management; this included obstetric care (24 percent vs 8 percent), inpatient care (55 percent vs 34 percent), and prenatal care (50 percent vs 10 percent). Similar differences from initial certifiers were present when comparisons were limited to recertifiers in practice for only 1 to 10 years.

The authors write that the pattern found in these results suggests that these differences are not generational, but whether they are due to limited practice support, employer constraints, or other causes remains to be determined.

“The benefits of family physicians providing a broader scope of practice may include lower overall health care costs and reduced hospitalizations, as well as increased availability of services in physician shortage areas. These findings suggest that graduating family medicine residents intend to provide a broad array of care commensurate with their training.”

The researchers note that further research should continue to examine subsequent years of initial certifiers to determine whether intentions to have abroad scope of practice remain. “Tracking these intentions may make it possible to correlate them with health system reforms or alterations in family medicine residency training requirements. It will be important to follow these new family physicians’ practice patterns to determine whether their intentions were realized and, if not, why. Strengthening relationships between practicing physicians and certifying boards offers the opportunity to monitor training outcomes and individual practice activities over time.”

(doi:10.1001/jama.2015.13734; Available pre-embargo to the media at http:/media.jamanetwork.com)

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

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EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, DECEMBER 8, 2015

Media Advisory: To contact Kevin R. Scott, M.D., call Katie Delach at 215-349-5964 or email

Katharine.Delach@uphs.upenn.edu.

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An analysis of more than 1.3 million emergency department visits found an increase in patient length of stay of approximately 5 minutes associated with the presence of medical students in the emergency department, which was statistically significant but likely too small to be of clinical relevance, according to a study in the December 8 issue of JAMA, a theme issue on medical education.

Quantitative assessments of how trainees affect patient care have been limited, especially in the emergency department (ED). As EDs host more core clerkship courses, less experienced students have become involved in bedside care. Kevin R. Scott, M.D., of the University of Pennsylvania, Philadelphia, and colleagues examined patient visits from 2000 through 2014, calculating length of stay (LOS) from arrival until ED discharge or admission, and comparing clerkship student presence with student absence from the ED. The study was conducted at 3 urban, academic EDs associated with the University of Pennsylvania Health System, Philadelphia.

More than 1.3 million ED visits were analyzed. Average LOS was 265 minutes overall; adjusted LOS was 4.6 minutes longer when clerkship students were present in the ED. This was significant across all 3 hospitals. Subanalysis of each year at each site showed that LOS was either longer when students were present or not significantly different from the control weeks.

“Future studies should assess different student experiences and other patient­centered or financial outcomes,” the authors write.

(doi:10.1001/jama.2015.16476; Available pre-embargo to the media at http:/media.jamanetwork.com)

Editor’s Note: The Department of Emergency Medicine, University of Pennsylvania, provided funding for this study. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, etc.

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EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, DECEMBER 8, 2015

Media Advisory: To contact Lorette A. Stammen, M.D., email l.stammen@maastrichtuniversity.nl. To contact editorial author Deborah Korenstein, M.D., call Nicole McNamara at 646-227-3633 or email mcnamarn@mskcc.org.

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Educational interventions to improve the provision of high-value, cost-conscious care by physicians are more effective by combining specific knowledge transmission, reflective practice, and a supportive environment, according to a study in the December 8 issue of JAMA, a theme issue on medical education.

Increasing costs of health care are a cause of concern to patients, governments, and the medical profession around the world. The United States has the highest health care expenses, with health care expenditures in 2015 approaching 18 percent of gross domestic product. Interventions targeting physicians and their medical expertise are proposed as a means to reduce health care waste (care that is not beneficial to patients) while maintaining the quality of care, according to background information in the article.

Lorette A. Stammen, M.D., of Maastricht University, Maastricht, the Netherlands, and colleagues examined how and under what circumstances educational interventions may help practicing physicians, resident physicians, and medical students deliver high-value, cost-conscious care. The study consisted of a review of 79 studies that included educational interventions on this topic.

Of the 79 studies, 14 were randomized clinical trials, of which 12 addressed knowledge transmission, 7 reflective practice, and 1 supportive environment; 10 (71 percent) concluded that the intervention was effective. The data analysis suggested that 3 factors aid successful learning:

• Effective transmission of knowledge, related, for example, to general health economics and prices of health services, to scientific evidence regarding guidelines and the benefits and harms of health care, and to patient preferences and personal values (67 articles);

• Facilitation of reflective practice, such as providing feedback or asking reflective questions regarding decisions related to laboratory ordering or prescribing to give trainees insight into their past and current behavior (56 articles);

• Creation of a supportive environment in which the organization of the health care system, the presence of role models of delivering high-value, cost-conscious care, and a culture of high-value, cost-conscious care reinforce the desired training goals (27 articles).

“These 3 factors combined provide a framework for the development and further research of educational programs that teach physicians to deliver high-value, cost-conscious care,” the authors write.

“Although the reported effectiveness of educational interventions seems to provide scope for medical education to bring about improvement, training physicians to deliver high-value, cost-conscious care remains a complex task. Further research should focus on what makes a good role model of high-value, cost-conscious care and how such attributes can be cultivated by means of medical education.”

“Additionally, there is a need to investigate how formal education can help mold the culture of the learning environment. Although measuring the value of care is extremely complex, outcome measures that focus solely on volume or costs might promote the incorrect assumption that cheaper is better. Therefore, thoughtful consideration of which outcome measures can be used to evaluate the effectiveness of interventions remains important.”

(doi:10.1001/jama.2015.16353; Available pre-embargo to the media at http:/media.jamanetwork.com)

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

Editorial: Charting the Route to High-Value Care

Deborah Korenstein, M.D., of the Memorial Sloan Kettering Cancer Center, New York, writes in an accompanying editorial that a large challenge involves designing educational approaches that acknowledge the complexity of high-value clinical care and characterizing educational end points that reflect generalizable skills.

“High-value clinical care is not one skill: its mastery requires a variety of teaching approaches and outcome measures. Thus far, approaches have generally been narrow, have often focused on cost, and have involved freestanding curricula as opposed to integration.”

“The education community must now develop novel curricula, meaningful assessment tools for curriculum evaluation, and measurable milestones that move beyond cost issues. These activities may provide the path to lead physicians toward the practice of high-value care.”

(doi:10.1001/jama.2015.15406; Available pre-embargo to the media at http:/media.jamanetwork.com)

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

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EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, DECEMBER 8, 2015

Media Advisory: To contact Henry M. Sondheimer, M.D., email Jamila Vernon at jvernon@aamc.org.

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The percentage of U.S. M.D. graduates entering graduate medical education (GME) the year of graduation has remained stable during the past decade despite an increase in the number of graduates, according to a study in the December 8 issue of JAMA, a theme issue on medical education.

Medical school enrollment has increased in the United States during the past decade; however, growth in GME positions has been slower, raising concerns about whether graduates will be able to obtain the GME necessary to qualify to practice medicine. Particular concerns have been raised about graduates from minority groups traditionally underrepresented in medicine. Henry M. Sondheimer, M.D., of the Association of American Medical Colleges, Washington, D.C., and colleagues evaluated graduates of all U.S. M.D.-granting medical schools from 2005 through 2015 to determine whether they entered GME training in the United States. The researchers reviewed the Association of American Medical Colleges Student Record System to identify all graduates. To identify those unplaced in GME upon medical school graduation who ultimately entered GME, the GMETrack First Year On-Duty file was searched in September 2015 for the years 2004 through 2014.

There were 186,937 graduates (48 percent female) during the study period, increasing from 15,762 in 2004-2005 to 18,705 in 2014-2015. The percentage of graduates unplaced in GME during the academic year of their graduation from medical school remained stable, ranging from 2.6 percent to 3.5 percent with an average of 3 percent. Unplaced black, Hispanic, and non-US citizen graduates increased over time. Racial/ethnic minority graduates were consistently less likely to begin GME the year they graduated than whites. However, within 6 years after graduation, more than 99 percent of all graduates entered GME or were found in practice in the United States. The racial/ethnic differences seen at graduation diminished with time but remained statistically significant.

“As the number of U.S. M.D. graduates continues to increase with the creation of new medical schools and the growth of existing schools, these trends should be closely monitored,” the authors write.

(doi:10.1001/jama.2015.15702; Available pre-embargo to the media at http:/media.jamanetwork.com)

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

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EMBARGOED FOR RELEASE: 10:30 A.M. (ET) SATURDAY, DECEMBER 5, 2015

Media Advisory: To contact Walter H. Dzik, M.D., call Michael Morrison at 617-724-6425 or email mdmorrison@mgh.harvard.edu. To contact Philip C. Spinella, M.D., F.C.C.M., call Judy Martin at 314-286-0105 or email Martinju@wustl.edu.

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Among children in Uganda with lactic acidosis due to severe anemia, transfusion of longer-storage red blood cells, compared with shorter-storage, resulted in a similar reduction of elevated blood lactate levels, a measure of tissue oxygenation, according to a study published by JAMA. The study is being released to coincide with its presentation at the American Society of Hematology annual meeting.

During storage, red blood cells (RBCs) undergo changes that might impair the capacity for tissue oxygenation by transfused RBCs. Although millions of transfusions are given annually worldwide, the effect of RBC unit storage duration on oxygen delivery is uncertain. Walter H. Dzik, M.D., of Harvard Medical School and Massachusetts General Hospital, Boston, and colleagues randomly assigned 290 children (age 6-60 months) with elevated blood lactate levels due to severe anemia to receive RBC units stored 25 to 35 days (longer-storage group; n = 145) vs 1 to10 days (shorter-storage group; n = 145). The study included children who presented to a university-affiliated national referral hospital in Kampala, Uganda.

The researchers found that RBC units maintained under standard storage conditions for 25 to 35 days were not inferior to RBC units stored for up to 10 days as measured either by resolution of lactic acidosis at 8 hours or by secondary outcomes defined by improvement in clinical symptoms, normalization of vital signs, correction of laboratory abnormalities, and improvement in cerebral tissue (brain) oxygen saturation. Average lactate levels were not statistically different between the 2 groups at 0, 2, 4, 6, 8, or 24 hours, and analysis indicated no statistical difference in lactate reduction between the 2 groups. Adverse events, survival, and 30-day recovery were also not significantly different between the groups.

“This study provides biological evidence that longer-storage RBCs correct lactic acidosis and increase cerebral tissue oxygenation as effectively as shorter-storage RBCs,” the authors write.

(doi:10.1001/jama.2015.139777; Available pre-embargo to the media at http:/media.jamanetwork.com)

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

Editorial: Storage Duration and Other Measures of Quality of Red Blood Cells for Transfusion

“More complete data throughout the continuum from donation to transfusion are needed to improve outcomes for patients requiring transfusions,” write Philip C. Spinella, M.D., F.C.C.M., of Washington University in St. Louis, and Jason Acker, M.B.A., Ph.D., of the University of Alberta, Edmonton, Canada, in an accompanying editorial.

“Blood collection centers and hospital blood banks need to collect and share information on donor characteristics and quality metrics from the RBCs donated. Hospitals should collect data on patients receiving transfusions, the indications for transfusion, the timing and dose of each blood product transfused, and the physiologic response to transfusion. Administrative data sets need to be linked to each of these data sets to allow cost-effective analyses to be performed. Only with better data can future studies determine which therapies or strategies are optimal to improve outcomes for patients requiring transfusions.”

(doi:10.1001/jama.2015.14714; Available pre-embargo to the media at http:/media.jamanetwork.com)

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

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EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, DECEMBER 1, 2015

Media Advisory: To contact Alex B. Haynes, M.D., M.P.H., call Deborah O’Neil at 305-215-5675 or email doneil@ariadnelabs.org; to contact Thomas G. Weiser, M.D., M.P.H., call Ruthann Richter at 650-725-8047 or email richter1@stanford.edu. To contact Mairead Black, M.R.C.O.G., email mairead.black@abdn.ac.uk. To contact editorial co-author Mary E. D’Alton, M.D., email Karin Eskenazi ket2116@cumc.columbia.edu.

To place an electronic embedded link to these studies and editorial in your story This will be the link to the 1^st study, which will be live at the embargo time: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.15553 This will be the link to the 2^nd study: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.16176 This will be the link to the editorial: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.15948
 

Two studies in the December 1 issue of JAMA examine the relationship between cesarean delivery rates and maternal and infant death, and adverse outcomes in childhood health following planned cesarean delivery at term.

In one study, Alex B. Haynes, M.D., M.P.H., of Ariadne Labs at Brigham and Women’s Hospital and the Harvard T.H. Chan School of Public Health, Boston, and Thomas G. Weiser, M.D., M.P.H., of the Stanford University Medical Center, Stanford, Calif., and colleagues collected data for 2005 to 2012 for all 194 World Health Organization (WHO) member states to estimate annual cesarean delivery rates. The year of analysis was 2012. Cesarean delivery rates were available for 54 countries for 2012. For the 118 countries for which 2012 data were not available, the 2012 cesarean delivery rate was imputed from other years. For the 22 countries for which no cesarean rate data were available, the rate was imputed from total health expenditure per capita, fertility rate, life expectancy, percent of urban population, and geographic region.

Cesarean delivery is lifesaving for obstructed labor and other emergency obstetrical conditions; however, as a surgical procedure, there are risks of complications and overuse can be harmful to both mothers and newborns. Based on older analyses, the WHO recommends that cesarean delivery rates should not exceed 10 to 15 per 100 live births to optimize maternal and neonatal (birth to four weeks) outcomes. Studies of the relationship between cesarean delivery rate and mortality have yielded inconsistent results.

In this study, the researchers found that the estimated global number of cesarean deliveries for 2012 was 22.9 million, yielding a global cesarean delivery rate estimate of 19.4 per 100 live births. Analysis indicated that the optimal cesarean delivery rate in relation to maternal and neonatal mortality was approximately 19 cesarean deliveries per 100 live births. Higher cesarean delivery rates were not correlated with maternal or neonatal mortality at a country level. A sensitivity analysis including only 76 countries with the highest-quality cesarean delivery rate information had a similar result; cesarean delivery rates greater than 6.9 to 20.1 per 100 live births were inversely correlated with the maternal mortality ratio. Cesarean delivery rates of 12.6 to 24.0 were inversely correlated with neonatal mortality.

