EMBARGOED FOR RELEASE: 4 P.M. (ET) THURSDAY, MAY 19, 2016

Media Advisory: To contact Jeffrey D. Williamson, M.D., M.H.S., call Marguerite Beck at 336-716-2415 or email marbeck@wakehealth.edu. To contact editorial author Aram V. Chobanian, M.D., email Gina DiGravio-Wilczewski at ginad@bu.edu.

To place an electronic embedded link to the study and editorial in your story  These links will be live at the embargo time: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2016.7050; https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2016.7070

Among adults 75 years of age or older, treating to a systolic blood pressure target of less than 120 mm Hg compared with less than 140 mm Hg resulted in significantly lower rates of fatal and nonfatal major cardiovascular events and death from any cause, according to a study published online by JAMA. The study is being released to coincide with its presentation at the American Geriatrics Society Annual Scientific Meeting.

In the United States, 75 percent of persons older than 75 years have hypertension, for whom cardiovascular disease complications are a leading cause of disability, illness and death. The optimal systolic blood pressure (SBP) treatment target in geriatric populations with hypertension remains uncertain. Jeffrey D. Williamson, M.D., M.H.S., of the Wake Forest School of Medicine, Winston-Salem, N.C., and colleagues analyzed a subgroup (persons age 75 years or older with hypertension but without diabetes) in the Systolic Blood Pressure Intervention Trial (SPRINT) who were randomly assigned to an SBP target of less than 120 mm Hg (intensive treatment group, n = 1,317) or an SBP target of less than 140 mm Hg (standard treatment group, n = 1,319).

Among the participants (average age, 80 years; 38 percent women), 95 percent provided complete follow-up data. At a median follow-up of 3.1 years, there was a significantly lower rate of the primary composite outcome (nonfatal heart attack, acute coronary syndrome not resulting in a heart attack, nonfatal stroke, nonfatal acute decompensated heart failure, and death from cardiovascular causes; 102 events in the intensive treatment group vs 148 events in the standard treatment group). There was also a significantly lower rate of all-cause death (73 deaths vs 107 deaths, respectively).

Additional analysis suggested that the benefit of intensive BP control was consistent among persons in this age range who were frail or had reduced gait speed.

The overall rate of serious adverse events was not different between treatment groups.

“Considering the high prevalence of hypertension among older persons, patients and their physicians may be inclined to underestimate the burden of hypertension or the benefits of lowering BP, resulting in undertreatment. On average, the benefits that resulted from intensive therapy required treatment with 1 additional antihypertensive drug and additional early visits for dose titration and monitoring,” the authors write.

“Future analyses of SPRINT data may be helpful to better define the burden, costs, and benefits of intensive BP control. However, the present results have substantial implications for the future of intensive BP therapy in older adults because of this condition’s high prevalence, the high absolute risk for cardiovascular disease complications from elevated BP, and the devastating consequences of such events on the independent function of older people.”

(doi:10.1001/jama.2016.7050; this study is available pre-embargo at the For The Media website.)

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

Editorial: SPRINT Results in Older Patients – How Low to Go?

“Currently, more than 40 percent of persons with hypertension in the United States do not have their blood pressure controlled to levels less than 140/90 mm Hg, and if the goal SBP were reduced to less than 130 mm Hg, more than one-half of persons with hypertension would be considered to have uncontrolled blood pressure,” writes Aram V. Chobanian, M.D., of the Boston University School of Medicine, in an accompanying editorial.

“Achieving the SBP goal of less than 130 mm Hg may be challenging for clinicians, because doing so could require use of additional medications, more careful monitoring, and more frequent clinic visits. Nevertheless, the important results reported by Williamson et al in this issue of JAMA cannot be discounted, and unless unexpected adverse effects are observed on further examination of the trial data, then major changes in treatment goals for patients 75 years or older with hypertension will be warranted.”

(doi:10.1001/jama.2016.7070; this editorial is available pre-embargo at the For The Media website.)

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

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

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EMBARGOED FOR RELEASE: 5:45 A.M. (ET) SUNDAY, MAY 22, 2016

Media Advisory: To contact Alexander Zarbock, M.D., email zarbock@uni-muenster.de.

To place an electronic embedded link to this study in your story  This link will be live at the embargo time: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2016.5828

In a study published online by JAMA, Alexander Zarbock, M.D., of University Hospital Munster, Germany, and colleagues examined whether early (compared with delayed) initiation of renal replacement therapy in patients who are critically ill with acute kidney injury reduces 90-day all-cause mortality. The study is being released to coincide with its presentation at the 53rd European Renal Association – European Dialysis and Transplant Association (ERA-EDTA) Congress.

Acute kidney injury (AKI) is a well-recognized complication of critical illness with a large effect on illness and death.  Despite increases in the knowledge of the management of patients who are critically ill, mortality associated with AKI remains high. The optimal timing of initiation of renal replacement therapy (RRT) in critically ill patients with AKI is still unknown. The researchers for this study randomly assigned 231 critically ill patients who had reached stage 2 AKI (per Kidney Disease: Improving Global Outcomes guidelines) and met other criteria, to early (within 8 hours of diagnosis of stage 2; n = 112) or delayed (within 12 hours of stage 3 AKI or no initiation; n = 119) initiation of RRT.

All patients in the early group and 108 of 119 patients (91 percent) in the delayed group received RRT. The researchers found that early initiation of RRT significantly reduced 90-day mortality compared with delayed initiation of RRT (39 percent vs 55 percent of patients died in each group, respectively).  More patients in the early group recovered renal function by day 90 (54 percent vs 39 percent). Duration of RRT (9 days vs 25 days) and length of hospital stay (51 days vs 82 days) were significantly shorter in the early group than in the delayed group. There was no significant effect on requirement of RRT after day 90, organ dysfunction, and length of ICU stay.

“Our study provides important feasibility data for an AKI stage-based, biomarker-guided interventional trial in AKI. However, an adequately powered multicenter trial is needed to confirm our results and establish the best time point for the initiation of RRT in critically ill patients with AKI,” the authors write.

(doi:10.1001/jama.2016.5828; this study is available pre-embargo at the For The Media website.)

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

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EMBARGOED FOR RELEASE: 9:45 A.M. (ET) TUESDAY, MAY 24, 2016

Media Advisory: To contact Gillian L. Booth, M.D., email Leslie Shepherd at ShepherdL@smh.ca. To contact editorial author Steven B. Heymsfield, M.D., email Alisha.prather@pbrc.edu or Stephanie.malin@pbrc.edu.

To place an electronic embedded link to this study and editorial in your story  These links will be live at the embargo time: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2016.5898; https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2016.5635

Urban neighborhoods in Ontario, Canada, that were characterized by more walkable design were associated with decreased prevalence of overweight and obesity and decreased incidence of diabetes between 2001 and 2012, according to a study appearing in the May 24/31 issue of JAMA.

The global increase in obesity is a major health problem. One approach to reduce obesity through diet and exercise that is gaining interest among public health professionals and urban planners is to redesign the built environment to offer more opportunities for physical activity and healthy eating. Neighborhoods that favor pedestrian activities—those with high population density, high numbers of destinations within walking distance of residential areas, and well-connected streets—are characterized by higher rates of walking and bicycling for transportation and lower rates of car use.

Gillian L. Booth, M.D., of the Li Ka Shing Knowledge Institute of St. Michael’s Hospital, Toronto, and colleagues examined whether urban neighborhoods that are more walkable are associated with a slower increase in overweight, obesity, and diabetes than less walkable neighborhoods. The researchers used annual provincial health care (n = 3 million per year) and biennial Canadian Community Health Survey (n = 5,500 per cycle) data for adults (30-64 years) living in Southern Ontario cities. Neighborhood walkability was derived from a validated index, which included 4 equally weighted components: population density, residential density, walkable destinations (number of retail stores, services [e.g., libraries, banks, community centers], and schools within a 10-minute walk), and street connectivity. Neighborhoods were ranked and classified into quintiles from lowest (quintile 1) to highest (quintile 5) walkability.