“Previously recommended national target rates for cesarean deliveries may be too low,” the authors write.

(doi:10.1001/jama.2015.15553; Available pre-embargo to the media at http:/media.jamanetwork.com)

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

Editorial: Cesarean Delivery Rates

“The study of Molina et al highlights the need for an evaluation of cesarean delivery rates by the international obstetrical community,” write Mary E. D’Alton, M.D., and Mark P. Hehir, M.D., of the Columbia University College of Physicians and Surgeons, New York, in an accompanying editorial.

“The optimal level of cesarean delivery cannot be as simple as a one-fits-all figure to be applied to all institutions and health care systems, and the obstetrical community must accept the fact that ‘the appropriate’ cesarean delivery rate remains unknown. However, it is not whether the cesarean delivery rate is high or low that really matters, but rather whether appropriate performance of cesarean delivery is part of a system that delivers optimal maternal and neonatal care after consideration of all relevant patient and health system information.”

(doi:10.1001/jama.2015.15948; Available pre-embargo to the media at http:/media.jamanetwork.com)

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

In another study, Mairead Black, M.R.C.O.G., of the University of Aberdeen, United Kingdom, and colleagues examined the relationship between planned cesarean delivery and offspring health problems or death in childhood.

Planned cesarean delivery comprises a significant proportion of births globally. Observational studies have shown that offspring born by cesarean delivery are at increased risk of ill health in childhood, but these studies have been unable to adjust for some key factors. Additionally, risk of death beyond the neonatal period has not yet been reported for offspring born by planned cesarean delivery.

This study included data on 321,287 term first-born offspring born in Scotland between 1993 and 2007, with follow-up until February 2015. Offspring born by planned cesarean delivery in a first pregnancy were compared with offspring born by unscheduled cesarean delivery and with offspring delivered vaginally.

The authors found that compared with offspring born by unscheduled cesarean delivery (17 percent), those born by planned cesarean delivery (3.8 percent) were at no significantly different risk for the outcomes examined in the study, including asthma requiring hospital admission, salbutamol inhaler prescription at age 5 years, obesity at age 5 years, inflammatory bowel disease, cancer, or death, but were at increased risk of type 1 diabetes (0.66 percent vs 0.44 percent). In comparison with children born vaginally (79 percent), offspring born by planned cesarean delivery were at increased risk of asthma requiring hospital admission (3.73 percent vs 3.41 percent), salbutamol inhaler prescription at age 5 years (10.3 percent vs 9.6 percent), and death (0.40 percent vs 0.32 percent), whereas there were no significant differences in risk of obesity at age 5 years, inflammatory bowel disease, type 1 diabetes, or cancer.

These findings suggest that avoidance of vaginal birth may be an important early-life factor in the growing global burden of asthma, although absolute increase in risk to individuals is low, the researchers write. “Health professionals and women considering planned cesarean delivery should be made aware of this. However, the magnitude of risk is such that in the presence of a medical indication for cesarean delivery, the apparent risk to offspring health is unlikely to justify a plan for vaginal birth.”

“Until indications for cesarean delivery can be fully accounted for and cause of mortality measured, it would be premature to assume that planned cesarean delivery increases the risk of death in childhood—but given the consistency of findings from published studies, it is important to investigate this further.”

(doi:10.1001/jama.2015.16176; Available pre-embargo to the media at http:/media.jamanetwork.com)

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

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EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, DECEMBER 1, 2015

Media Advisory: To contact Kellee M. Miller, Ph.D., email t1dstats@jaeb.org.

To place an electronic embedded link to this study in your story This link for the study will be live at the embargo time: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.16174

In a randomized trial that included overweight and obese adolescents with type 1 diabetes, the addition of metformin to insulin did not improve glycemic control after 6 months, according to a study in the December 1 issue of JAMA.

For youth with type 1 diabetes, being overweight or obese potentially has serious metabolic consequences, especially during adolescence. Among these individuals, the high doses of insulin required to overcome the insulin resistance of obesity and puberty contribute to difficulties in glycemic control and may promote further weight gain. Metformin is an oral glucose-lowering agent commonly used in treating type 2 diabetes. Previous studies assessing the effect of metformin on glycemic control in adolescents with type 1 diabetes have produced inconclusive results, according to background information in the article.

Kellee M. Miller, Ph.D., of the Jaeb Center for Health Research, Tampa, Fla., and colleagues randomly assigned 140 adolescents (age 12 to 19 years) with type 1 diabetes (average duration, 7 years) to receive metformin (n = 71) (2,000 mg/d or less) or placebo (n = 69) for six months. The trial was conducted at 26 pediatric endocrinology clinics.

The researchers found that despite a small decrease in HbA_1c (glycated hemoglobin; used to identify the average plasma glucose concentration over prolonged periods) favoring the metformin group at 13 weeks, average HbA_1c levels increased by approximately 0.2 percent from baseline values of 8.8 percent in each treatment group at 26 weeks. There also were no statistically or clinically significant differences from baseline to 26 weeks in continuous glucose monitoring between treatment groups. The authors add that it does not seem likely that different glycemic control results would have been achieved with a longer treatment period.

Metformin compared with placebo was associated with reductions in weight gain, body mass index, body fat, and total daily insulin dose, although the clinical relevance of these treatment group differences is uncertain. Metformin treatment failed to improve a number of clinical and biochemical risk factors for future cardiovascular disease, including blood pressure and plasma lipid concentrations.

Gastrointestinal adverse events were reported by more participants in the metformin group than in the placebo group.

“These results do not support prescribing metformin to adolescents to improve glycemic control,” the researchers write.

(doi:10.1001/jama.2015.16174; Available pre-embargo to the media at http:/media.jamanetwork.com)

Editor’s Note: Funding was provided by the Juvenile Diabetes Research Foundation. Part of Dr. Katz’s time was supported by the National Institute of Diabetes and Digestive and Kidney Diseases. 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, DECEMBER 1, 2015

Media Advisory: To contact Mark D. Peterson, Ph.D., M.S., email Kylie O’Brien at kylieo@med.umich.edu.

To place an electronic embedded link to this study in your story This link for the study will be live at the embargo time: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.11025

Adults with cerebral palsy (CP) have higher odds for chronic health conditions such as asthma, hypertension and arthritis compared with adults without CP, according to a study in the December 1 issue of JAMA.

Adults with CP represent an increasing population whose health status and health care needs are poorly understood. Mortality records reveal that death due to ischemic heart disease and cancer is higher among adults with CP; however, there have been no national surveillance efforts to track disease risk in this population. Mark D. Peterson, Ph.D., M.S., of the University of Michigan, Ann Arbor, and colleagues used data from 9 years (2002-2010) of the Medical Expenditure Panel Survey (MEPS) to estimate the rate of chronic conditions among adults with CP. The MEPS is an ongoing, nationally representative survey. Age-adjusted prevalence rates for 8 chronic conditions were evaluated in adults with and without CP: diabetes, asthma, hypertension, other heart conditions (including cardiovascular disease, heart attack, angina, and other cardiovascular conditions), stroke, emphysema, joint pain, and arthritis.

Of the 207,615 adults included in the study, 1,015 had CP. Age-adjusted prevalence rates of chronic conditions were significantly greater among adults with CP vs without CP, including diabetes (9 percent vs 6 percent, respectively), asthma (21 percent vs 9 percent), hypertension (30 percent vs 22 percent), other heart conditions (15 percent vs 9 percent), stroke (5 percent vs 2 percent), emphysema (4 percent vs 1 percent), joint pain (44 percent vs 28 percent), and arthritis (31 percent vs 17 percent). The adjusted odds ratios were significantly different for all conditions except diabetes. Age, sex, weight, physical disability, overall health, and physical activity were also associated with chronic conditions.

The authors write that the findings of this study raise “important questions about preventable health complications in this [CP] population.”

“Accelerated functional losses are a concern in the aging CP population. A large percentage of individuals who were once mobile eventually stop ambulating due to fatigue, inefficiency of gait, and/or muscle and joint pain. The current findings demonstrated that level of mobility impairment was strongly associated with chronic conditions.”

“Future efforts are needed to better understand the health care use associated with chronic conditions for persons with CP and to characterize the relationships among mobility impairments, sedentary lifestyles, and chronic conditions.”

(doi:10.1001/jama.2015.11025; Available pre-embargo to the media at http:/media.jamanetwork.com)

Editor’s Note: Dr. Peterson’s work was funded by a grant from the National Institutes of Health. The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.

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EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, DECEMBER 1, 2015

Media Advisory: To contact Malcolm Kohler, M.D., email malcolm.kohler@usz.ch.

To place an electronic embedded link to this study in your story This link for the study will be live at the embargo time: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.16303

Among patients with obstructive sleep apnea, a comparison of the treatments continuous positive airway pressure and mandibular advancement devices found both were associated with similar reductions in systolic and diastolic blood pressure, according to a study in the December 1 issue of JAMA.

Obstructive sleep apnea is associated with higher levels of blood pressure (BP), which can lead to increased cardiovascular risk. Malcolm Kohler, M.D., of University Hospital Zurich, Zurich, Switzerland, and colleagues conducted a meta-analysis and compared the association of continuous positive airway pressure (CPAP) vs mandibular advancement devices (MADs) and vs an inactive control (e.g., placebo or no treatment) with changes in systolic BP (SBP) and diastolic BP (DBP) in patients with obstructive sleep apnea. Mandibular advancement devices work by protruding the mandible and tongue to keep airways open during sleep.

A total of 51 studies (4,888 patients) met criteria for the meta-analysis. Of these studies, 44 compared CPAP with an inactive control (4,289 patients), compared MADs with an inactive control (229 patients), 1 compared CPAP with MADs (126 patients), and 3 compared CPAP, MADs, and an inactive control (244 patients). Results of the meta-analysis found that compared with an inactive control, CPAP was associated with a reduction in SBP of 2.5 mm Hg and in DBP of 2.0 mm Hg; MADs were associated with a reduction in SBP of 2.1 mm Hg and in DBP of 1.9 mm Hg.

The authors note that even though there was no statistically significant difference between the associations of CPAP and MADs with change in BP in the meta-analysis, CPAP had a considerably higher probability of having the strongest association with SBP reduction. “The associations of both CPAP and MADs with DBP reduction were more similar; however, the association of CPAP with reductions of both SBP and DBP is likely to be greater in patients using CPAP for longer periods at night or in those with higher baseline BP levels.”

(doi:10.1001/jama.2015.16303; Available pre-embargo to the media at http:/media.jamanetwork.com)

Editor’s Note: This research was supported by a grant from the Swiss National Science Foundation and by funding from the University of Zurich Clinical Research Priority Program Sleep and Health. The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.

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EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, NOVEMBER 24, 2015

Media Advisory: To contact Xuesong Han, Ph.D., email Evelyn Barella at evelyn.barella@cancer.org.

To place an electronic embedded link to this study in your story This link for the study will be live at the embargo time: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.10546

Although based on early data, study findings suggest an association between the Affordable Care Act Dependent Coverage Expansion provision and cervical cancer stage at diagnosis and receipt of fertility-sparing treatment among young women age 21 to 25 years, but not among women aged 26 to 34 years, according to a study in the November 24 issue of JAMA.

In September 2010, the Affordable Care Act Dependent Coverage Expansion (ACA-DCE) went into effect, allowing young adults to remain on their parents’ health insurance plans until age 26 years. Implementation of the ACA-DCE was followed by a net increase in private health insurance coverage among young adults age 19 to 25 years. Persons without private health insurance are less likely to be screened and more likely to be diagnosed at an advanced stage of cancer.

Since November 2009, the American College of Obstetricians and Gynecologists has recommended cervical cancer screening begin at age 21 years. Diagnosis of cervical cancer at early stages also allows use of fertility-sparing treatments. Xuesong Han, Ph.D., of the American Cancer Society, Atlanta, and colleagues used data before and after the ACA-DCE to compare changes in cervical cancer stage at diagnosis and initial treatment among women 21 to 25 years (DCE-eligible) and 26 to 34 years (non-DCE-eligible). The National Cancer Data Base, a national hospital-based cancer registry, was used to obtain data on cases of invasive cervical cancer, with stage at diagnosis classified as early (stages I/II) or late (stages III/IV).

The researchers identified 3,937 cervical cancer cases diagnosed pre-DCE and 2,480 cases post-DCE. Patients with private insurance were more likely than those with Medicaid or uninsured to be diagnosed with early-stage disease (78 percent with private insurance vs 65 percent with Medicaid and 67 percent uninsured) and more likely to receive fertility-sparing treatments (24 percent with private insurance vs 12 percent with Medicaid and 17 percent uninsured).

Between the pre- and post-DCE periods, compared with 26- to 34-year-olds, women 21 to 25 years of age experienced a net increase of 9 percentage points in early-stage disease and 11.9 percentage points in receipt of fertility-sparing treatments. Among women age 21 to 25 years, the proportion of early-stage disease increased from 68 percent in 2009 to 84 percent in 2011 and decreased to 72 percent in 2012. The authors note that this increase in 2011 followed by a decrease in 2012 may reflect detection of prevalent early-stage disease associated with increased access to care or random fluctuation.

The proportion of women 21 to 25 years of age receiving fertility-sparing treatment increased throughout the study period.

“Future work should continue to monitor cancer care and outcomes in populations targeted by the ACA.”

(doi:10.1001/jama.2015.10546; Available pre-embargo to the media at http:/media.jamanetwork.com)

Editor’s Note: This work was supported by the Intramural Research Department of the American Cancer Society. The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.

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EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, NOVEMBER 24, 2015

Media Advisory: To contact Fahad Razak, M.D., M.Sc., email Leslie Shepherd at ShepherdL@smh.ca.