There were 8,777 neighborhoods included in the study. In 2001, the adjusted prevalence of overweight and obesity was lower in quintile 5 vs quintile 1 (43 percent vs 54 percent). Between 2001 and 2012, the prevalence increased in less walkable neighborhoods, while the prevalence did not significantly change in areas of higher walkability. In 2001, the adjusted diabetes incidence was lower in quintile 5 than other quintiles and declined by 2012. In contrast, diabetes incidence did not change significantly in less walkable areas.

Rates of walking or cycling and public transit use were significantly higher, and that of car use lower in quintile 5 vs quintile 1 at each time point, although daily walking and cycling frequencies increased only modestly from 2001 to 2011 in highly walkable areas. Leisure-time physical activity, diet, and smoking patterns did not vary by walkability and were relatively stable over time.

The authors note that the “ecologic nature of these findings and the lack of evidence that more walkable urban neighborhood design was associated with increased physical activity suggest that further research is necessary to assess whether the observed associations are causal.”

(doi:10.1001/jama.2016.5898; this study is available pre-embargo at the For The Media website.)

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

Editorial: Can Walkable Urban Design Play a Role in Reducing the Incidence of Obesity-Related Conditions?

Andrew G. Rundle, Dr.P.H., of Columbia University, New York, and Steven B. Heymsfield, M.D., of the Pennington Biomedical Research Center, LSU System, Baton Rouge, comment on the findings of this study in an accompanying editorial.

“The findings of the study by Creatore et al reported in this issue of JAMA provide further large-scale and longitudinal support for the hypothesis that urban design choices promoting pedestrian activity are associated with greater engagement in active transport (walking and cycling), lower prevalence of overweight/obesity, and lower diabetes incidence at the population level. This study will make a prominent contribution to the research base that informs the urban design and health policy debates for years to come.”

(doi:10.1001/jama.2016.5635; this editorial is available pre-embargo at the For The Media website.)

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

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EMBARGOED FOR RELEASE: 9:45 A.M. (ET) TUESDAY, MAY 24, 2016

Media Advisory: To contact Jenna Wong, M.Sc., email Cynthia Lee at cynthia.lee@mcgill.ca.

To place an electronic embedded link to this study in your story  This link will be live at the embargo time: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2016.3445

In a study appearing in the May 24/31 issue of JAMA, Jenna Wong, M.Sc., of McGill University, Montreal, Canada, and colleagues analyzed treatment indications for antidepressants and assessed trends in antidepressant prescribing for depression.

Antidepressant use in the United States has increased over the last 2 decades. A suspected reason for this trend is that primary care physicians are increasingly prescribing antidepressants for nondepressive indications, including unapproved (off-label) indications that have not been evaluated by regulatory agencies. For this study, the researchers used data from an electronic medical record and prescribing system that has been used by primary care physicians in community-based, fee-for-service practices around 2 major urban centers in Quebec, Canada. The study included prescriptions written for adults between January 2006 and September 2015 for all antidepressants except monoamine oxidase inhibitors. Physicians participating in the study had to document at least 1 treatment indication per prescription using a drop-down menu containing a list of indications or by typing the indication(s).

During the study period, 101,759 antidepressant prescriptions (6 percent of all prescriptions) were written by 158 physicians for 19,734 patients. Only 55 percent of antidepressant prescriptions were indicated for depression. Physicians also prescribed antidepressants for anxiety disorders (18.5 percent), insomnia (10 percent), pain (6 percent) and panic disorders (4 percent).  For 29 percent of all antidepressant prescriptions (66 percent of prescriptions not for depression), physicians prescribed a drug for an off-label indication, especially insomnia and pain. Physicians also prescribed antidepressants for several indications that were off-label for all antidepressants, including migraine, vasomotor symptoms of menopause, attention-deficit/hyperactivity disorder, and digestive system disorders.

“The findings indicate that the mere presence of an antidepressant prescription is a poor proxy for depression treatment, and they highlight the need to evaluate the evidence supporting off-label antidepressant use,” the authors write.

(doi:10.1001/jama.2016.3445; this study is available pre-embargo at the For The Media website.)

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: 9:45 A.M. (ET) TUESDAY, MAY 24, 2016

Media Advisory: To contact Jiang He, M.D., Ph.D., email Keith Brannon at kbrannon@tulane.edu.

To place an electronic embedded link to this study in your story  This link will be live at the embargo time: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2016.4447

In a study appearing in the May 24/31 issue of JAMA, Jiang He, M.D., Ph.D., of the Tulane University School of Public Health and Tropical Medicine, New Orleans, and colleagues evaluated more than 3,500 participants with chronic kidney disease (CKD), examining the association between urinary sodium excretion and clinical cardiovascular disease (CVD) events. The study is being released to coincide with its presentation at the 53rd European Renal Association – European Dialysis and Transplant Association (ERA-EDTA) Congress.

Chronic kidney disease affects approximately 11 percent of the U.S. population and is associated with increased risk of CVD and all-cause mortality. Greater than 1 in 3 U.S. adults has CVD, and it is the leading cause of death in the United States. A positive association between sodium intake and blood pressure is well established. However, the association between sodium intake and clinical CVD remains less clear, and this relationship has not been investigated in patients with CKD.

This study included 3,757 patients with CKD from 7 locations in the U.S. enrolled in the Chronic Renal Insufficiency Cohort (CRIC) Study and were followed up from May 2003 to March 2013. Participants were requested to provide urine specimens at study entry and the first 2 annual follow-up visits. Among the participants (average age, 58 years; 45 percent women), 804 composite CVD events (congestive heart failure, stroke, or heart attack) occurred during a median 6.8 years of follow-up. The researchers found a significantly increased risk of CVD in individuals with the highest urinary sodium excretion independent of several important CVD risk factors, including use of antihypertensive medications and history of CVD. The cumulative incidence of CVD events in the highest quartile of calibrated sodium excretion compared with the lowest was 23.2 percent vs 13.3 percent for heart failure, 10.9 percent vs 7.8 percent for heart attack, and 6.4 percent vs 2.7 percent for stroke at median follow-up.

Findings were consistent across subgroups and independent of further adjustment for total caloric intake and systolic blood pressure.

“These findings, if confirmed by clinical trials, suggest that moderate sodium reduction among patients with CKD and high sodium intake may lower CVD risk,” the authors write.

(doi:10.1001/jama.2016.4447; this study is available pre-embargo at the For The Media website.)

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

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EMBARGOED FOR RELEASE: 12:00 P.M. (ET) SUNDAY, MAY 15, 2016

Media Advisory: To contact Hormuzd A. Katki, Ph.D., or Anil K. Chaturvedi, Ph.D., call the NCI Press Office at 301-496-6641 or email ncipressofficers@mail.nih.gov. To contact editorial author Michael K. Gould, M.D., M.S., email Sandra Hernandez-Millett at sandra.d.hernandez-millett@kp.org.
To place electronic embedded links to these papers in your story  These links will be live at the embargo time: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2016.6255; https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2016.5986

Among a group of U.S. ever-smokers age 50 to 80 years, application of an individual-risk-based model for computed tomography (CT) screening for lung cancer compared with selecting risk-factor-based subgroups for screening (such as current U.S. Preventive Services Task Force recommendations) was estimated to be associated with a greater number of lung cancer deaths prevented over 5 years, according to a study published online by JAMA. The study is being released to coincide with its presentation at the American Thoracic Society International Conference.