To place an electronic embedded link to this study in your story This link for the study will be live at the embargo time: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.15666

Among women in 60 low- and middle-income countries, the prevalence of body mass index (BMI) lower than 16 (the most severe category of adult malnutrition) was about 2 percent, and was associated with poverty and low education levels, according to a study in the November 24 issue of JAMA. The prevalence of this level of BMI did not decrease over time in most countries studied.

In 1998, the United Nations sought a method to quantify the population prevalence of severe chronic undernutrition, and designated a BMI lower than 16 as a definition of severe chronic energy deficiency, which is associated with substantial illness, increased mortality, and poor maternal-fetal outcomes such as low-birth-weight newborns. Little is known about the prevalence and distribution of BMI lower than 16 in low- and middle-income countries (LMIC). Fahad Razak, M.D., M.Sc., of the Li Ka Shing Knowledge Institute of St. Michael’s Hospital, Toronto, and colleagues analyzed data composed of nationally representative surveys from 1993 through 2012 from the Demographic and Health Surveys Program. Data from women 20 through 49 years of age from 60 LMIC (n = 500,761) and a subset of 40 countries with repeated surveys (n = 604,144) were examined.

Among countries examined, the prevalence of BMI lower than 16 was 1.8 percent, with the highest prevalence in India (6.2 percent), followed by Bangladesh (3.9 percent), Madagascar (3.4 percent), Timor-Leste (2.9 percent), Senegal (2.5 percent), and Sierra Leone (2.2 percent). Six countries had prevalences lower than 0.1 percent (Albania, Bolivia, Egypt, Peru, Swaziland, and Turkey).

The prevalence of BMI lower than 16 was highest in women with no education (1.8 percent) vs those with secondary education or higher (0.51 percent) and higher for those residing in rural areas (1.3 percent) compared with those residing in urban areas (0.50 percent). The prevalence of BMI lower than 16 was 0.43 percent for women in the highest wealth quintile, and 1.5 percent for women in the lowest wealth quintile. Among the 24 of 39 countries with repeated surveys, there was no decrease in prevalence. In Bangladesh and India, rates were declining.

“The 60 LMIC studied here represent an estimated 3 billion individuals. There are 2 major findings. First, using the most recently available nationally representative data on a large range of LMIC, BMI lower than 16 remains a critically important public health entity. BMI lower than 16 was associated with poverty and low education. Second, the prevalence of BMI lower than 16 was not decreasing in most countries. The prevalence and total population burden of individuals with BMI lower than 16 remains high globally, and if prevalence estimates are generalizable, more than 18 million women are affected in the countries studied,” the authors write.

“The finding of a large and, in some countries, persistent burden of individuals with BMI lower than 16 supports the need for further study of why mortality rates are increased and supports the value of intervention studies to examine whether mortality can be reduced.”

The researchers add that nutritional supplementation over a short term has shown some encouraging effects among those with BMI lower than 16, but many questions remain unanswered about potentially increased long-term cardiovascular and chronic disease risk when chronic nutritional deprivation is reversed in adulthood.

(doi:10.1001/jama.2015.15666; Available pre-embargo to the media at http:/media.jamanetwork.com)

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

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EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, NOVEMBER 17, 2015

Media Advisory: To contact Ahmedin Jemal, D.V.M., Ph.D., email David Sampson at david.sampson@cancer.org. To contact Jesse D. Sammon, D.O., call Tammy Battaglia at 248-881-0809 or email Tammy.Battaglia@hfhs.org. To contact editorial author David F. Penson, M.D., M.P.H., call Craig Boerner at 615-322-4747 or email craig.boerner@vanderbilt.edu.

To place an electronic embedded link to this study and editorial in your story This link to the 1^st study will be live at the embargo time: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.14905 This link to the 2^nd study will be live at the embargo time: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.7273 This will be the link to the editorial: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.13775

Two studies in the November 17 issue of JAMA examine the change in prostate-specific antigen (PSA) screening and prostate cancer incidence before and after the 2012 U.S. Preventive Services Task Force (USPSTF) screening recommendations.

Ahmedin Jemal, D.V.M., Ph.D., of the American Cancer Society, Atlanta, and colleagues examined trends in stage-specific prostate cancer incidence and PSA-based screening for men 50 years and older subsequent to the 2008 and 2012 USPSTF recommendations using the most recent population-based incidence and nationally representative screening data. Prostate cancer incidence in men 75 years and older substantially decreased following the 2008 USPSTF recommendation against PSA-based screening for this age group. It has been unknown whether incidence has changed since the USPSTF recommendation against screening for all men in May 2012.

The researchers determined prostate cancer incidence (newly diagnosed cases/100,000 men 50 years of age and older) by stage from 2005 through 2012 using data from 18 population-based Surveillance, Epidemiology, and End Results (SEER) registries. The PSA screening rate was determined for men 50 years and older without a history of prostate cancer who responded to the 2005 (n = 4,580), 2008 (n = 3,476), 2010 (n = 4,157), and 2013 (n = 6,172) National Health Interview Survey.

The researchers found that prostate cancer incidence per 100,000 in men 50 years and older (n = 446,009 in SEER areas) was 535 in 2005, 541 in 2008, 505 in 2010, and 416 in 2012; rates began decreasing in 2008 and the largest decrease occurred between 2011 and 2012, from 498 to 416. The number of men 50 years and older diagnosed with prostate cancer nationwide declined by 33,519, from 213,562 in 2011 to 180,043 in 2012. The decreases in incidence were evident in both non-Hispanic white and non-Hispanic black individuals and across regions.

The percentage of men 50 years and older reporting PSA screening in the past 12 months was 37 percent in 2005, 41 percent in 2008, 38 percent in 2010, and 31 percent in 2013. In relative terms, screening rates increased by 10 percent between 2005 and 2008 and then decreased by 18 percent between 2010 and 2013. Similar screening patterns were found in age subgroups 50 to 74 years and 75 years and older.

“Using the most recent population-based incidence and nationally representative self-reported PSA screening data, we report reductions in early-stage prostate cancer incidence and PSA-based screening rates in men 50 years and older, coinciding with the 2012 USPSTF recommendation against PSA-based screening,” the authors write. “Longer follow-up is needed to see whether these decreases are associated with trends in mortality.”

(doi:10.1001/jama.2015.14905; Available pre-embargo to the media at http:/media.jamanetwork.com)

Editor’s Note: This project was supported by the Intramural Research Department of the American Cancer Society. All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.

In another study, Jesse D. Sammon, D.O., of Brigham and Women’s Hospital, Boston, and colleagues examined PSA screening data from the 2000, 2005, 2010, and 2013 National Health Interview Survey to determine the prevalence and determinants of screening before and after the 2012 USPSTF recommendations (draft released October 2011), as well as the association between the new USPSTF recommendations and the prevalence of screening.

The final study population included 20,757 men. The prevalence of PSA screening was 34 percent in 2000 and 2005. Between 2010 and 2013, the prevalence decreased from 36 percent to 31 percent overall. In a pooled analysis, survey year 2013 (vs 2010) was associated with lower odds of PSA screening. However, declines were seen only in men younger than 75 years vs men 75 and older. The largest declines were seen among men age 50-54 years (from 23 percent to 18 percent) and among men 60-64 years of age (from 45 percent to 35 percent). After adjusting for patient factors, there were significant reductions in PSA screening associated with the 2012 USPSTF recommendations.

“The 2008 USPSTF recommendations against PSA screening in men aged 75 years or older have not been associated with changes in screening practices. However, we found a decrease in the prevalence of PSA screening following the 2012 recommendations, particularly in men younger than 75 years,” the authors write.

“These findings using nationally representative data suggest that younger men may be altering health care behavior at a higher rate than older men following the new USPSTF recommendations, changes in clinician PSA screening practices have occurred in response to the policy change, or both. Alternatively, the findings may reflect the broad effects of the economic recession on health care use or a delayed response to the 2008 guidelines.”

(doi:10.1001/jama.2015.7273; Available pre-embargo to the media at http:/media.jamanetwork.com)

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

Editorial: The Pendulum of Prostate Cancer Screening

“There is reason to be concerned about the decline in prostate cancer screening and prostate cancer incidence reported by Sammon et al and Jemal et al,” writes David F. Penson, M.D., M.P.H., of Vanderbilt University, Nashville, in an accompanying editorial.

“Certainly, physicians have been overly aggressive in their approach to prostate cancer screening and treatment during the past 2 decades, but the pendulum may be swinging back the other way. It is time to accept that prostate cancer screening is not an ‘all­or-none’ proposition and to accelerate development of personalized screening strategies that are tailored to a man’s individual risk and preferences. By doing this, it should be possible to reach some consensus around this vexing problem and ultimately help men by stopping the swinging pendulum somewhere in the middle.”

(doi:10.1001/jama.2015.13775; Available pre-embargo to the media at http:/media.jamanetwork.com)

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

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EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, NOVEMBER 17, 2015

Media Advisory: To contact Leonard B. Bacharier, M.D., call Judy Martin at 314-286-0105 or email Martinju@wustl.edu. To contact editorial co-author Robyn T. Cohen, M.D., M.P.H., call Elissa Snook at 617- 638-6823 or email Elissa.Snook@bmc.org.

To place an electronic embedded link to this study and editorial in your story This link to the study will be live at the embargo time: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.13896 This will be the link to the editorial: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.14953

Among young children with histories of recurrent severe lower respiratory tract illness (LRTI), the use of azithromycin early during an apparent RTI compared with placebo significantly reduced the risk of experiencing progression to severe LRTI, according to a study in the November 17 issue of JAMA.

Acute episodes of severe LRTI are common among preschoolers, and up to 14 percent to 26 percent of preschoolers present with recurrent wheezing during the first 6 years of life. These severe episodes are often associated with substantial illness, and may result in visits to urgent care and emergency departments. Although viral infections are often present, bacteria may also contribute to illness development. Identification of treatment approaches that lessen the severity of these recurrent episodes would provide substantial benefit to preschool children with recurrent severe LRTI, according to background information in the article.

Leonard B. Bacharier, M.D., of the Washington University in St. Louis School of Medicine, and colleagues randomly assigned 607 children (age 12 months through 71 months) with histories of recurrent, severe LRTIs to receive the antibiotic azithromycin (for 5 days; n = 307) or matching placebo (n = 300), started early during each predefined RTI (child’s signs or symptoms prior to development of LRTI), based on individualized action plans. The trial was conducted across 9 academic U.S. medical centers in the National Heart, Lung, and Blood Institute’s AsthmaNet network.

A total of 937 treated RTIs (azithromycin group, 473; placebo group, 464) were experienced by 443 children (azithromycin group, 223; placebo group, 220), including 92 severe LRTIs (azithromycin group, 35; placebo group, 57). The azithromycin group experienced a significantly lower risk of progressing to severe LRTI than the placebo group. Adverse events were infrequently observed.

Although limited to 86 participants at a single study site, the researchers found numerically higher rates of acquisition of azithromycin-resistant organisms in oropharyngeal samples in participants receiving azithromycin and those who did not, along with evidence of acquisition of azithromycin-resistant organisms even in participants not treated with azithromycin. “Real-world rates of development of azithromycin-resistant organisms may be greater, potentially due to failure to complete the full duration of therapy often seen in clinical practice. Given the small sample size, further studies are needed to assess the potential increased risk of antibiotic resistance vs the comparative effectiveness of azithromycin with respect to other asthma medications to prevent severe LRTI,” the authors write.

“In children with the phenotype of wheezing studied herein, clinicians may consider a therapeutic trial of azithromycin early in the course of RTIs based on a parent-initiated individualized plan. Children who demonstrate an azithromycin response, as reflected by less-severe episodes of RTI, may benefit from repeating such therapy with subsequent illnesses.”

“Studies replicating the findings reported herein would provide further support to this conclusion, and future studies comparing the relative benefits of early azithromycin therapy with either daily or intermittent high-dose inhaled corticosteroids may help determine the relative efficacies of these treatment strategies.”

(doi:10.1001/jama.2015.13896; Available pre-embargo to the media at http:/media.jamanetwork.com)

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

Editorial: Individual Benefit vs Societal Effect of Antibiotic Prescribing for Preschool Children With Recurrent Wheeze

“Limiting children’s loss of days from school (or parents’ days from work) and relieving the anxiety that an RTI that may progress to a hospitalization is almost certainly to be of benefit to children and families,” write Robyn T. Cohen, M.D., M.P.H., and Stephen I. Pelton, M.D., of the Boston University School of Medicine, in an accompanying editorial

“The question is how to determine (through studies incorporating biomarkers, airway endotyping, or genetics) which children are most likely to obtain the largest benefit from early initiation of azithromycin. Until a higher-risk population can be prospectively identified (rather than all children with intermittent wheezing associated with viral RTI) for progression to severe LRTI, the consequences of widespread use of azithromycin, both known and hypothesized, outweigh the benefit for most children.”

(doi:10.1001/jama.2015.14953; Available pre-embargo to the media at http:/media.jamanetwork.com)

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

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EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, NOVEMBER 17, 2015

Media Advisory: To contact Cunlin Wang, M.D., Ph.D., call Sarah Peddicord at 301-796-2805 or email sarah.peddicord@fda.hhs.gov.

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Cunlin Wang, M.D., Ph.D., of the U.S. Food and Drug Administration, Silver Spring, Md., and colleagues studied recipients of intravenous (IV) iron (n = 688,183) enrolled in the fee-for-service Medicare program from January 2003 to December 2013. The study appears in the November 17 issue of JAMA.

In 2010, anemia affected one third of the global population, and iron deficiency was the most common cause. Oral iron replacement is the primary treatment strategy for iron deficiency anemia but may be inadequate for some patients due to intolerance, impaired absorption, significant ongoing bleeding, or nonadherence. For these patients, intravenous iron may be indicated. As of June 2013, there were 5 IV iron products marketed in the United States. While their efficacy is established, the most important safety concern relates to the risk of serious and fatal anaphylaxis (an allergic reaction to a substance), which may occur at both first and subsequent exposures. The comparative safety of each product has not been well established, according to background information in the article.

This study examined administrations of IV iron dextran, gluconate, sucrose, or ferumoxytol. A total of 274 anaphylaxis cases were identified at first exposure, with an additional 170 cases identified during subsequent IV iron administrations. The researchers found that iron dextran was associated with increased anaphylaxis risk compared with nondextran formulations at first administration. Among the nondextran products, the risk of anaphylaxis at first administration was higher with both iron gluconate and ferumoxytol than with iron sucrose.

Because each IV iron product has a specific recommended dose and schedule of administration, the cumulative risk of anaphylaxis was also calculated based on both the number of administrations and clinically relevant repletion level of iron (1000 mg) achieved within 12 weeks. Both analyses showed iron dextran was associated with the highest cumulative risk of anaphylaxis and iron sucrose with the lowest risk.

The authors note that the mechanism of anaphylactic reaction after IV iron remains unknown.

(doi:10.1001/jama.2015.15572; Available pre-embargo to the media at http:/media.jamanetwork.com)

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

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EMBARGOED FOR RELEASE: 5:50 P.M. (ET) FRIDAY, NOVEMBER 13, 2015

Media Advisory: To contact Lee M. Jampol, M.D., DRCR Network Chair, email l-jampol@northwestern.edu; to contact Adam R. Glassman, M.S., Director DRCR.net Coordinating Center, email aglassman@jaeb.org. To contact editorial author Timothy W. Olsen, M.D., call Joy Bell at 404-778-3711 or email JBELL@emory.edu.

Video and Audio Content: There will be a video and audio report for this study, posted under embargo by 1 p.m. ET Wednesday, November 11 at https://media.jamanetwork.com/. This will include broadcast-quality downloadable video and audio files, B-roll, scripts, and other images.

To place an electronic embedded link to this study and editorial in your story This link to the study will be live at the embargo time: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.15217 This will be the link to the editorial: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.15409
Among patients with proliferative diabetic retinopathy, treatment with an injection in the eye of the drug ranibizumab resulted in visual acuity that was not worse than panretinal photocoagulation at 2 years, according to a study appearing in JAMA. This study is being released to coincide with its presentation at the American Academy of Ophthalmology annual meeting.

Proliferative diabetic retinopathy (PDR; a more advanced form of the disease) is a leading cause of vision loss in patients with diabetes mellitus, resulting in 12,000 to 24,000 new cases of blindness each year in the United States. Panretinal photocoagulation (PRP; procedure that involves use of a laser) is the standard treatment for reducing severe visual loss from PDR. However, PRP can cause permanent peripheral visual field loss and decreased night vision and may exacerbate diabetic macular edema (DME; swelling of the retina in diabetes mellitus due to leaking of fluid from blood vessels within the macula), which makes alternative treatments desirable, according to background information in the article.

When used as treatment of DME, intravitreous (in the vitreous, the fluid behind the lens in the eye) anti-vascular endothelial growth factor (VEGF) agents reduce the risk of diabetic retinopathy worsening and increase the chance of improvement, making these agents a potentially viable PDR treatment. Adam R. Glassman, M.S., of Jaeb Center for Health Research, Tampa, Fla., and the Writing Committee for the Diabetic Retinopathy Clinical Research Network, and colleagues conducted a study that included 305 adults with PDR; both eyes were enrolled for 89 participants (1 eye to each study group), with a total of 394 study eyes. Individual eyes were randomly assigned to receive PRP treatment, completed in 1 to 3 visits (n = 203 eyes), or the anti-VEGF agent ranibizumab, by intravitreous injection at study entry and as frequently as every 4 weeks based on a structured retreatment protocol (n = 191 eyes). Eyes in both treatment groups could receive ranibizumab for DME. The trial was conducted at 55 U.S. sites.

The researchers found that intravitreous ranibizumab met a prespecified noninferiority (not worse than) outcome of visual acuity change at 2 years than in the PRP group. There was no statistically significant visual acuity difference between the groups at 2 years, with the authors noting that 53 percent of the PRP group received ranibizumab injections for DME.

More peripheral visual field loss occurred, more vitrectomies (removal of the gel [vitreous] from within the eyeball) were performed, and DME development was more frequent in the PRP group compared with the ranibizumab group. No systemic safety concerns with ranibizumab were identified in the prespecified major safety outcomes.

“Although longer-term follow-up is needed, ranibizumab may be a reasonable treatment alternative at least through 2 years for patients with PDR,” the authors write.

(doi:10.1001/jama.2015.15217; Available pre-embargo to the media at http:/media.jamanetwork.com)

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

Editorial: Anti-VEGF Pharmacotherapy as an Alternative to Panretinal Laser Photocoagulation for Proliferative Diabetic Retinopathy

“In summary, this important study by the Diabetic Retinopathy Clinical Research [DRCR].net investigators represents a major step forward for patients with PDR by providing the ophthalmologists who manage their retinal disease with new options,” writes Timothy W. Olsen, M.D., of Emory University, Atlanta, in an accompanying editorial.

“The short-term role (2 years) for using anti-VEGF agents seems to represent a viable alternative therapy for adherent patients with high-risk PDR. Nevertheless, PRP represents the standard of care for PDR and may represent the best long-term treatment option for high-risk PDR. It is certainly not time to abandon PRP in favor of exclusively treating patients with PDR using only intravitreal anti­VEGF injections. Clinical judgment and timing of initiation of either therapy are viable options, and the findings reported by the DRCR.net researchers provide clinicians with evidence to support the alternative option of anti-VEGF pharmacotherapy for high-risk PDR. Further advances in pharmacologic management and sustained delivery systems will help expand this alternative therapy for PDR.”

(doi:10.1001/jama.2015.15409; Available pre-embargo to the media at http:/media.jamanetwork.com)

Editor’s Note: This work was supported by an unrestricted departmental grant from Research to Prevent Blindness, New York, NY. Please see the article for additional information, including financial disclosures, etc.

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EMBARGOED FOR RELEASE: 3:45 P.M. (ET) SUNDAY, NOVEMBER 8, 2015

Media Advisory: To contact Mihai Gheorghiade, M.D., email Marla Paul at marla-paul@northwestern.edu.

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Mihai Gheorghiade, M.D., of the Northwestern University Feinberg School of Medicine, Chicago, and colleagues randomly assigned 456 patients with worsening chronic HF and reduced left ventricular ejection fraction (a measure of how well the left ventricle of the heart pumps with each beat) to receive placebo or 1 of 4 daily target doses of the medication vericiguat for 12 weeks. This JAMA study is being released to coincide with its presentation at the American Heart Association’s Scientific Sessions 2015.

More than 1 million hospitalizations for heart failure (HF) occur annually in the United States alone, and more than 80 percent of these hospitalized patients have worsening chronic HF. Despite an often rapid and substantial in-hospital improvement in HF signs and symptoms with standard therapy, approximately 25 percent of patients are rehospitalized within 30 days and 30 percent of patients may die within 1 year.

This phase 2 study, which included patients from across Europe, North America, and Asia, was conducted to determine the optimal dose and tolerability of the drug vericiguat to reduce elevated natriuretic peptide levels. Natriuretic peptides are produced by the heart in response to high pressures inside the heart, which is typical in heart failure. Elevated levels are seen in the setting of worsening heart failure and correlate with severity of symptoms and risk of death.

Overall, 351 patients (77 percent) completed treatment with the study drug with valid 12-week N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels and no major protocol deviation. In the primary analysis, change in NT-proBNP levels from baseline to week 12 was not significantly different between the pooled vericiguat group and placebo. The secondary analysis suggested a dose-response relationship, such that higher vericiguat doses were associated with greater reductions in NT-proBNP level. Rates of any adverse event were 77 percent and 71 percent among the placebo and 10-mg vericiguat groups, respectively.

“Among patients with worsening chronic HF and reduced LVEF, compared with placebo, vericiguat did not have a statistically significant effect on change in NT-proBNP level at 12 weeks but was well-tolerated. Further clinical trials of vericiguat based on the dose-response relationship in this study are needed to determine the potential role of this drug for patients with worsening chronic HF,” the authors write.

(doi:10.1001/jama.2015.15734; Available pre-embargo to the media at http:/media.jamanetwork.com)

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

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EMBARGOED FOR RELEASE: 4:00 P.M. (ET) SUNDAY, NOVEMBER 8, 2015

Media Advisory: To contact Anna Svatikova, M.D., Ph.D., call Traci Klein at 507-990-1182 or email Klein.Traci@mayo.edu.

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Anna Svatikova, M.D., Ph.D., of the Mayo Clinic, Rochester, Minn., and colleagues randomly assigned 25 healthy volunteers (age 18 years or older) to consume a can (480 mL; 16 fl. oz.) of a commercially available energy drink (Rockstar; Rockstar Inc) and placebo drink within 5 minutes, in random order on 2 separate days, maximum 2 weeks apart. The placebo drink, selected to match the nutritional constituents of the energy drink, was similar in taste, texture, and color but lacked caffeine and other stimulants of the energy drink (240 mg of caffeine, 2,000 mg of taurine, and extracts of guarana seed, ginseng root, and milk thistle). This JAMA study is being released to coincide with its presentation at the American Heart Association’s Scientific Sessions 2015.

Energy drink consumption has been associated with serious cardiovascular events, possibly related to caffeine and other stimulants. The researchers examined the effect of energy drink consumption on hemodynamic changes, such as blood pressure and heart rate. Participants were fasting and abstained from caffeine and alcohol 24 hours prior to each study day. Serum levels of caffeine, plasma glucose, and norepinephrine (noradrenaline) were measured and blood pressure and heart rate were obtained at baseline and 30 minutes after drink ingestion.

Caffeine levels remained unchanged after the placebo drink, but increased significantly after energy drink consumption. Consumption of the energy drink elicited a 6.2 percent increase in systolic blood pressure; diastolic blood pressure increased by 6.8 percent; average blood pressure increased after consumption of the energy drink by 6.4 percent. There was no significant difference in heart rate increase between the 2 groups. The average norepinephrine level increased from 150 pg/mL to 250 pg/mL after consumption of the energy drink and from 140 pg/mL to 179 pg/mL after placebo (change rate: 74 percent vs 31 percent, respectively).

“These acute hemodynamic and adrenergic changes may predispose to increased cardiovascular risk,” the authors write. “Further research in larger studies is needed to assess whether the observed acute changes are likely to increase cardiovascular risk.”

(doi:10.1001/jama.2015.13744; Available pre-embargo to the media at http:/media.jamanetwork.com)

Editor’s Note: This research was supported by a grant from the Mayo Foundation and the National Center for Advancing Translational Sciences, National Institutes of Health. The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.

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EMBARGOED FOR RELEASE: 9:00 A.M. (ET) MONDAY, NOVEMBER 9, 2015

Media Advisory: To contact Nihar R. Desai, M.D., M.P.H., call Karen Peart at 203-432-1326 or email karen.peart@yale.edu. To contact editorial author Robert A. Harrington, M.D., email Tracie White at traciew@stanford.edu.

To place an electronic embedded link to this study and editorial in your story This link to the study will be live at the embargo time: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.13764 This will be the link to the editorial: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.13764

Nihar R. Desai, M.D., M.P.H., of the Yale School of Medicine, New Haven, Conn., and colleagues examined trends in percutaneous coronary intervention use, patient selection, and procedural appropriateness following the introduction of Appropriate Use Criteria. This JAMA study is being released to coincide with its presentation at the American Heart Association’s Scientific Sessions 2015.

In 2009, the American College of Cardiology and the American Heart Association, along with other professional societies, released Appropriate Use Criteria for Coronary Revascularization to critically examine and improve patient selection for percutaneous coronary intervention (PCI; commonly known as coronary angioplasty, a non-surgical procedure used to open narrow or blocked coronary arteries) as well as address concerns about potential overuse. Prior studies demonstrated that 1 in 6 nonacute PCIs were classified as inappropriate, indicating that the benefits of the procedure were unlikely to outweigh the risks. National trends in the appropriateness of PCI have not been examined since the introduction of the Appropriate Use Criteria, according to background information in the article.

This analysis included patients undergoing PCI between July 2009 and December 2014 at hospitals continuously participating in the National Cardiovascular Data Registry CathPCI registry over the study period. The researchers determined the proportion of nonacute PCIs classified as inappropriate at the patient and hospital level using the 2012 Appropriate Use Criteria for coronary revascularization.

A total of 2.7 million PCI procedures from 766 hospitals were included. Annual PCI volume of acute indications was consistent over the study period, but the volume of nonacute PCIs decreased from 89,704 in 2010 to 59,375 in 2014. The proportion of nonacute PCIs classified as inappropriate decreased from 26 percent to 13 percent, and the absolute number of inappropriate PCIs decreased from 21,781to 7,921. Hospital-level variation in the proportion of PCIs classified as inappropriate persisted over the study period (median, 13 percent in 2014).

Among patients undergoing nonacute PCI, there were significant increases in angina severity, use of antianginal medications prior to PCI, and high-risk findings on noninvasive testing, but only modest increases in multivessel coronary artery disease.

“This analysis provides details about changes in the clinical profiles of patients undergoing PCI and suggests that the observed reductions in inappropriate PCI in part reflect improvements in patient selection and clinical decision making as well as better documentation of the key elements used to determine procedural appropriateness,” the authors write. “These findings may indicate that clinicians are doing a better job of identifying and limiting nonacute PCI procedures to those patients most likely to benefit from revascularization.”

“Collectively, these findings suggest that the practice of interventional cardiology has evolved since the introduction of Appropriate Use Criteria in 2009.”

(doi:10.1001/jama.2015.13764; Available pre-embargo to the media at http:/media.jamanetwork.com)

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

Editorial: Appropriate Use Criteria for Coronary Revascularization and the Learning Health System

“As reported by Desai et al, the use of the National Cardiovascular Data Registry has allowed temporal review of the PCI appropriate use criteria,” writes Robert A. Harrington, M.D., of Stanford University, Stanford, Calif., in an accompanying editorial.