Lung cancer is the most common cause of cancer death in the United States. The U.S. Preventive Services Task Force (USPSTF) recommends CT lung cancer screening for ever-smokers age 55 to 80 years who have smoked at least 30 pack-years with no more than 15 years since quitting. Selecting individuals at highest lung cancer risk, as determined by individual risk calculations (i.e., risk-based selection) rather than by risk factor-based subgroups, might lead to more efficient screening. Risk-based selection more precisely delineates the benefits and harms of screening by accommodating detailed information on all lung cancer risk factors.

Hormuzd A. Katki, Ph.D., and Anil K. Chaturvedi, Ph.D., of the National Cancer Institute, Bethesda, Md., and colleagues conducted a comparison of modeled outcomes from risk-based CT lung-screening strategies vs USPSTF recommendations. The study included empirical risk models for lung cancer incidence and death in the absence of CT screening using data on ever-smokers from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO; 1993-2009) control group. Model validation in the chest radiography groups of the PLCO and the National Lung Screening Trial (NLST; 2002-2009), with additional validation of the death model in the National Health Interview Survey (NHIS; 1997-2001), a representative sample of the United States. Models were applied to U.S. ever-smokers age 50 to 80 years (NHIS 2010-2012) to estimate outcomes of risk-based selection for CT lung screening, assuming screening for all ever-smokers, and yield the percent changes in lung cancer detection and death observed in the NLST.

The researchers found that under USPSTF recommendations, the models estimated 9.0 million U.S. ever-smokers would qualify for lung cancer screening and 46,488 lung cancer deaths were estimated as screen-avertable over 5 years (estimated number needed to screen [NNS] to prevent 1 lung cancer death, 194). In contrast, risk-based selection screening of the same number of ever-smokers (9.0 million) at highest 5-year lung cancer risk was estimated to avert 20 percent more deaths (55,717) and was estimated to reduce the estimated NNS by 17 percent (NNS, 162).

“The key observation from the models is that compared with selecting risk-factor-based subgroups for screening (such as current USPSTF recommendations), individual-risk-based selection of smokers was estimated to prevent more deaths, improve screening effectiveness (defined as the NNS to prevent 1 lung cancer death), and improve screening efficiency (defined as the ratio of false-positive CT screening examinations to prevented deaths),” the authors write.

“Although CT screening can reduce lung cancer mortality by approximately 20 percent, the majority of lung cancer deaths are not screen-preventable at this time. The best way for smokers to avoid lung cancer, and all smoking-related illness, remains to quit smoking as early as possible.”

(doi:10.1001/jama.2016.6255; this study is available pre-embargo at the For The Media website.)

Editor’s Note: This study was supported by the Intramural Research Program of the U.S. 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: Who Should Be Screened for Lung Cancer? And Who Gets to Decide?

“In clinical practice, the decision to screen is very personal and should be individualized for each patient,” writes Michael K. Gould, M.D., M.S., of Kaiser Permanente Southern California, Pasadena, in an accompanying editorial.

“Screening should be offered to high-risk patients who do not meet USPSTF or Medicare criteria so they can decide whether to undergo testing. By extension, a patient who meets USPSTF or Medicare criteria may reasonably decide that the risks of screening outweigh the benefits. The challenge for clinicians is to make sure that individual patients receive the information they need to make the best decision possible about whether screening is the right choice for them.”

(doi:10.1001/jama.2016.5986; this study is available pre-embargo at the For The Media website.)

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

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EMBARGOED FOR RELEASE: 12:00 P.M. (ET) SUNDAY, MAY 15, 2016

Media Advisory: To contact Frank C. Sciurba, M.D., call Lawerence Synett at 412-647-9816 or email synettl@upmc.edu.

To place an electronic embedded link to this study in your story  This link will be live at the embargo time: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2016.6261

In a study published online by JAMA, Frank C. Sciurba, M.D., of the University of Pittsburgh, and colleagues assessed the 1-year effectiveness and safety of endobronchial coils on exercise tolerance, quality of life, and lung function in patients with severe emphysema. The study is being released to coincide with its presentation at the American Thoracic Society International Conference.

The endobronchial coils in this study were nitinol (a metal alloy) wires that were implanted in the lungs with an endoscope. The coils regain their preformed shape following deployment and restore elastic properties in lung tissue and improve ventilatory mechanical function. Patients with advanced emphysema and severe lung hyperinflation (an abnormal increase in lung capacity) have few treatment options to relieve dyspnea (shortness of breath).  Preliminary clinical trials have demonstrated that endobronchial coils may improve lung function, exercise tolerance, and symptoms in patients with emphysema and severe lung hyperinflation.

For this study, the researchers randomly assigned patients with severe emphysema to continue usual care alone (guideline based, including pulmonary rehabilitation and bronchodilators; n = 157) or usual care plus bilateral coil treatment (n = 158) involving 2 sequential procedures 4 months apart in which 10 to 14 coils were placed in a single lobe of each lung.

Among the study participants, 90 percent completed the 12-month follow-up. Median change in 6-minute walk distance (a measure of exercise tolerance) at 12 months was 10.3 m (33.8 feet) with coil treatment vs -7.6 m (24.9 feet) with usual care, with a between-group difference of 14.6 m (47.9 feet). Improvement of at least 25 m (82 feet) occurred in 40 percent of patients in the coil group vs 27 percent with usual care. Patients in the coil group also showed overall clinically important improvements in quality of life and greater improvement on a measure of lung function, although less than a clinically important difference.

Major complications (including pneumonia requiring hospitalization and other potentially life-threatening or fatal events) occurred in 35 percent of coil participants vs 19 percent of usual care. Other serious adverse events including pneumonia and pneumothorax (free air in the chest outside the lung) occurred more frequently in the coil group.

“Among patients with emphysema and severe hyperinflation treated for 12 months, the use of an endobronchial coil compared with usual care resulted in an improvement in median exercise tolerance that was modest and of uncertain clinical importance, with a higher likelihood of major complications. Further follow-up is needed to assess long-term effects on health outcomes,” the authors write.

(doi:10.1001/jama.2016.6261; this study is available pre-embargo at the For The Media website.)

Editor’s Note: This study was supported by PneumRx Inc., a BTG International group company. Drs. Sciurba, Criner, and Slebos receive institutional support from Pulmonx. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, etc.

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EMBARGOED FOR RELEASE: 5:15 P.M. (ET) SUNDAY, MAY 15, 2016

Media Advisory: To contact Daryl J. Kor, M.D., M.Sc., call Sharon Theimer at 507-284-5005 or email newsbureau@mayo.edu.

To place an electronic embedded link to this study in your story This link will be live at the embargo time: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2016.6330

In a study published online by JAMA, Daryl J. Kor, M.D., M.Sc., of the Mayo Clinic, Rochester, Minn., and colleagues evaluated the efficacy and safety of early aspirin administration for the prevention of acute respiratory distress syndrome (ARDS). The study is being released to coincide with its presentation at the American Thoracic Society International Conference.

Acute respiratory distress syndrome remains a life-threatening critical care syndrome. The median time to onset of ARDS is 2 days after hospital presentation. The period between hospital presentation and development of ARDS presents a brief window for possible prevention. ARDS is viewed as an inflammatory condition. Observational studies have suggested a potential preventive role for antiplatelet therapy in patients at high risk for ARDS.

Dr. Kor and colleagues randomly assigned patients at risk for ARDS (based on a lung injury prediction score) administration of aspirin (n = 195) or placebo (n = 195) within 24 hours of emergency department presentation and continued to hospital day 7, discharge, or death. The study was conducted at 16 U.S. academic hospitals.

The researchers found that the administration of aspirin, compared with placebo, did not significantly reduce the incidence of ARDS at 7 days (20 patients [10.3 percent] in the aspirin group vs 17 patients [8.7 percent] in the placebo group). No significant differences were seen in secondary outcomes or adverse events, such as ventilator-free days, hospital and intensive care unit length of stay, 28-day and 1-year survival.

“The findings of this phase 2b trial do not support continuation to a larger phase 3 trial,” the authors write.

(doi:10.1001/jama.2016.6330; this study is available pre-embargo at the For The Media website.)

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

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EMBARGOED FOR RELEASE: 5:15 P.M. (ET) SUNDAY, MAY 15, 2016

Media Advisory: To contact John P. Kress, M.D., email John Easton at John.Easton@uchospitals.edu. To contact editorial co-author Jeremy R. Beitler, M.D., M.P.H., email Michelle Brubaker at mmbrubaker@ucsd.edu.

To place electronic embedded links to these papers in your story  These links will be live at the embargo time: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2016.6338; https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2016.5987

In a study published online by JAMA, Bhakti K. Patel, M.D., and John P. Kress, M.D., of the University of Chicago, and colleagues examined whether noninvasive ventilation delivered by helmet, compared with a face mask, improves intubation rate among patients with acute respiratory distress syndrome (ARDS). The study is being released to coincide with its presentation at the American Thoracic Society International Conference.

Noninvasive ventilation (NIV) with a face mask is relatively ineffective at preventing endotracheal intubation (placement of a tube into the windpipe [trachea] through the mouth or nose) in patients with ARDS. Complications of endotracheal intubation include pneumonia, excessive sedation and delirium. An alternative is to deliver NIV via a helmet interface—a transparent hood that covers the entire head of the patient with a soft collar neck seal. This interface offers several advantages over a face mask including improved tolerability and less air leak due to the helmet’s lack of contact with the face and improved seal integrity at the neck. This could reduce intubation rates and extend the benefits of NIV to more patients with ARDS.

Dr. Kress and colleagues randomly assigned patients with ARDS requiring NIV delivered by face mask for at least 8 hours while in the medical intensive care unit to continue face mask NIV or switch to a helmet for NIV support. The final analysis included 44 patients randomly assigned to the helmet group and 39 to the face mask group.

The intubation rate was 61.5 percent for the face mask group and 18.2 percent for the helmet group. The median number of ventilator-free days was significantly higher in the helmet group (28 vs 12.5). At 90 days, 15 patients (34 percent) in the helmet group died compared with 22 patients (56 percent) in the face mask group. Adverse events included 3 interface-related skin ulcers for each group.

“Multicenter studies are needed to replicate these findings,” the authors write.

(doi:10.1001/jama.2016.6338; this study is available pre-embargo at the For The Media website.)

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

Editorial: Unmasking a Role for Noninvasive Ventilation in Early Acute Respiratory Distress Syndrome

Several key clinical messages can be gained from this study, writes Jeremy R. Beitler, M.D., M.P.H., of the University of California, San Diego, and colleagues in an accompanying editorial.

“The helmet interface has unique advantages and disadvantages that may influence efficacy of NIV depending on patient and disease characteristics. External validation of the findings by Patel et al and clarification of appropriate eligibility criteria, optimal ventilator settings, and potential mechanisms of effect are needed before clinicians could consider an expanded role for helmet NIV in routine management of select patients with ARDS. Whether helmet NIV affords benefit over high-flow nasal cannula warrants testing in a multicenter trial. Regardless, it is increasingly clear that there may be an important albeit under-investigated role for some form of high-level noninvasive respiratory support to prevent intubation, and perhaps mortality, in acute hypoxemic respiratory failure.”

(doi:10.1001/jama.2016.5987; this study is available pre-embargo at the For The Media website.)

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

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EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, MAY 17, 2016

Media Advisory: To contact Douglas B. White, M.D., M.A.S., call Allison Hydzik at 412-647-9975 or email hydzikam@upmc.edu.

To place an electronic embedded link to this study in your story  This link will be live at the embargo time: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2016.5351

Among critically ill patients, expectations about prognosis often differ between physicians and surrogate decision makers, and the causes are more complicated than the surrogate simply misunderstanding the physicians’ assessments of prognosis, according to a study appearing in the May 17 issue of JAMA.

In 2010, it was estimated that nearly half of U.S. adults near the end of life were unable to make decisions for themselves about whether to accept life-prolonging technologies. Family members or other individuals are asked to serve as surrogate decision makers for these often difficult decisions. Douglas B. White, M.D., M.A.S., of the University of Pittsburgh Medical Center, Pittsburgh, and colleagues examined the prevalence of and factors related to physician-surrogate discordance about prognosis in intensive care units (ICUs). The study included surveys and qualitative interviews conducted in 4 ICUs at a major U.S. medical center involving surrogate decision makers and physicians caring for patients at high risk of death.

Two hundred twenty-nine surrogate decision makers and 99 physicians were involved in the care of 174 critically ill patients. Physician-surrogate discordance about prognosis (defined as a difference between a physician’s and a surrogate’s prognostic estimates of at least 20 percent) occurred in 122 of 229 instances (53 percent). In 65 instances (28 percent), discordance was related to both misunderstandings by surrogates and differences in belief about the patient’s prognosis; 17 percent were related to misunderstandings by surrogates only; 3 percent were related to differences in belief only; and data were missing for 12.

Seventy-five patients (43 percent) died. Surrogates’ prognostic estimates were much more accurate than chance alone, but physicians’ prognostic estimates were statistically significantly more accurate than surrogates’. Among 71 surrogates interviewed who had beliefs about the prognosis that were more optimistic than that of the physician, the most common reasons for optimism were a need to maintain hope to benefit the patient (n = 34), a belief that the patient had unique strengths unknown to the physician (n = 24), and religious belief (n = 19).

“There are at least 2 clinical implications of our findings. First, given the high rates of discordance about prognosis, clinicians communicating with surrogates of patients with advanced critical illness should routinely check in with surrogates about their perceptions of prognosis prior to engaging in decision making about goals of care,” the authors write.

“Second, when clinicians recognize that surrogates’ expectations about prognosis diverge from their own, they should explore the possibility that causes other than misunderstanding may be contributing, such as a belief that the patient is stronger than average, a belief that expressing optimism will improve the patient’s outcome, or a belief that religious rather than biomedical considerations will determine the patient’s outcome. This is important because interventions to reconcile discordance about prognosis may differ for misunderstandings compared with differences in belief.”

(doi:10.1001/jama.2016.5351; this study is available pre-embargo at the For The Media website.)

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

Note: Also available pre-embargo at the For The Media website is an accompanying editorial, “Communication With Family Caregivers in the Intensive Care Unit – Answers and Questions,” by Elie Azoulay, M.D., Ph.D., of Hopital Saint-Louis, Paris, and colleagues.

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EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, MAY 17, 2016

Media Advisory: To contact Andrew M. Ibrahim, M.D., email Kara Gavin at kegavin@med.umich.edu.

To place an electronic embedded link to this study in your story  This link will be live at the embargo time: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2016.5618

In a study appearing in the May 17 issue of JAMA, Andrew M. Ibrahim, M.D., of the University of Michigan, Ann Arbor, and colleagues compared the surgical outcomes and associated Medicare payments at critical access hospitals vs non-critical access hospitals.

Critical access hospital designation was created to help ensure access to the more than 59 million people living in rural populations. Previous reports suggest these centers provide lower quality of care for common medical admissions. Little is known about the outcomes and costs of patients admitted for surgical procedures.

This study included a review of 1,631,904 Medicare beneficiary admissions to critical access hospitals (n = 828) and non-critical access hospitals (n = 3,676) for 1 of 4 common types of surgical procedures: appendectomy, gall bladder removal, removal of all or part of the colon, and hernia repair. The researchers compared risk-adjusted outcomes and adjusted for patient factors, admission type (elective, urgent, emergency), and type of operation.