“However, these data analyses are retrospective. What is needed is a national system that allows immediate real-time decision support for clinical activities fully integrated with clinical research capabilities that use constantly accumulating data and sophisticated data analytics, including randomization when appropriate. Only at that point will the continuously learning health care system be a reality.”

(doi:10.1001/jama.2015.13764; Available pre-embargo to the media at http:/media.jamanetwork.com)

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

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EMBARGOED FOR RELEASE: 9:00 A.M. (ET) MONDAY, NOVEMBER 9, 2015

Media Advisory: To contact Josep Rodes-Cabau, M.D., email Josep.Rodes@criucpq.ulaval.ca.

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Josep Rodes-Cabau, M.D., of Laval University, Quebec City, Canada, and colleagues randomly assigned 171 patients with an indication for atrial septal defect (ASD) closure and no history of migraine to receive dual antiplatelet therapy (aspirin + clopidogrel [the clopidogrel group], n = 84) or single antiplatelet therapy (aspirin + placebo [the placebo group], n = 87) for 3 months following transcatheter ASD closure. This JAMA study is being released to coincide with its presentation at the American Heart Association’s Scientific Sessions 2015.

An atrial septal defect is a hole in the part of the septum (wall) that separates the upper chambers of the heart. Occurrence of new-onset migraine attacks has been reported in approximately 15 percent of patients following transcatheter ASD closure, with the majority of initial episodes occurring within the days to weeks following the procedure. Aspirin is often prescribed for 6 months following the procedure. Preliminary studies have suggested an association with a lower incidence and severity of migraine headaches following ASD closure when ticlopidine or clopidogrel is added to aspirin treatment.

The researchers found that patients in the clopidogrel group had a reduced average number of monthly migraine days within the 3 months following the procedure (0.4 days) vs the placebo group (1.4 days) and a lower incidence of migraine attacks (9.5 percent for the clopidogrel group vs 22 percent for the placebo group). Among patients with migraines, those in the clopidogrel group had less-severe migraine attacks (zero patients with moderately or severely disabling migraine attacks vs 37 percent [7 patients] in the placebo group). No significant increase in adverse events was observed with the use of dual vs single antiplatelet therapy.

“Further studies are needed to assess generalizability and durability of this effect,” the authors write.

(doi:10.1001/jama.2015.13919; Available pre-embargo to the media at http:/media.jamanetwork.com)

Editor’s Note: This study was funded by unrestricted grants from Sanofi and St. Jude Medical and a grant from the Foundation of the Quebec Heart and Lung 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: 10:45 A.M. (ET) TUESDAY, NOVEMBER 10, 2015

Media Advisory: To contact Myeong-Ki Hong, M.D., Ph.D., email mkhong61@yuhs.ac.

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Myeong-Ki Hong, M.D., Ph.D., of the Yonsei University College of Medicine, Seoul, Korea and colleagues randomly assigned 1,400 patients with long coronary lesions to receive intravascular ultrasound-guided (n = 700) or angiography-guided (n = 700) everolimus-eluting stent implantation. This JAMA study is being released to coincide with its presentation at the American Heart Association’s Scientific Sessions 2015.

Even though recent guidelines recommend the use of intravascular ultrasound (IVUS) to optimize stent implantation for select patients, the effect of IVUS-guided drug-eluting (releasing) stent implantation on clinical outcomes remains uncertain because of the limited number of properly powered randomized trials.

For this trial, one-year follow-up was complete in 1,323 patients (94.5 percent). Major adverse cardiac events (including cardiac death, target lesion-related heart attack, or ischemia-driven target lesion revascularization) at 1 year occurred in 39 patients (5.8 percent) undergoing angiography-guided and in 19 patients (2.9 percent) undergoing IVUS-guided stent implantation (a 2.9 percent absolute reduction and 48 percent relative reduction). The difference was driven by a lower risk of ischemia-driven target lesion revascularization in patients undergoing IVUS-guided (17 [2.5 percent]) compared with angiography-guided (33 [5 percent]) stent implantation.

Cardiac death and target lesion-related heart attack were not significantly different between the 2 groups. For cardiac death, there were 3 patients (0.4 percent) in the IVUS-guided group and 5 patients (0.7 percent) in the angiography-guided group. Target lesion-related heart attack occurred in 1 patient in the angiography-guided stent implantation group.

“Our findings suggest better clinical outcomes for major adverse cardiac events with IVUS-guided stent implantation compared with angiography-guided stent implantation, particularly for diffuse long lesions,” the authors write.

(doi:10.1001/jama.2015.15454; Available pre-embargo to the media at http:/media.jamanetwork.com)

Editor’s Note: This study was supported by the Cardiovascular Research Center (Seoul, Korea) and funded by Abbott Vascular Inc. The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.

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EMBARGOED FOR RELEASE: 11 A.M. (ET) SUNDAY, NOVEMBER 8, 2015

Media Advisory: To contact Kevin G. Volpp, M.D., Ph.D., call Katie Delach at 215-349-5964 or email Katharine.Delach@uphs.upenn.edu.

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In a study examining the effect of financial incentives to improve lipid levels among patients in primary care practices, shared financial incentives for physicians and patients, but not incentives to physicians or patients alone, resulted in a modest reduction of low-density lipoprotein cholesterol (LDL-C) levels after 12 months, according to a study in the November 10 issue of JAMA. This issue, a cardiovascular disease theme issue, coincides with the American Heart Association’s Scientific Sessions 2015.

Cardiovascular disease is the leading cause of death in the United States, and studies indicate that taking statins to lower cholesterol reduces the risk of heart attack by about 30 percent. Despite proven benefits, the relatively low cost, once-a-day dosing, and few adverse effects, the population effectiveness of statins is limited for several reasons, including physicians underprescribing statins or failing to intensify treatment when indicated, and poor medication adherence among patients. Financial incentives to physicians or patients are increasingly used, but their effectiveness is not well established, according to background information in the article.

David A. Asch, M.D., and Kevin G. Volpp, M.D., Ph.D., of the University of Pennsylvania, Philadelphia, and colleagues conducted a study in which primary care physicians were randomly assigned to one of four groups: control, physician incentives, patient incentives, or shared physician-patient incentives. Physicians in the physician incentives group were eligible to receive up to $1,024 per enrolled patient meeting LDL-C goals. Patients in the patient incentives group were eligible for the same amount, distributed through daily lotteries tied to medication adherence. Physicians and patients in the shared incentives group shared these incentives. Physicians and patients in the control group received no incentives tied to outcomes, but all patient participants received up to $355 each for trial participation.

The clinical trial was conducted in 3 health care delivery systems in the northeastern United States. Three hundred forty eligible primary care physicians (PCPs) were enrolled from a pool of 421. Of 25,627 potentially eligible patients of those PCPs, 1,503 were enrolled.

After 12 months, the average reduction in LDL-C levels for patients was:

25.1 mg/dL for patients in the control group;

25.1 mg/dL for patients in the patient incentives group;

27.9 mg/dL for patients in the physician incentives group;

33.6 mg/dL for patients in the shared physician-patient incentives group.

Only patients in the shared physician-patient incentives group achieved reductions in LDL-C levels statistically different from those in the control group (difference of 8.5 mg/dl). “This outcome is supported by the finding that 49 percent of the patients in the shared patient and physician incentive group achieved the LDL-C goal in comparison with 36 percent to 40 percent in the other 3 groups. The superiority of a shared approach makes sense because success at LDL-C reduction is likely to be driven by both provision of medication by physicians and patient adherence to that medication. Consistent with this hypothesis, patients in the shared group were more likely to receive medication intensification and to adhere to medication use than patients in other groups.”

The author note that the reduction in LDL-C levels achieved by the patients in the shared physician-patient incentives group were modest, and that further information is needed to understand whether this approach represents good value.

(doi:10.1001/jama.2015.14850; Available pre-embargo to the media at http:/media.jamanetwork.com)

Editor’s Note: This study received support from the National Institute on Aging. 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) SUNDAY, NOVEMBER 8, 2015

Media Advisory: To contact David A. Bluemke, M.D., Ph.D., email Molly Freimuth at molly.freimuth@nih.gov.

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In a multiethnic, middle-aged and older study population, the prevalence of myocardial scars (evidence of a heart attack) was nearly 8 percent, of which nearly 80 percent were unrecognized by electrocardiography or clinical evaluation, according to a study in the November 10 issue of JAMA. This issue, a cardiovascular disease theme issue, coincides with the American Heart Association’s Scientific Sessions 2015.

Ischemic heart disease is an important public health concern, but a considerable proportion of myocardial infarctions (MIs; heart attacks) are clinically unrecognized. Given the aging of the U.S. population, it is important to understand the prevalence, risk factors, and prognosis of unrecognized MI. In patients who survive a heart attack, normal contractile (having the property of contracting) tissue is replaced by noncontractile fibrosis (formation of excess fibrous connective tissue in a reparative process) (scar). Myocardial scarring leads to abnormal heart function and poor prognosis. The prevalence of and factors associated with unrecognized MI and scar have not been previously defined using contemporary methods in a multiethnic U.S. population, according to information in the article.

David A. Bluemke, M.D., Ph.D., of the National Institute of Biomedical Imaging and Bioengineering, Bethesda, Md., and colleagues examined the prevalence of myocardial scar using cardiac magnetic resonance (CMR; considered a standard of reference for defining the presence of myocardial scar). Participants were multiethnic, 45 through 84 years of age and free of clinical cardiovascular disease (CVD) at study entry in 2000-2002. In the 10th year examination (2010-2012), 1,840 participants (average age, 68 years; 52 percent men) underwent CMR imaging with gadolinium to detect myocardial scar. Cardiovascular disease risk factors and coronary artery calcium (CAC) scores were measured at study entry and year 10.

The overall prevalence of myocardial scar by CMR was 7.9 percent (146 of 1,840). The prevalence of previously unrecognized myocardial scar was 6.2 percent, whereas 1.7 percent had clinically recognized MI. Thus, 78 percent (114 of 146) of myocardial scars were unrecognized by clinical or electrocardiography (ECG) evaluation. Men had a higher prevalence of myocardial scar than women (12.9 percent vs 2.5 percent).

Of individual risk factors, age, male sex, CAC score, body mass index, current smoking, and use of antihypertensive medications at study entry were associated with higher odds of myocardial scar.

“The clinical significance of unrecognized myocardial scar remains to be defined, although prior myocardial scar has been noted pathologically in more than 70 percent of patients with sudden cardiac death but without prior known coronary artery disease,” the authors write. “Further studies are needed to understand the clinical consequences of these undetected scars.”

(doi:10.1001/jama.2015.14849; Available pre-embargo to the media at http:/media.jamanetwork.com)

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

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EMBARGOED FOR RELEASE: 11 A.M. (ET) SUNDAY, NOVEMBER 8, 2015

Media Advisory: To contact Adrian F. Hernandez, M.D., M.H.S., call Sarah Avery at 919-660-1306 or email sarah.avery@duke.edu.

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Although frequent laboratory monitoring of patients with heart failure following initiation of mineralocorticoid receptor antagonists is supported by the results of large clinical trials and recommended in guidelines, there appears to be low rates of monitoring in clinical practice, according to a study in the November 10 issue of JAMA. This issue, a cardiovascular disease theme issue, coincides with the American Heart Association’s Scientific Sessions 2015.

Mineralocorticoid receptor antagonists (MRAs) are a cornerstone of heart failure therapy but carry a risk of hyperkalemia (elevated potassium in the blood). Clinical guidelines recommend close monitoring of kidney function and electrolyte (including potassium) levels throughout the course of therapy. No large studies have examined whether laboratory monitoring occurs routinely in community practice. Adrian F. Hernandez, M.D., M.H.S., of the Duke University School of Medicine, Durham, N.C., and colleagues analyzed a group of patients (10,443 Medicare beneficiaries) with heart failure who had initiated MRA therapy (eplerenone or spironolactone). The researchers examined the frequency of measurement of serum creatinine and potassium levels before and after MRA initiation.

The researchers found that combined, 756 patients (7 percent) received appropriate testing before and after MRA initiation. After initiation of MRA therapy, 13 percent and 30 percent of patients received appropriate testing in early and extended follow-up, respectively. In contrast, 55 percent and 22 percent received no testing in early or extended follow-up, respectively. Atrial fibrillation, anemia, chronic kidney disease, chronic obstructive pulmonary disease, hypothyroidism, osteoporosis, and use of diuretics were associated with a greater likelihood of appropriate laboratory testing during all periods.

“The landmark trials of MRAs in heart failure showed MRAs significantly reduced mortality and cardiovascular readmission compared with placebo. However, an analysis of community practice found similar outcomes among patients treated or not treated with an MRA. One possible explanation may be less rigorous monitoring outside clinical trial settings, which may increase risks of adverse events associated with MRAs,” the authors write.

“Closing the gap between the efficacy and effectiveness of MRAs in heart failure will require clinicians to address this issue. Quality improvement initiatives to improve appropriate laboratory monitoring are needed.”

(doi:10.1001/jama.2015.11904; Available pre-embargo to the media at http:/media.jamanetwork.com)

Editor’s Note: This project was supported in part by a grant from the Agency for Healthcare Research and Quality. Dr. Cooper was supported by a grant from 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) SUNDAY, NOVEMBER 8, 2015

Media Advisory: To contact M.G. Myriam Hunink, M.D., Ph.D., email m.hunink@erasmusmc.nl. To contact editorial author Mary McGrae McDermott, M.D., email Marla Paul at marla-paul@northwestern.edu.

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Among patients with peripheral artery disease and intermittent claudication (cramping pain in the legs due to poor circulation in the arteries, aggravated by walking), a combination therapy of endovascular revascularization (an invasive procedure to improve blood flow in an artery) followed by supervised exercise resulted in greater improvement in walking distances and health-related quality-of-life measures at one year compared with supervised exercise only, according to a study in the November 10 issue of JAMA. This issue, a cardiovascular disease theme issue, coincides with the American Heart Association’s Scientific Sessions 2015.