Patients (average age, 77 years) undergoing surgery at critical access hospitals were less likely to have chronic medical problems, and they had lower rates of heart failure (7.7 percent vs 10.7 percent), diabetes (20 percent vs 22 percent), obesity (6.5 percent vs 10.6 percent), or multiple co-existing diseases (percent of patients with 2 or more comorbidities; 60 percent vs 70 percent). After adjustment for patient factors, critical access and non-critical access hospitals had no statistically significant differences in 30-day mortality rates (5.4 percent vs 5.6 percent).

Critical access vs non-critical access hospitals had significantly lower rates of serious complications (6 percent vs 14 percent). Medicare expenditures adjusted for patient factors and procedure type were lower at critical access hospitals than non-critical access hospitals ($14,450 vs $15,845).

“This study had 2 principal findings regarding how surgical care is delivered at critical access hospitals. First, the study found that performance of 4 common surgical procedures at critical access hospitals was associated with no difference in 30-day mortality and lower complication rates compared with non-critical access hospitals,” the authors write.

“Second, despite the reimbursement structure for critical access hospitals established in the Medicare Rural Hospital Flexibility Program, there was no evidence of higher expenditures for common surgical procedures. Both of these findings contrast previously published literature about nonsurgical admissions in these same settings and inform legislators about the valuable role critical access hospitals provide in the U.S. health care system.”

(doi:10.1001/jama.2016.5618; this study is available pre-embargo at the For The Media website.)

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

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EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, MAY 17, 2016

Media Advisory: To contact Giancarlo Natalucci, M.D., email giancarlo.natalucci@usz.ch.

To place an electronic embedded link to this study in your story  This link will be live at the embargo time: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2016.5504

In a study appearing in the May 17 issue of JAMA, Giancarlo Natalucci, M.D., of the University of Zurich, Switzerland, and colleagues randomly assigned 448 preterm infants born between 26 weeks 0 days’ and 31 weeks 6 days’ gestation to receive either high-dose recombinant human erythropoietin (rhEPO) or placebo (saline) intravenously within 3 hours, at 12 to 18 hours, and at 36 to 42 hours after birth.

Although outcome in very preterm infants has improved in recent decades, they still experience significant long-term neurodevelopmental delay. Among several pharmacological candidates to prevent brain injury or improve development, EPO has been shown to be among the most promising. An association has been reported between early high-dose rhEPO and a reduced incidence of white and gray matter injuries assessed by cerebral magnetic resonance imaging in a group of very preterm infants.

Among the preterm infants in the study (average gestational age, 29 weeks; average birth weight, 1,210 g [2.7 lbs.]), 228 were randomly assigned to rhEPO and 220 to placebo. Neurodevelopmental outcome data were available for 365 (81 percent) at an average age of 23.6 months. The researchers found that cognitive development, as assessed with the Mental Development Index, was not significantly different between the rhEPO group and the placebo group. No differences were found between groups in secondary outcomes such as motor development, cerebral palsy, hearing or visual impairment, and anthropometric growth parameters.

“To the best of our knowledge, this study evaluated the largest population to date of very preterm infants treated with high-dose rhEPO during the first days of life. It is possible that rhEPO does not have a neuroprotective role,” the authors write.

“Follow-up for cognitive and physical problems that may not become evident until later in life is required.”

(doi:10.1001/jama.2016.5351; this study is available pre-embargo at the For The Media website.)

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

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EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, MAY 17, 2016

Media Advisory: To contact Reshma Jagsi, M.D., D.Phil., email Nicole Fawcett at nfawcett@med.umich.edu.

To place an electronic embedded link to this study in your story  This link will be live at the embargo time: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2016.2188

In a study appearing in the May 17 issue of JAMA, Reshma Jagsi, M.D., D.Phil., of the University of Michigan, Ann Arbor, and colleagues conducted a survey of clinician-researchers on career and personal experiences, including questions on gender bias and sexual harassment.

In a 1995 survey, 52 percent of U.S. academic medical faculty women reported harassment in their careers compared with 5 percent of men. These women had begun their careers when women constituted a minority of the medical school class; less is known about the prevalence of such experiences among more recent faculty cohorts.

This study included 1,719 new recipients of career development awards (K-awards) from the National Institutes of Health in 2006-2009. The response rate to the survey was 62 percent (1,066 individuals). Average respondent age was 43 years; 46 percent were women; 71 percent were white. Women were more likely than men to report perceptions (70 percent vs 22 percent) and experience (66 percent vs 10 percent) of gender bias in their careers. Women were more likely to report having personally experienced sexual harassment (30 percent vs 4 percent). Among women reporting harassment (n = 150), 40 percent described more severe forms, 59 percent perceived a negative effect on confidence in themselves as professionals, and 47 percent reported that these experiences negatively affected their career advancement.

“Although a lower proportion reported these experiences [sexual harassment] than in a 1995 sample, the difference appears large given that the women began their careers after the proportion of female medical students exceeded 40 percent,” the authors write.

“Recognizing sexual harassment is important because perceptions that such experiences are rare may, ironically, increase stigmatization and discourage reporting. Efforts to mitigate the effect of unconscious bias in the workplace and eliminate more overtly inappropriate behaviors are needed.”

(doi:10.1001/jama.2016.2188; this study is available pre-embargo at the For The Media website.)

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

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EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, MAY 10, 2016

Media Advisory: To contact Børge G. Nordestgaard, M.D., D.M.Sc., email Boerge.Nordestgaard@regionh.dk.

To place an electronic embedded link to this study in your story  This link will be live at the embargo time: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2016.4666

In a study appearing in the May 10 issue of JAMA, Børge G. Nordestgaard, M.D., D.M.Sc., of Copenhagen University Hospital, Herlev, Denmark and colleagues examined whether the body mass index (BMI) value that is associated with the lowest all-cause mortality has increased in the general population over a period of 3 decades.

Previous findings indicate that while average BMI has increased over time in most countries, the prevalence of cardiovascular risk factors may be decreasing among obese individuals. Thus, the BMI associated with lowest all-cause mortality may have changed over time. This study included three groups from the same general population enrolled at different times: the Copenhagen City Heart Study in 1976-1978 (n = 13,704) and 1991-1994 (n = 9,482) and the Copenhagen General Population Study in 2003-2013 (n = 97,362). All participants were followed up from inclusion in the studies to November 2014, emigration, or death, whichever came first.

The researchers found that the BMI value associated with the lowest all-cause mortality has increased by 3.3 over 3 decades from 1976-1978 to 2003-2013, from 23.7 to 27. In addition, the risk for all-cause mortality that was associated with BMI of 30 or greater vs BMI of 18.5 to 24.9 decreased from an adjusted hazard ratio of 1.3 to 1.0 over this 30-year period. “These latter findings were robust in analyses stratified by age, sex, smoking status, and history of cardiovascular disease or cancer.”

The authors write that an interesting finding in this study is that the optimal BMI in relation to mortality is placed in the overweight category in the most recent 2003-2013 cohort. “This finding was consistent in both the whole population sample (optimal BMI, 27), and in a subgroup of never-smokers without history of cardiovascular disease or cancer (optimal BMI, 26.1). If this finding is confirmed in other studies, it would indicate a need to revise the WHO categories presently used to define overweight, which are based on data from before the 1990s.”

Regarding the increase in the BMI value associated with the lowest all-cause mortality, the researchers write that “further investigation is needed to understand the reason for this change and its implications.”

(doi:10.1001/jama.2016.4666; this study is available pre-embargo at the For The Media website.)

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

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EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, MAY 10, 2016

Media Advisory: To contact Sian Taylor-Phillips, Ph.D., email s.taylor-phillips@warwick.ac.uk.

To place an electronic embedded link to this study in your story  This link will be live at the embargo time: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2016.5257

Longer time spent by film readers interpreting screening mammograms did not result in a reduced rate of breast cancer detection, according to a study appearing in the May 10 issue of JAMA.

Interpreting screening mammograms is a difficult and repetitive visual search task, for which characteristics of cancer are disguised among background breast parenchyma (tissue) resulting in false-positive recalls and missed cancers. In similar visual search tasks, a vigilance decrement (decreasing detection rates with time on task) has been observed in a large number of psychological laboratory experiments, including assembly line inspection tasks and airport baggage screening.  In the United Kingdom (U.K.), 2 film readers independently evaluate each mammogram for signs of cancer.

Sian Taylor-Phillips, Ph.D., of the University of Warwick, Coventry, U.K., and colleagues investigated whether a vigilance decrement to detect cancer in breast screening practice exists and whether changing the order in which 2 experts examined a batch of mammograms could increase the cancer detection rate, through readers’ experiencing peak vigilance at differing points within the reading batch when examining different women’s mammograms. The study was conducted at 46 specialized breast screening centers from the National Health Service (NHS) Breast Screening Program in England for 1 year. Three hundred sixty readers participated, all fully qualified to report mammograms in the NHS breast screening program. The 2 readers examined each batch of digital mammograms in the same order in the control group and in the opposite order to one another in the intervention group.

Among 1,194,147 women who had screening mammograms (596,642 in the intervention group; 597,505 in the control group), the images were interpreted in 37,688 batches (median batch size, 35), with each reader interpreting a median of 176 batches. After completion of all subsequent diagnostic tests, a total of 10,484 cases (0.88 percent) of breast cancer were detected. There was no significant difference in cancer detection rate with 5,272 cancers (0.88 percent) detected in the intervention group vs 5,212 cancers (0.87 percent) detected in the control group (recall rate, 4.14 percent vs 4.17 percent; rate of reader disagreements, 3.43 percent vs 3.48 percent).

“The intervention did not influence cancer detection rate, recall rate, or rate of disagreement between readers. There was no pattern of decreasing cancer detection rate with time on task as predicted by previous research on vigilance decrements as a psychological phenomenon,” the authors write.

(doi:10.1001/jama.2016.5257; this study is available pre-embargo at the For The Media website.)

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

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EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, MAY 10, 2016

Media Advisory: To contact Ateev Mehrotra, M.D., call Angela Alberti at 617-432-3038 or email Angela_Alberti@hms.harvard.edu.

To place an electronic embedded link to this study in your story  This link will be live at the embargo time: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2016.2186

Although the number of Medicare telemedicine visits increased more than 25 percent a year for the past decade, in 2013, less than 1 percent of rural Medicare beneficiaries received a telemedicine visit, according to a study appearing in the May 10 issue of JAMA.

Medicare limits telemedicine reimbursement to select live video encounters with the patient at a clinic or facility in a rural area. Federal legislation has been proposed to expand Medicare telemedicine coverage. Ateev Mehrotra, M.D., of Harvard Medical School, Boston, and colleagues examined trends in telemedicine utilization in Medicare from 2004-2013 using claims from a 20 percent random sample of traditional Medicare beneficiaries.

The researchers found that telemedicine visits among rural Medicare beneficiaries increased from 7,015 in 2004 to 107,955 in 2013 (annual visit growth rate, 28 percent); 0.7 percent of rural beneficiaries received a telemedicine visit in 2013. Most visits occurred in outpatient clinics; 12.5 percent occurred in a hospital or skilled nursing facility. Mental health conditions were responsible for 79 percent of visits. Rural beneficiaries who received a 2013 telemedicine visit were more likely to be younger than 65 years, have entered Medicare due to disability, have more illnesses, and live in a poorer community compared with those who did not receive a telemedicine visit.

“Proposed federal legislation would encourage greater use of telemedicine through expanded reimbursement. In contrast to others, we found that state laws that mandate commercial insurance reimbursement of telemedicine were not associated with faster growth in Medicare telemedicine use. Our results emphasize that nonreimbursement factors may be limiting growth of telemedicine including state licensure laws and restrictions that a patient must be hosted at a clinic or facility,” the authors write.

(doi:10.1001/jama.2016.2186; this study is available pre-embargo at the For The Media website.)

Editor’s Note: This article was supported by an unrestricted gift to Harvard Medical School by Melvin Hall and CHSi Corporation. 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, MAY 10, 2016

Media Advisory: To contact Dinesh Khanna, M.D., call Kylie O’Brien at 734-764-2220 or email kylieo@med.umich.edu.

To place an electronic embedded link to this study in your story  This link will be live at the embargo time: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2016.5258

In an article appearing in the May 10 issue of JAMA, Dinesh Khanna, M.D., of the University of Michigan Scleroderma Program, Ann Arbor, and colleagues evaluated the efficacy of the drug macitentan in reducing the number of new digital ulcers in patients with systemic sclerosis.

Systemic sclerosis is a chronic multisystem autoimmune disease and multiorgan disease affecting the connective tissue of the skin and several internal organs. Digital ulcers occur in 35 percent to 68 percent of patients with systemic sclerosis and are associated with pain, disfigurement, poor quality of life, and disability. For this study, two clinical trials (DUAL-1, DUAL-2) were conducted in which patients with systemic sclerosis and active digital (finger) ulcers at trial entry were randomly assigned to receive oral doses of 3 mg of macitentan, 10 mg of macitentan, or placebo once daily and stratified according to number of digital ulcers at baseline. Macitentan is a drug approved for long-term treatment of pulmonary arterial hypertension.

In DUAL-1, among 289 randomized patients, 226 completed the study. Among 265 patients randomized in DUAL-2, 216 completed the study. The researchers found that macitentan did not reduce the cumulative number of new digital ulcers over 16 weeks compared with placebo. Regardless of treatment, patients had few new digital ulcers, and their overall digital ulcer condition remained stable over 16 weeks.

Adverse events more frequently associated with macitentan than with placebo were headache, peripheral edema, skin ulcer, anemia, upper respiratory tract infection and diarrhea.

“These results do not support the use of macitentan for the treatment of digital ulcers in this patient population,” the authors write.

(doi:10.1001/jama.2016.5258; this study is available pre-embargo at the For The Media website.)

Editor’s Note: DUAL-1 and DUAL-2 were funded by Actelion Pharmaceuticals Ltd. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, etc.

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EMBARGOED FOR RELEASE: 8 A.M. (ET) SATURDAY, APRIL 30, 2016

Media Advisory: To contact Stephen B. Freedman, M.D.C.M., M.Sc., call Kathryn Kazoleas at 403-220-5012 or email kjslonio@ucalgary.ca.

To place an electronic embedded link to this study in your story  This link will be live at the embargo time: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2016.5352

Children with mild gastroenteritis and minimal dehydration experienced fewer treatment failures such as IV rehydration or hospitalization when offered half-strength apple juice followed by their preferred fluid choice compared with children who received electrolyte maintenance solution to replace fluid losses, according to a study published online by JAMA. The study is being released to coincide with its presentation at the Pediatric Academic Societies meeting.

Gastroenteritis is a common pediatric illness. Electrolyte maintenance solution is recommended to treat and prevent dehydration, although it is relatively expensive and its taste can limit use. Its advantage in minimally dehydrated children is unproven. Stephen B. Freedman, M.D.C.M., M.Sc., of the University of Calgary, Canada, and colleagues randomly assigned children age 6 to 60 months with gastroenteritis and minimal dehydration to receive color-matched half-strength apple juice/preferred fluids (n = 323) or apple-flavored electrolyte maintenance solution (n = 324). After discharge, the half-strength apple juice/preferred fluids group was administered fluids as desired; the electrolyte maintenance solution group replaced losses with electrolyte maintenance solution.

The primary outcome for the study was a composite of treatment failure defined by any of the following occurring within 7 days of enrollment: intravenous rehydration, hospitalization, subsequent unscheduled physician encounter, protracted symptoms, crossover, and 3 percent or more weight loss or significant dehydration at in-person follow-up.