Intermittent claudication is the classic symptomatic form of peripheral artery disease (PAD), affecting approximately 20 to 40 million people worldwide and increasing rapidly with the aging world population. Patients with claudication experience significant functional disability often resulting in a sedentary lifestyle and reduced quality of life. Supervised exercise is recommended as a first-line treatment. A combination therapy of endovascular revascularization plus supervised exercise may be beneficial, but few data comparing the two therapies are available, according to background information in the article.

M.G. Myriam Hunink, M.D., Ph.D., of the Erasmus University Medical Center, Rotterdam, the Netherlands, and colleagues randomly assigned 212 patients with PAD and intermittent claudication to endovascular revascularization plus supervised exercise (n = 106) or supervised exercise only (n = 106). The primary measured outcome for the study was the difference in maximum treadmill walking distance at 12 months between the groups.

The researchers found that endovascular revascularization plus supervised exercise (combination therapy) was associated with greater improvement in maximum walking distance compared with the supervised exercise only group, and in pain-free walking distance. Also, the combination therapy group demonstrated significantly greater improvement in health-related quality-of-life.

“The present study reopens the debate for revascularization in patients with claudication, in particular in terms of an approach using endovascular revascularization first. By improving lower extremity blood flow, early percutaneous revascularization of the target lesion gives an impulse to patient mobility and quality of life in the short-term. This, in turn, facilitates subsequent exercising and allows the patient to profit from the long-term benefits of an additional supervised exercise program,” the authors write.

(doi:10.1001/jama.2015.14851; Available pre-embargo to the media at http:/media.jamanetwork.com)

Editor’s Note: All study funding was provided by the Netherlands Organisation for Health Research and Development. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, etc.

Editorial: Erasing Disability in Peripheral Artery Disease

The results of this trial (ERASE) underscore once again the benefits of supervised treadmill exercise for patients with peripheral artery disease, writes Mary McGrae McDermott, M.D., of the Northwestern University Feinberg School of Medicine, Chicago, and Senior Editor, JAMA, in an accompanying editorial.

“Randomized trial evidence already convincingly demonstrates that supervised treadmill exercise improves walking performance compared with no exercise. The ERASE trial newly demonstrates that supervised exercise also improves lower extremity outcomes after endovascular revascularization. Current reimbursement strategies in the United States provide significant incentives for clinicians to offer endovascular revascularizations to patients with peripheral artery disease, whereas supervised exercise remains expensive and inaccessible to patients. Reducing disability from peripheral artery disease in the 21st century requires strategies to ensure that effective exercise programs are accessible for all patients with peripheral artery disease.”

(doi:10.1001/jama.2015.15116; Available pre-embargo to the media at http:/media.jamanetwork.com)

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

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EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, NOVEMBER 3, 2015

Media Advisory: To contact Elizabeth D. Kantor, Ph.D., M.P.H., call Nicole McNamara at 646-227-3633 or email mcnamarn@mskcc.org.

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Between 1999-2012, overall prescription drug use increased among U.S. adults, with this increase seen for the majority of but not all drug classes, according to a study in the November 3 issue of JAMA.

Use of prescription drugs represents a major expenditure in the United States, and research suggests that use of prescription drugs is increasing. Yet much of the information about prescription use is derived from pharmacy databases or expenditure data, neither of which directly captures use at the population level. It is important to document patterns of prescription drug use to inform both clinical practice and research, according to background information in the article.

Elizabeth D. Kantor, Ph.D., M.P.H., formerly of the Harvard T.H. Chan School of Public Health, Boston, and colleagues evaluated trends in prescription drug use using nationally representative data from the National Health and Nutrition Examination Survey (NHANES). Participants included 37,959 U.S. adults, age 20 years and older. Seven NHANES cycles were included (1999-2000 to 2011-2012), and the sample size per cycle ranged from 4,861 to 6,212. Within each NHANES cycle, use of prescription drugs in the prior 30 days was assessed overall and by drug class.

The researchers found that the prevalence of prescription drug use increased from 51 percent in 1999-2000 to 59 percent in 2011-2012, while the prevalence of polypharmacy (use of five or more prescription drugs) increased from 8 percent to 15 percent. Use of medications for hypertension increased (20 percent-27 percent), as did medications to treat hyperlipidemia, a trend largely driven by statins (7 percent-17 percent). Use of antidepressants also increased (7 percent-13 percent). Among the 18 drug classes used by more than 2.5 percent of the population at any point over the study period, the prevalence of use increased in 11 drug classes.

Prescription drug use increased significantly among persons 40 to 64 years of age and also among those 65 years and older, but not among adults 20 to 39 years old.

The most commonly used individual drug in 2011-2012 was simvastatin (7.9 percent), increasing from 2.0 percent in 1999-2000. The remaining top 10 drugs included lisinopril, levothyroxine, metoprolol, metformin, hydrochlorothiazide, omeprazole, amlodipine, atorvastatin, and albuterol; all of the top 10 most commonly used drugs increased over the study period except atorvastatin.

“Eight of the 10 most commonly used drugs in 2011-2012 are used to treat components of the cardiometabolic syndrome, including hypertension, diabetes, and dyslipidemia. Another is a proton-pump inhibitor used for gastroesophageal reflux, a condition more prevalent among individuals who are overweight or obese. Thus, the increase in use of some agents may reflect the growing need for treatment of complications associated with the increase in overweight and obesity,” the authors write.

(doi:10.1001/jama.2015.13766; Available pre-embargo to the media at http:/media.jamanetwork.com)

Editor’s Note: Elizabeth D. Kantor, Ph.D., M.P.H., is now with the Memorial Sloan Kettering Cancer Center, New York. 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, NOVEMBER 3, 2015

Media Advisory: To contact Saleh A. Almenawer, M.D., call Veronica McGuire at 905-525-9140, ext. 22169 or email vmcguir@mcmaster.ca. To contact editorial co-author Joanna M. Wardlaw, M.D., F.R.C.R., email joanna.wardlaw@ed.ac.uk.

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In a meta-analysis of randomized clinical trials for the treatment of acute ischemic stroke, an endovascular intervention (such as use of a very small catheter to remove a blood clot) compared to standard medical care (administration of a clot dissolving agent) was associated with improved functional outcomes and higher rates of functional independence at 90 days, but no significant difference in symptomatic intracranial hemorrhage (bleeding in the brain) or all-cause mortality, according to a study in the November 3 issue of JAMA.

The current standard therapy for acute ischemic stroke is intravenous administration of tissue plasminogen activator (tPA). Although intravenous tPA improves survival and functional outcomes when administered as early as possible after onset of ischemic stroke, its use is limited by the narrow therapeutic time window (<4.5 hours), and by several contraindications. As few as 10 percent of patients presenting with ischemic stroke can be eligible for treatment with intravenous tPA. The limitations of its use have led to interest in endovascular therapy for acute ischemic stroke. Endovascular intervention improves blood flow but clinical studies examining this therapy have yielded variable results, warranting further examination, according to background information in the article.

Saleh A. Almenawer, M.D., of McMaster University, Hamilton, Ontario, Canada, and colleagues conducted a meta-analysis that included data from 8 trials involving 2,423 patients with acute ischemic stroke (average age, 67 years; 47 percent women), including 1,313 who underwent endovascular thrombectomy and 1,110 who received standard medical care with tPA. For this analysis, endovascular therapy was defined as the intra-arterial use of a microcatheter or other device for mechanical thrombectomy (clot removal), with or without the use of a chemical thrombolytic (clot busting) agent.

The researchers found that endovascular therapy was associated with a significant treatment benefit across measures of functional outcomes. Functional independence at 90 days occurred among 45 percent of the patients in the endovascular therapy group vs 32 percent of the patients in the standard medical care group. Compared with standard medical care, endovascular thrombectomy was associated with significantly higher rates of angiographic revascularization at 24 hours but no significant difference in rates of symptomatic intracranial hemorrhage (5.7 percent vs 5.1 percent) or all-cause mortality at 90 days (218 deaths [16 percent] vs 201 deaths [18 percent]).

“This meta-analysis synthesizes evidence from multicenter randomized clinical trials, and may help inform the design and execution of future studies examining the efficacy of endovascular therapy for acute ischemic stroke. Additional trials are needed to systematically study the relationship of patient-, disease-, and treatment-related variables with outcomes following mechanical thrombectomy, and to identify the ideal patient to undergo endovascular therapy.”

(doi:10.1001/jama.2015.13767; Available pre-embargo to the media at http:/media.jamanetwork.com)

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

Editorial: Thrombectomy for Acute Ischemic Stroke

“Thrombectomy appears to improve functional outcome for selected patients with internal carotid artery or middle cerebral artery main stem thrombus who have limited comorbidities and who are younger than 80 years. For these patients, intravenous recombinant tissue plasminogen activator should be initiated quickly (if the patient has no contraindications) while rapidly preparing for thrombectomy. Perfusion imaging is not essential,” write Joanna M. Wardlaw, M.D., F.R.C.R., and Martin S. Dennis, M.D., F.R.C.P., of the University of Edinburgh, United Kingdom, in an accompanying editorial.

“However, clinicians should realize that thrombectomy is not necessarily safer than standard medical care, with similar risks of symptomatic intracranial hemorrhage and all-cause mortality reported by Badhiwala et al, along with potential procedural risks.”

“Additional rigorous trials would help to define which additional patients might benefit from thrombectomy and, by how much, including consideration of the effects of comorbidities, advanced age, limits of extractable thrombus location or extent and the latest time window (probably >6 hours). Studies also are needed to determine how to implement thrombectomy in routine practice, including testing the thorny question of who should perform the procedure, and whether the balance of benefit, cost, and service efficiency favor treating just those patients who individually will gain most or treating all patients with a reasonable chance of some worthwhile benefit.”

(doi:10.1001/jama.2015.14674; Available pre-embargo to the media at http:/media.jamanetwork.com)

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

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EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, NOVEMBER 3, 2015

Media Advisory: To contact Robert D. Kirkcaldy, M.D., M.P.H., email Brian Katzowitz at wxq5@cdc.gov.

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Although gonorrhea susceptibility to the antibiotic cefixime has been improving in recent years, suggesting a halt of a drift towards antibiotic resistance, data for 2014 indicates a worsening of susceptibility, according to a study in the November 3 issue of JAMA.

Gonorrhea is a common sexually transmitted disease that, if untreated, can cause a number of reproductive and general health complications. Treatments for gonorrhea have been repeatedly jeopardized by antimicrobial resistance. To ensure effective treatment, the U.S. Centers for Disease Control and Prevention (CDC) periodically updates guidelines based on resistance trends. Following declining cephalosporin susceptibility in several countries, the CDC updated its treatment recommendation in 2010 from single-dose cephalosporin (injectable ceftriaxone or oral cefixime) to a higher dose of ceftriaxone or cefixime plus a second antimicrobial. In 2012, the CDC again updated treatment guidelines and recommended ceftriaxone-based combination therapy as the single recommended therapy.

Robert D. Kirkcaldy, M.D., M.P.H., of the CDC, Atlanta, and colleagues examined recent gonorrhea susceptibility trends (when antibiotics are effective at killing or stopping the growth of a certain bacteria in the laboratory, the bacteria is known as susceptible to antibiotics) to third generation cephalosporin antibiotics (injectable ceftriaxone or oral cefixime). The researchers analyzed data from the CDC’s Gonococcal Isolate Surveillance Project, a system that monitors antimicrobial susceptibility in urethral (opening through which urine is discharged) isolates from men with gonorrhea treated at U.S. public clinics for sexually transmitted disease.

During 2006-2014, 51,144 isolates were collected in 34 cities. The percentage of participants treated with 250 mg of ceftriaxone intramuscularly increased from 8.7 percent in 2006 to 96.6 percent in 2014. The percentage of isolates with reduced cefixime susceptibility increased from 0.1 percent in 2006 to 1.4 percent in 2011, and then declined to 0.4 percent in 2013. In 2014, the percentage of resistant isolates increased to 0.8 percent.

“Although this improvement in susceptibility appears temporally correlated with treatment guideline changes, we cannot establish a causal relationship,” the authors write. “The 2014 data, however, suggest that improvements in susceptibility may be short-lived.”

“The increased prevalence of reduced cefixime susceptibility in 2014 highlights the need to maintain surveillance, search for new therapeutics, and ensure that gonorrhea is treated according to the CDC’s guidelines.”

(doi:10.1001/jama.2015.10347; Available pre-embargo to the media at http:/media.jamanetwork.com)

Editor’s Note: The Gonococcal Isolate Surveillance Project is funded by the CDC. 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, NOVEMBER 3, 2015

Media Advisory: To contact Morten Olsen, M.D., Ph.D., email mo@clin.au.dk

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Although the absolute risk was low, researchers found an increased risk of childhood-onset epilepsy among children in Denmark who had a hospital-diagnosed pertussis infection, compared with the general population, according to a study in the November 3 issue of JAMA.

Pertussis, an acute respiratory tract infection, is among the most common vaccine-preventable childhood diseases in developed countries. Worldwide, an estimated 16 million cases occur each year; almost 50,000 pertussis cases were reported in the United States in 2012. Pertussis is characterized by spasms of coughing and a protracted course. During the acute phase, pertussis is associated with seizures in infants, but the likelihood of developing epilepsy has not been known. Epilepsy is the most common neurologic childhood disorder, and its cause is poorly understood, according to background information in the article.

Morten Olsen, M.D., Ph.D., of the Aarhus University Hospital, Aarhus N, Denmark, and colleagues used population-based medical registries covering all Danish hospitals to identify all patients with pertussis born between 1978 and 2011, followed up through 2011. A database was used to identify 10 individuals from the general population for each patient with pertussis, matched on sex and year of birth.

The researchers identified 4,700 patients with pertussis (48 percent male), of whom 53 percent were diagnosed before age 6 months. In the pertussis cohort, 90 children were diagnosed with epilepsy, compared with 511 children in the comparison cohort. The cumulative incidence of epilepsy at age 10 years was 1.7 percent for patients in the pertussis cohort and 0.9 percent for members of the comparison cohort. Patients older than 3 years when diagnosed with pertussis were not at increased risk of epilepsy compared with the general population.