Among 647 randomized children (average age, 28 months; 68 percent without evidence of dehydration), 644 completed follow-up. Children who were administered diluted apple juice experienced treatment failure less often than those given electrolyte maintenance solution (17 percent vs 25 percent). Fewer children administered apple juice/preferred fluids received intravenous rehydration (2.5 percent vs 9 percent). Hospitalization rates and diarrhea and vomiting frequency were not significantly different between groups.

The authors write that these results challenge the recommendation to routinely administer electrolyte maintenance solution when diarrhea begins, based primarily on an unblinded study in which blocks of participants were provided instructions for use of electrolyte maintenance solution or instructions plus a prescription for electrolyte maintenance solution at no charge. “The present study findings, derived from a larger and more heterogeneous population, confirmed via provincial registries, and conducted in an era when complicated episodes of gastroenteritis have become uncommon, may more accurately reflect the effect rehydration fluid choice has on unscheduled medical visits.”

“In many high-income countries, the use of dilute apple juice and preferred fluids as desired may be an appropriate alternative to electrolyte maintenance fluids in children with mild gastroenteritis and minimal dehydration.”

(doi:10.1001/jama.2016.5352; this study is available pre-embargo at the For The Media website.)

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

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EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, MAY 3, 2016

Media Advisory: To contact Katherine E. Fleming-Dutra, M.D., call Melissa Brower at 404-639-4718 or email mbrower@cdc.gov. To contact editorial co-author Sara E. Cosgrove, M.D., call Kim Polyniak at 443-287-8589 or email kpolyni1@jhmi.edu.

To place an electronic embedded link to this study and editorial in your story  These links will be live at the embargo time: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2016.4151; https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2016.4286

An estimated 30 percent of outpatient oral antibiotic prescriptions in the U.S. in 2010-2011 may have been inappropriate, findings that support the need for establishing a goal for outpatient antibiotic stewardship, according to a study appearing in the May 3 issue of JAMA.

Antibiotic-resistant infections affect 2 million people and are associated with 23,000 deaths annually in the United States, according to the Centers for Disease Control and Prevention. Antibiotic use is the primary driver of antibiotic resistance and leads to adverse events ranging from allergic reactions to Clostridium difficile infections. In the United States in 2011, 262 million outpatient antibiotic prescriptions were dispensed. However, the fraction of antibiotic use that is inappropriate and amenable to reduction has been unknown.

Katherine E. Fleming-Dutra, M.D., of the Centers for Disease Control and Prevention, Atlanta, and colleagues used the 2010-2011 National Ambulatory Medical Care Survey and National Hospital Ambulatory Medical Care Survey to estimate the rates of outpatient oral antibiotic prescribing by age and diagnosis and the estimated portions of antibiotic use that may be inappropriate in adults and children in the U.S.

Of the 184,032 sampled visits, 12.6 percent of visits resulted in antibiotic prescriptions. Sinusitis was the diagnosis associated with the most antibiotic prescriptions per 1,000 population (56), followed by suppurative otitis media (ear infection; 47 prescriptions), and pharyngitis (common cause of sore throat; 43 prescriptions). Collectively, acute respiratory conditions per 1,000 population led to 221 antibiotic prescriptions annually, but only 111 antibiotic prescriptions were estimated to be appropriate for these conditions. Per 1,000 population, among all conditions and ages combined in 2010-2011, an estimated 506 antibiotic prescriptions were written annually, and, of these, 353 antibiotic prescriptions were estimated to be appropriate.

“Half of antibiotic prescriptions for acute respiratory conditions may have been unnecessary, representing 34 million antibiotic prescriptions annually. Collectively, across all conditions, an estimated 30 percent of outpatient, oral antibiotic prescriptions may have been inappropriate. Therefore, a 15 percent reduction in overall antibiotic use would be necessary to meet the White House National Action Plan for Combating Antibiotic-Resistant Bacteria goal of reducing inappropriate antibiotic use in the outpatient setting by 50 percent by 2020,” the authors write.

“This estimate of inappropriate outpatient antibiotic prescriptions can be used to inform antibiotic stewardship programs in ambulatory care by public health and health care delivery care systems in the next 5 years.”

(doi:10.1001/jama.2016.4151; this study is available pre-embargo at the For The Media website.)

Editor’s Note: This project was made possible through a partnership with the Centers for Disease Control and Prevention Foundation. Support for this project was provided by Pew Charitable Trusts. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, etc.

Editorial: Addressing the Appropriateness of Outpatient Antibiotic Prescribing in the United States – An Important First Step

“Despite the likely conservative estimate of inappropriate outpatient antibiotic use reported in the study by Fleming-Dutra et al, these findings offer an important and useful starting point to understand prescribing practices in the ambulatory care setting. Such estimates are necessary to guide public health and outpatient stewardship efforts,” write Pranita D. Tamma, M.D., M.H.S., and Sara E. Cosgrove, M.D., M.S., of the Johns Hopkins University School of Medicine, Baltimore, in an accompanying editorial.

“Attempts to improve outpatient antibiotic prescribing likely require 2 complementary strategies: (1) changing clinician behavior to alleviate concerns related to diagnostic uncertainty, alienating patients, and not conforming to peer practices and (2) educating patients and families about the role of antibiotics in medical care.”

(doi:10.1001/jama.2016.4286; this editorial is available pre-embargo at the For The Media website.)

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

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EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, MAY 3, 2016

Media Advisory: To contact Ateev Mehrotra, M.D., M.P.H., call Angela Alberti at 617-432-3038 or email Angela_Alberti@hms.harvard.edu. To contact editorial author Kevin G. Volpp, M.D., Ph.D., call Katie Delach at 215-349-5964 or email Katharine.Delach@uphs.upenn.edu.

To place electronic embedded links to this study and editorial in your story  These links will be live at the embargo time: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2016.4288; https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2016.4325
Offering a health care services price transparency tool to employees at 2 large companies was not associated with lower outpatient spending, according to a study appearing in the May 3 issue of JAMA.

More than half of U.S. states have passed legislation establishing price transparency websites or mandating that health plans, hospitals, or physicians make price information available to patients to help them identify less expensive care. Despite the enthusiasm for price transparency efforts, little is known about their association with health care spending. Ateev Mehrotra, M.D., M.P.H., of Harvard Medical School, Boston, and colleagues compared the health care spending patterns of employees (n=148,655) of two companies that offered a price transparency tool in the year before and after it was introduced with patterns among employees (n=295,983) of other companies that did not offer the tool. The tool provided users information about what they would pay out of pocket for services from different physicians, hospitals, or other clinical sites.

Average outpatient spending among employees offered the tool was $2,021 in the year before the tool was introduced and $2,233 in the year after. In comparison, among controls, average outpatient spending changed from $1,985 to $2,138. After adjusting for demographic and health characteristics, being offered the tool was associated with an average $59 increase in outpatient spending and an average $18 increase in out-of-pocket spending. The tool was used by only a small percentage of eligible employees. In the first 12 months, 10 percent of employees who were offered the tool used it at least once.

The authors write that offering price transparency could increase spending if patients equate higher prices with higher quality and therefore use the tool to selectively choose higher-priced clinicians. “The tool reports both total price and out-of­ pocket amounts, and patients may use total price to identify higher-priced clinicians when their out-of-pocket price are the same. However, given the statistically significant increase in spending was not observed in all subanalyses and given findings of prior work on price transparency, this is speculative and would need to be confirmed in future studies. A more conservative interpretation is that the study failed to find evidence of meaningful savings associated with availability of a price transparency tool.”

(doi:10.1001/jama.2016.4288; this study is available pre-embargo at the For The Media website.)

Editor’s Note: This work was supported by a grant from the Laura and John Arnold Foundation and the Marshall J. Seidman Center for Studies in Health Economics and Health Care Policy at Harvard Medical School. All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.