The authors write that potential mechanisms underlying the observed association include hypoxic brain damage from coughing, perhaps via increased intrathoracic and intra-abdominal pressure and central nervous system hemorrhages.

(doi:10.1001/jama.2015.13971; Available pre-embargo to the media at http:/media.jamanetwork.com)

Editor’s Note: The study was supported by grants from the Program for Clinical Research Infrastructure established by the Lundbeck Foundation and the Novo Nordisk 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, NOVEMBER 3, 2015

Media Advisory: To contact Louise Kuhn, Ph.D., call Stephanie Berger at 212-305-4372 or email sb2247@columbia.edu. To contact editorial author Ram Yogev, M.D., call Julie Pesch at 312-227-4261 or email jpesch@luriechildrens.org.

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Louise Kuhn, Ph.D., of Columbia University, New York, and colleagues evaluated whether HIV-infected children in South Africa who had achieved viral suppression with one treatment could transition to efavirenz-based therapy without risk of viral failure. The study appears in the November 3 issue of JAMA.

Implementation of pediatric antiretroviral treatment (ART) programs in sub-Saharan Africa has resulted in significant reductions in morbidity and mortality among children infected with human immunodeficiency virus (HIV), changing a rapidly fatal disease into a chronic condition. For infants and young children, ritonavir-boosted lopinavir-based therapy is recommended as first-line ART. In adults and older children, efavirenz is recommended as part of first-line ART. Advantages of this regimen include once-daily dosing, simplification of co-treatment for tuberculosis, preservation of ritonavir-boosted lopinavir for second-line treatment, and alignment of adult and pediatric treatment regimens. However, there have been concerns about possible reduced viral efficacy of efavirenz in children exposed to nevirapine for prevention of mother-to-child transmission.

This study, conducted at a hospital in Johannesburg, South Africa, included HIV-infected children 3 years of age or older exposed to nevirapine for prevention of mother-to-child transmission and who had plasma HIV RNA of less than 50 copies/ml during ritonavir-boosted lopinavir-based therapy. Participants were randomly assigned to switch to efavirenz-based therapy (n = 150) or continue ritonavir-boosted lopinavir-based therapy (n = 148). The children were followed up to 48 weeks after randomization.

The researchers found that switching to efavirenz-based therapy compared with continuing ritonavir-boosted lopinavir-based therapy did not result in significantly higher rates of viral rebound (i.e., HIV RNA >50 copies/mL) or viral failure (i.e., confirmed HIV RNA >1000 copies/mL). “This therapeutic approach may offer advantages in children such as these.”

“There is little guidance available as to what clinicians ought to do when confronted with a child older than 3 years who has begun treatment with ritonavir-boosted lopinavir. As a result, it has been left to individual interpretation, and there are anecdotal reports of clinicians switching to efavirenz in the absence of data to support such a practice. This study provides evidence to support the safety and efficacy of switching to efavirenz, the recommended drug for children older than 3 years, among children with viral suppression,” the authors write.

(doi:10.1001/jama.2015.13631; Available pre-embargo to the media at http:/media.jamanetwork.com)

Editor’s Note: The study was supported by a grant from the Eunice Kennedy Shriver National Institute of Child Health and Human Development. All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.

Editorial: Antiretroviral Therapy for Nevirapine-Exposed Children With HIV Infection

Ram Yogev, M.D., of Lurie Children’s Hospital, Chicago, comments on the findings of this study in an accompanying editorial.

“The study by Coovadia et al is an important contribution in the evolving science of how to treat perinatally HIV­infected children. Even when combination ART controls the viral load, HIV-related complications remain (e.g., cardiovascular disease), and strategies to improve patient outcomes are needed that include early treatment and chemoprophylaxis as well as research on vaccines and an effective cure.”

(doi:10.1001/jama.2015.13763; Available pre-embargo to the media at http:/media.jamanetwork.com)

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

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EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, OCTOBER 27, 2015

Media Advisory: To contact Jiemin Ma, Ph.D., M.H.S., email David Sampson at david.sampson@cancer.org. To contact editorial author J. Michael McGinnis, M.D., M.P.P., email Jennifer Walsh at jwalsh@nas.edu.

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An analysis of deaths in the United States between 1969 and 2013 finds an overall decreasing trend in the age-standardized death rate for all causes combined and for heart disease, cancer, stroke, unintentional injuries, and diabetes, although the rate of decrease appears to have slowed for heart disease, stroke, and diabetes, according to a study in the October 27 issue of JAMA.

A comprehensive examination of long-term trends in mortality is important for health planning and priority setting and for identifying modifiable factors that may contribute to the trends. Jiemin Ma, Ph.D., M.H.S., of the American Cancer Society, Atlanta, and colleagues analyzed U.S. national vital statistics data from 1969 through 2013 to determine total and annual percent change in age-standardized death rates and years of potential life lost before age 75 years for all causes combined and for the leading causes.

Between 1969 and 2013, the age-standardized death rate for all causes combined decreased from 1,279 per 100,000 population to 730 (43 percent reduction) – an average annual decrease of 1.3 percent. Five of the six leading causes of death experienced an overall decline in death rates during this time period. The rate of death (per 100,000) decreased for stroke by 77 percent; for heart disease, by 68 percent; for unintentional injuries, by 40 percent; for cancer, by 18 percent; and for diabetes, by 17 percent. The death rate for chronic obstructive pulmonary disease (COPD) increased by 101 percent during this period. However, during the last time segment in the analysis, the death rate for COPD in men began to decrease and the declines in rates slowed for heart disease, stroke, and diabetes. For example, the annual decline for heart disease slowed from 3.9 percent during the 2000-2010 period to 1.4 percent during the 2010-2013 period.

Between 1969 and 2013, age-standardized years of potential life lost per 1,000 decreased from 1.9 to 1.6 for diabetes (14.5 percent reduction); a 41 percent reduction for cancer; 48 percent for unintentional injuries; 68 percent for heart disease; and 75 percent for stroke. For COPD, the rate for years of potential life lost did not decrease over this time interval.

The researchers write that the progress against heart disease and stroke is attributed to improvements in control of hypertension and hyperlipidemia, smoking cessation, and medical treatment. “The reduction in cancer deaths since the early 1990s is also an outcome of tobacco control efforts, as well as advances in early detection and treatment. Notably, the years-of-potential-life lost rate from cancer has been decreasing since 1969, preceding the decline in cancer death rates by about 20 years. This may reflect the importance of smoking cessation in substantially reducing premature mortality. The overall decrease in the death rate for unintentional injuries has been largely attributed to continuous declines in motor vehicle–related deaths.”

The authors note that the observed recent slowing of the decline in death rates for obesity-related diseases (e.g., heart disease, stroke, and diabetes) may reflect the lagged consequences of increased obesity prevalence since the 1980s.

“Further disease-specific studies are needed to investigate these trends. Regardless of the changes in death rates, the increasing numbers of old persons in the United States and growth of the U.S. population will pose a considerable challenge for health care delivery in the coming decades, in view of the shortage of primary care physicians and geriatricians, increasing cost of health care, and the lag between healthy life and life expectancies.”

(doi:10.1001/jama.2015.12319; Available pre-embargo to the media at http:/media.jamanetwork.com)

Editor’s Note: This work was supported by the Intramural Research Department of the American Cancer Society. All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.

Editorial: Mortality Trends and Signs of Health Progress in the United States

“Death rate may have at one time served as a sufficient measure of health system performance, but assessment now requires more textured insights, including those that reflect the improving capacity to measure health status, risk prevalence, and service access, effectiveness, and affordability,” writes J. Michael McGinnis, M.D., M.P.P., of the National Academy of Medicine, Washington D.C., in an accompanying editorial.

“What is needed is a set of national vital health indicators that is broader than mortality, but still a limited number, tightly constructed, standardized, and reliably available at all levels from local to national. Earlier this year, an Institute of Medicine Committee on Core Metrics for Better Health at Lower Cost, released its report, Vital Signs: Core Metrics for Health and Health Care Progress. The Committee recommended 15 core measures across 4 domains—healthy people, quality care, affordable care, and engaged people—which could be assembled from a manageable set of standardized measures to be collected system-wide. Whether through adoption of this or some other expanded notion of what should constitute the nation’s truly vital signs, the time has arrived to match the capacity with the potential and the need.”

(doi:10.1001/jama.2015.12391; Available pre-embargo to the media at http:/media.jamanetwork.com)

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

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EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, OCTOBER 27, 2015

Media Advisory: To contact corresponding author Elliot Israel, M.D., call Lori Schroth at 617-525-6374 or email ljschroth@partners.org.

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Among black adults with asthma treated with an inhaled corticosteroid, adding a long-acting beta-agonist did not improve the time to an asthma exacerbation compared with adding the anticholinergic tiotropium, according to a study in the October 27 issue of JAMA.

National treatment recommendations suggest increasing inhaled corticosteroid (ICS) dose or adding a long-acting beta-agonist (LABA) to asthma patients with poor asthma control on low-dose ICS. However, asthma experts and the U.S. Food and Drug Administration have questioned the safety of LABA therapy, noting possible increases in serious events, including hospitalizations and death. Data suggest that LABA risks, if they exist, may disproportionately affect black populations and that black individuals may not benefit from LABAs to the same degree as individuals of other races. Investigations in predominantly white populations have attempted to determine if long-acting anticholinergics (a class of drugs that inhibit the transmission of certain nerve impulses, reducing spasms of smooth muscles, such as in the lungs) can substitute for LABAs in asthma, according to background information in the article.

Michael E. Wechsler, M.D., M.Sc., of National Jewish Health, Denver, and Elliot Israel, M.D., of Brigham and Women’s Hospital, Boston, and colleagues randomly assigned black adults with moderate to severe asthma to receive ICS plus either once-daily tiotropium (n = 532) or twice-daily LABAs (n = 538). Patients completed monthly questionnaires and were followed up for up to 18 months. Patients also underwent genetic testing. Some studies have suggested that a genetic variation may be associated with increased rates of adverse outcomes when LABAs are used for asthma, especially among black patients.

The researchers found that the primary outcome, time to first exacerbation, did not differ significantly between groups. In addition, LABA + ICS was not superior to tiotropium + ICS for secondary outcomes that addressed additional dimensions of asthma control, such as patient-reported outcomes (quality of life, asthma control, symptom index, symptom-free days), spirometry (a test of the air capacity of the lungs), rescue medication use, and asthma deteriorations.

Genetic variants were not associated with differential responses to therapy.

“These findings do not support the superiority of LABA + ICS compared with tiotropium + ICS for black patients with asthma,” the authors write.

“Although we could not detect a difference in exacerbations between either combination therapy, we found that, despite combination therapy, this population experienced a high rate of exacerbations. Additional targeted interventions and further study are needed to reduce the rate of asthma exacerbations in this population.”

(doi:10.1001/jama.2015.13277; Available pre-embargo to the media at http:/media.jamanetwork.com)

Editor’s Note: This project was supported by a grant from the Agency for Healthcare Research and Quality. 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, OCTOBER 27, 2015

Media Advisory: To contact co-author Benjamin D. Sommers, M.D., Ph.D., call Todd Datz at 617-432-8413 or email tdatz@hsph.harvard.edu.

To place an electronic embedded link to this study in your story This link for the study will be live at the embargo time: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.9375

In a study of federal marketplace insurance plans, nearly 15 percent completely lacked in-network physicians for at least 1 specialty, a practice found among multiple states and issuers, raising concerns regarding patient access to specialty care, according to a study in the October 27 issue of JAMA.

Nearly 12 million individuals have enrolled in coverage through the Affordable Care Act’s insurance marketplaces. The U.S. Department of Health and Human Services regulates plans, applying a “reasonable access” standard to ensure access to “a sufficient number and type of providers.” Concerns remain about network adequacy, according to background information in the article.

Stephen C. Dorner, M.Sc., of the Harvard T. H. Chan School of Public Health, Boston, and colleagues examined physician networks in 34 states offering plans through the federal marketplace during 2015 open enrollment; this analysis included 135 plans. Using plans’ online directories, the authors searched for in-network specialist physicians for various specialties.

Using a 100 mile and 50 mile search radius, 18 (13 percent) and 19 (14 percent), respectively, of 135 plans were specialist-deficient plans (plans without a specialist physician). Endocrinology, rheumatology, and psychiatry were most commonly excluded, and an additional 7-14 plans had fewer than 5 in-network physicians in those specialties. There was no significant difference in the proportion of specialist­ deficient plans across insurance plan premium levels. Nine of 34 states (24 percent) had at least 1 specialist-deficient plan. Twelve different insurers had at least 1 specialist-deficient plan.

Beneficiaries of specialist-deficient plans had high out-of-network costs; 5 of 19 (26 percent) plans did not cover out-of-network services, whereas 11 of the remaining 14 plans (79 percent) required cost-sharing of 50 percent or more. Nine of 19 (47 percent) did not cover medications prescribed by out-of-network physicians. There was no significant difference in premiums between specialist-deficient plans and other plans.

Regarding plans that lack in-network physicians for at least 1 specialty, “this likely violates network adequacy requirements, raising concerns regarding patient access to specialty care,” the authors write. “Such plans precipitate high out-of-pocket costs and may lead to adverse selection (i.e., sicker individuals choosing plans with broader networks), which is similar to concerns over restrictive drug formularies.”

(doi:10.1001/jama.2015.9375; Available pre-embargo to the media at http:/media.jamanetwork.com)

Editor’s Note: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr. Sommers reported currently serving part-time as a senior advisor to the U.S. Department of Health and Human Services. No other disclosures were reported.

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EMBARGOED FOR RELEASE: 11 A.M. (ET) MONDAY, OCTOBER 26, 2015

Media Advisory: To contact Bridget K. Ambrose, Ph.D., M.P.H., call Michael Felberbaum at 240-402-9548 or email michael.felberbaum@fda.hhs.gov.

To place an electronic embedded link to this study in your story This link for the study will be live at the embargo time: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.13802

JAMA

Among a survey of youth 12 to 17 years of age, the majority who self-reported ever experimenting with tobacco started with a flavored product, and most current tobacco users reported use of flavored products, according to a study published by JAMA.

Most tobacco use begins during youth and young adulthood. Recent declines in prevalence of cigarette smoking among youth have coincided with increased use of e-cigarettes and hookahs. Although flavors other than menthol are prohibited in cigarettes in the United States, flavored noncigarette tobacco products are widely available and may appeal to youth, according to background information in the article.

Bridget K. Ambrose, Ph.D., M.P.H., of the Center for Tobacco Products, U.S. Food and Drug Administration, Silver Spring, Md., and colleagues examined flavored tobacco use among U.S. youth using data from the Population Assessment of Tobacco and Health Study, a household-based, nationally representative study of 45,971 adults and youth (12-17 years) in the United States. Youth responded to questions about ever and past 30-day use of tobacco products including cigarettes, e-cigarettes, hookahs, cigars, pipe tobacco, all types of smokeless tobacco, dissolvable tobacco, bidis, and kreteks. For each product ever used, youth answered whether the first product they used was flavored (e.g., “Was the first e-cigarette you used flavored to taste like menthol, mint, clove, spice, candy, fruit, chocolate, alcohol [such as wine or cognac], or other sweets?”).

Of the 13,651 youth enrolled and included in this analysis, 51 percent were male, 55 percent non-Hispanic white, 14 percent non-Hispanic black, and 23 percent Hispanic; average age was 14.5 years. The majority of youth ever-users reported that the first product they had used was flavored, including 89 percent of ever hookah users, 81 percent of ever e-cigarette users, 65 percent of ever users of any cigar type, and 50 percent of ever cigarette smokers. For past 30-day youth tobacco use, the overall proportion of flavored product use was 80 percent among users of any product and 89 percent among hookah users, 85 percent among e-cigarette users, 72 percent among users of any cigar type, and 60 percent among cigarette smokers. Youth consistently reported product flavoring as a reason for use across all product types, including e-cigarettes, hookahs, cigars, smokeless tobacco, and snus pouches.

“Consistent with national school-based estimates, this study confirms widespread appeal of flavored products among youth tobacco users. In addition to continued proven tobacco control and prevention strategies, efforts to decrease use of flavored tobacco products among youth should be considered,” the authors write.

(doi:10.1001/jama.2015.13802; Available pre-embargo to the media at http:/media.jamanetwork.com)

Editor’s Note: Funded by the National Institute on Drug Abuse, National Institutes of Health, and the U.S. FDA, Department of Health and Human Services. The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.

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EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, OCTOBER 20, 2015

Media Advisory: To contact corresponding author Robert A. Smith, Ph.D., of the American Cancer Society, email David Sampson at david.sampson@cancer.org. To contact editorial co-author Nancy L. Keating, M.D., M.P.H., email David Cameron at David_Cameron@hms.harvard.edu.

To place an electronic embedded link to this study and editorial in your story This link to the study will be live at the embargo time: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.12783 This will be the link to the editorial: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.13086

Among the changes in the American Cancer Society’s updated breast cancer screening guideline is that women with an average risk of breast cancer should undergo regular, annual screening mammography beginning at age 45 years, with women having an opportunity to choose to begin annual screening as early as age 40; women 55 years and older should transition to screening every other year (vs annual), but still have the opportunity to continue with annual screening; and routine screening clinical breast examination is no longer recommended, according to an article in the October 20 issue of JAMA.

Breast cancer is the most common cancer in women worldwide. In the United States, it is estimated that approximately 230,000 women will be diagnosed with breast cancer in 2015. Breast cancer continues to rank second, after lung cancer, as a cause of cancer death in women in the U.S., and is a leading cause of premature mortality for women. Even though death from breast cancer has declined steadily since 1990, largely due to improvements in early detection and treatment, an estimated 40,300 women in the U.S. will die of breast cancer in 2015. Early detection is associated with reduced breast cancer illness and death, according to background information in the article.

Since the last American Cancer Society (ACS) breast cancer screening update for average-risk women was published in 2003, new evidence has accumulated from long-term follow-up of randomized controlled trials and observational studies of organized, population-based screening programs. Evan R. Myers, M.D., M.P.H., of the Duke Evidence Synthesis Group, Duke Clinical Research Institute, Durham, N.C., and colleagues conducted a systematic review of the breast cancer screening literature to update the American Cancer Society 2003 breast cancer screening guideline for women at average risk for breast cancer (this study appears in JAMA); Diana L. Miglioretti, Ph.D., of the University of California Davis School of Medicine, and colleagues performed an analysis of Breast Cancer Surveillance Consortium mammography registry data to address questions related to screening intervals (this study appears in JAMA Oncology). Formulation of recommendations was based on the quality of the evidence and judgment (incorporating values and preferences) about the balance of benefits and harms.

The 2015 recommendations for breast cancer screening for women at average risk:

Women should undergo regular screening mammography starting at age 45.

Women 45 to 54 years of age should be screened annually.

Women 55 years and older should transition to biennial screening or have the opportunity to continue screening annually.

Women should have the opportunity to begin annual screening between the ages of 40 and 44 years.

Women should continue screening mammography as long as their overall health is good and they have a life expectancy of 10 years or longer.

Clinical breast examination is not recommended for breast cancer screening among average-risk women at any age.

“The ACS endorses beginning annual screening mammography at age 45 years and transitioning to biennial screening at age 55 years, while retaining the option to continue annual screening, which some women may elect based on personal preference, clinical guidance, or both,” the authors write. “After careful examination of the burden of disease among women aged 40 to 54 years, the guideline development group (GDG) concluded that the lesser, but not insignificant, burden of disease for women aged 40 to 44 years and the higher cumulative risk of adverse outcomes no longer warranted a direct recommendation to begin screening at age 40 years.”

Regarding no longer recommending periodic clinical breast examination (CBE), the researchers write that “the absence of clear evidence that CBE contributed significantly to breast cancer detection prior to or after age 40 years led the GDG to conclude that it could no longer be recommended for average-risk women at any age.”

“This guideline is intended to provide guidance to the public and clinicians, and it is especially designed for use in the context of a clinical encounter. Women should be encouraged to be aware of and to discuss their family history and medical history with a clinician, who should periodically ascertain whether a woman’s risk factor profile has changed. If the woman has an average risk of developing breast cancer, the ACS encourages a discussion of screening around the age of 40 years. The ACS also recommends that women be provided with information about risk factors, risk reduction, and the benefits, limitations, and harms associated with mammography screening.”

“In conclusion, the ACS recommendations are made in the context of maximizing reductions in breast cancer mortality and reducing years of life lost while minimizing the associated harms among the population of women in the United States. The ACS recognizes that the balance of benefits and harms will be close in some instances and that the spectrum of women’s values and preferences will lead to varying decisions. The intention of this new guideline is to provide both guidance and flexibility for women about when to start and stop screening mammography and how frequently to be screened for breast cancer.”

(doi:10.1001/jama.2015.12783; Available pre-embargo to the media at http:/media.jamanetwork.com)

Editor’s Note: The American Cancer Society supported the development of this guideline through the use of general funds. Dr. Oeffinger was supported in part through a Cancer Center Support Grant from the National Institutes of Health/National Cancer Institute. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, etc.

Editorial: New Guidelines for Breast Cancer Screening in U.S. Women

“Will the new ACS guideline make it easier for clinicians and women to make decisions about screening mammography? In some ways, the messages from ACS and the U.S. Preventive Services Task Force (USPSTF), 2 major guidelines, are now more consistent. Both guidelines agree that for average-risk women younger than 45 years, the harms of mammography screening likely outweigh the benefits,” write Nancy L. Keating, M.D., M.P.H., of Harvard Medical School, Boston, and Lydia E. Pace, M.D., M.P.H., of Brigham and Women’s Hospital, Boston, in an accompanying editorial.

“For women older than 55 years, biennial mammography is likely to provide the best balance of benefits to harms. The new ACS recommendation to stop screening older women with life expectancies of less than 10 years is practical and consistent with the increasing emphasis on functional vs chronologic age. The more challenging decisions are for women aged 45 to 54 years, for whom ACS recommends annual screening, but for whom the USPSTF recommends no routine screening (age 45-49 years) or biennial screening (age 50-54 years). In communicating with patients, clinicians will have to balance the ACS’ recommendation for more frequent screening against the fact that younger women experience a lower absolute benefit from screening mammography.”

(doi:10.1001/jama.2015.13086; Available pre-embargo to the media at http:/media.jamanetwork.com)

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

Note: The video below is a helpful summary of the updated breast cancer screening recommendations.

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EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, OCTOBER 20, 2015

Media Advisory: To contact Benjamin W. Friedman, M.D., M.S., call Helene Guss at 718-920-4712 or email hguss@montefiore.org.

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Among patients with acute, low back pain presenting to an emergency department, neither the nonsteroidal anti-inflammatory drug (NSAID) naproxen combined with oxycodone/acetaminophen or the muscle relaxant cyclobenzaprine provided better pain relief or improvement in functional outcomes than naproxen combined with placebo, according to a study in the October 20 issue of JAMA.

Low back pain (LBP) is responsible for 2.4 percent of visits to U.S. emergency departments, resulting in more than 2.5 million visits annually. These patients are usually treated with NSAIDs, acetaminophen, opioids, or skeletal muscle relaxants, often in combination. Pain outcomes for these patients are generally poor.

Benjamin W. Friedman, M.D., M.S., of the Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, N.Y., and colleagues randomly assigned 323 patients who presented to an emergency department with nontraumatic, nonradicular LBP of 2 weeks’ duration or less to receive a 10-day course of naproxen + placebo (n = 107); naproxen + cyclobenzaprine (5 mg) (n = 108); or naproxen + oxycodone, 5 mg/acetaminophen, 325 mg (n = 108). Participants were instructed to take 1 or 2 of these tablets every 8 hours, as needed for LBP; naproxen, 500 mg, was to be taken twice a day. Patients also received a standardized 10-minute LBP educational session prior to discharge.

The researchers found that neither naproxen combined with oxycodone/acetaminophen nor naproxen combined with cyclobenzaprine provided better pain relief or better improvement in functional outcomes than naproxen combined with placebo. Measures of pain, functional impairment, and use of health care resources were not different between the study groups at 7 days or at 3 months after the emergency department visit.

Regardless of allocation, nearly two-thirds of patients demonstrated clinically significant improvement in LBP and function 1 week later. However, 40 percent of the cohort reported moderate or severe pain, half reported functionally impairing LBP, and nearly 60 percent were still using medication for their LBP 1 week later. By 3-month follow-up, nearly one-fourth of the cohort reported moderate or severe pain and use of medications for LBP. Three months after the emergency department visit, regardless of study group, opioid use for LBP was uncommon, with fewer than 3 percent of patients reporting use of an opioid within the previous 72 hours.

“These findings do not support the use of these additional medications in this setting,” the authors write.

(doi:10.1001/jama.2015.13043; Available pre-embargo to the media at http:/media.jamanetwork.com)

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

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EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, OCTOBER 20, 2015

Media Advisory: To contact Nathalie Auger, M.D., M.Sc., F.R.C.P.C., email William Raillant-Clark at w.raillant-clark@umontreal.ca.

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An analysis of more than 1.9 million mother and infant pairs finds that preeclampsia was significantly associated with noncritical heart defects in offspring, and preeclampsia with onset before 34 weeks was associated with critical heart defects; however, the absolute risk of congenital heart defects was low, according to a study in the October 20 issue of JAMA.

Congenital heart defects are the most common anomalies in infants, affecting every 8 births per 1,000, and are a major cause of infant illness and death, despite significant advancements in medical care. The causes and risk factors for congenital heart defects are mostly unknown. Some studies have shown that the pathology of preeclampsia (a disorder of pregnancy characterized by high blood pressure and excess protein in the urine) begins early and possibly even at the start of pregnancy, around the time of fetal heart morphogenesis. Despite the plausible link, evidence that preeclampsia is associated with congenital heart defects has largely been absent, according to background information in the article.

Nathalie Auger, M.D., M.Sc., F.R.C.P.C., of the University of Montreal, Quebec, Canada and colleagues conducted an analysis of live births before discharge (1989-2012) for the entire province of Quebec, comprising a quarter of Canada’s population. All women who delivered an infant with or without heart defects in any Quebec hospital were included (n = 1,942,072 neonates). The researchers examined the presence of any critical or noncritical congenital heart defect detected in infants at birth, comparing prevalence in those exposed and not exposed to preeclampsia. In general, critical heart defects lead to significant mortality and morbidity if not diagnosed promptly after birth; for noncritical defects, mortality and morbidity are much lower.
The overall prevalence of heart defects was 8.9 per 1,000 infants. Prevalence was higher for infants of women with preeclampsia than without preeclampsia (16.7 vs 8.6 per 1,000). Risk was elevated for defects affecting all general structures of the heart, including the aorta, pulmonary artery, valves, ventricles, and septa. Infants of women with preeclampsia had no increased prevalence of critical heart defects but did have an increased prevalence of noncritical heart defects compared with infants of non-preeclamptic women. Compared with infants of women with late-onset preeclampsia, those with early onset (<34 weeks) had greater prevalence of critical and noncritical heart defects. The absolute risk of congenital heart defects was low.

“Our results help advance the current understanding of the pathophysiology of preeclampsia and congenital heart defects. The relationship between them supports the notion that these disorders share common risk factors and etiology, beginning very early in pregnancy and involving a long cascade of events affecting the development of fetal heart structures throughout gestation,” the authors write.

“Prevention of both preeclampsia and heart defects may well depend on the ability to elucidate these pathways more clearly in future research. Until then, clinicians should be alert to the possibility that preeclampsia may increase the risk of heart defects in fetuses, although more research is needed in other settings to confirm our findings before modification of clinical practice.”

(doi:10.1001/jama.2015.12505; Available pre-embargo to the media at http:/media.jamanetwork.com)

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

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