Editorial: Price Transparency – Not a Panacea for High Health Care Costs

“It is not surprising that price transparency tools that offer patients as consumers information on relative prices fail to lower the rate of spending, given that this information is often offered without accompanying data about quality and for services that would exceed the deductibles of patients,” writes Kevin G. Volpp, M.D., Ph.D., of the Philadelphia VA Medical Center, University of Pennsylvania Perelman School of Medicine, Wharton School of Medicine and Health Care Management, Philadelphia, in an accompanying editorial.

“Perhaps by providing meaningful relative information on price and quality and focusing on services with prices lower than a patient’s deductible, such tools could succeed in driving patients to choose higher-value services. However, that will only happen to the degree that patients value this information and want to use it, and it is as yet unknown whether the low engagement rates with these tools reflect true consumer disinterest or that these tools have not yet figured out how to engage consumers.”

“Price transparency tools are not likely the panacea that many have hoped for with respect to controlling health care costs. Health plans could create incentives to use price transparency tools as part of benefit design, but given the results reported by Desai et al and the related considerations, health plans might exercise caution because doing so may be unlikely to reduce health care spending.”

(doi:10.1001/jama.2016.4325; this editorial is available pre-embargo at the For The Media website.)

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

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EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, MAY 3, 2016

Media Advisory: To contact Claudia Buntrock, M.Sc., email buntrockclaudia@gmail.com.

To place an electronic embedded link to this study in your story  This link will be live at the embargo time: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2016.4326

Among patients experiencing some symptoms of depression, the use of a web-based guided self-help intervention reduced the incidence of major depressive disorder over 12 months compared with enhanced usual care, according to a study appearing in the May 3 issue of JAMA.

Major depressive disorder (MDD) is a common condition associated with substantial illness and economic costs. It is projected that MDD will be the leading cause of premature mortality and disability in high-income countries by 2030. Evidence-based treatments for MDD are not very successful in improving functional and health outcomes. Attention has increasingly been focused on the prevention of MDD.

Claudia Buntrock, M.Sc., of Leuphana University Lueneburg, Germany, and colleagues randomly assigned 406 adults with subthreshold depression (some symptoms of depression, but no current MDD per certain criteria) to either a web-based guided self-help intervention (cognitive-behavioral and problem-solving therapy supported by an online trainer; n = 202) or a web-based psychoeducation program (n = 204). All participants had unrestricted access to usual care (visits to the primary care clinician).

Among the patients (average age, 45 years; 74 percent women), 335 (82 percent) completed the telephone follow-up at 12 months. The researchers found that 55 participants (27 percent) in the intervention group experienced MDD compared with 84 participants (41 percent) in the control group. The number needed to treat to avoid 1 new case of MDD was 6.

“Results of the study suggest that the intervention could effectively reduce the risk of MDD onset or at least delay onset,” the authors write. “Further research is needed to understand whether the effects are generalizable to both first onset of depression and depression recurrence as well as efficacy without the use of an online trainer.”

(doi:10.1001/jama.2016.4326; this study is available pre-embargo at the For The Media website.)

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

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EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, MAY 3, 2016

Media Advisory: To contact Pascal Hammel, M.D., email pascal.hammel@aphp.fr.

To place an electronic embedded link to this study in your story  This link will be live at the embargo time: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2016.4324

In a study appearing in the May 3 issue of JAMA, Pascal Hammel, M.D., of Beaujon Hospital, Clichy, France and colleagues assessed whether chemoradiotherapy improves overall survival of patients with locally advanced pancreatic cancer controlled after 4 months of gemcitabine-based induction chemotherapy, and assessed the effect of erlotinib on survival. Gemcitabine and erlotinib are drugs used to treat cancer.

In locally advanced pancreatic cancer, the role of chemoradiotherapy is controversial and the efficacy of erlotinib is unknown. For this study, the researchers first randomly assigned 449 patients to receive gemcitabine alone (n = 223) and 219 patients received gemcitabine plus erlotinib. In the second randomization involving patients with progression-free disease after 4 months, 136 patients received 2 months of the same chemotherapy and 133 underwent chemoradiotherapy (54 Gy [a measure of radiation dose] plus the chemotherapy drug capecitabine).

A total of 442 of the 449 patients enrolled underwent the first randomization. Of these, 269 underwent the second randomization. With a median follow-up of 36.7 months, the researchers found no survival benefit of chemoradiotherapy compared with chemotherapy, with median overall survival from the date of the first randomization of 15.2 months and 16.5 months, respectively. Also, there was no significant difference in overall survival with gemcitabine (13.6 months) compared with gemcitabine plus erlotinib (11.9 months).

(doi:10.1001/jama.2016.4324; this study is available pre-embargo at the For The Media website.)

Editor’s Note: This trial was supported by Roche and the French National Institute of Cancer. 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, MAY 3, 2016

Media Advisory: To contact Anette-Gabriele Ziegler, M.D., email anette-g.ziegler@helmholtz-muenchen.de.

To place an electronic embedded link to this study in your story  This link will be live at the embargo time: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2016.2181

In a study appearing in the May 3 issue of JAMA, Anette-Gabriele Ziegler, M.D., of Helmholtz Zentrum Munchen, Munich, Germany, and colleagues examined associations between infection types during the first 2 years of life and between respiratory tract infections in the first 6 months and type l diabetes (T1D). Viral infections, particularly enteroviruses, have been hypothesized to cause T1D. Recent studies suggest that respiratory tract infections are associated with increased T1D risk if they are encountered within the first 6 months.

Using data for patients in Bavaria, Germany, the study included 295,420 infants, of whom 720 were diagnosed with T1D over a median follow-up of 8.5 years, for an incidence of 29 diagnoses per 100,000 children annually. At least 1 infection was reported during the first 2 years of life in 93 percent of all children, and in 97 percent of children with T1D.

Most children experienced respiratory and viral infections. The researchers found that T1D risk was increased in children who had a respiratory tract infection between birth and 2.9 months or between 3 and 5.9 months of age compared with children who had no respiratory tract infections in these age intervals. T1D risk was also increased among children who experienced a viral infection between birth and 5.9 months of age.

“It is unknown whether the association with early infections reflects increased exposure to virus or an impairment of the immune system response, perhaps due to genetic susceptibility,” the authors write. “The association of respiratory tract infections in the first 6 months with T1D is consistent with smaller studies assessing autoantibody development, suggesting that the first half-year of life is crucial for the development of the immune system and autoimmunity.”

(doi:10.1001/jama.2016. 2181; this study is available pre-embargo at the For The Media website.)

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

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EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, APRIL 26, 2016

Media Advisory: To contact Celine Vetter, Ph.D., call Elaine St. Peter at 617-525-6375 or email estpeter@partners.org.

To place an electronic embedded link to this study in your story  This link will be live at the embargo time: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2016.4454

Among female registered nurses, working a rotating night shift for 5 years or more was associated with a small increase in the risk of coronary heart disease, according to a study appearing in the April 26 issue of JAMA.

The disruption of social and biological rhythms that occur during shift work have been hypothesized to increase chronic disease risk, and evidence supports an association between shift work and coronary heart disease (CHD), metabolic disorders, and cancer. Prospective studies linking shift work to CHD have been inconsistent and limited by short follow-up. Celine Vetter, Ph.D., of Brigham and Women’s Hospital and Harvard Medical School, Boston, and colleagues examined the incidence of CHD in 189,158 initially healthy women followed up over 24 years in the Nurses’ Health Studies (NHS [1988-2012]: n = 73,623 and NHS2 [1989-2013]: n = 115,535). The researchers determined the lifetime history of rotating night shift work (3 night shifts or more per month in addition to day and evening shifts) of the nurses at baseline (updated every 2 to 4 years in the NHS2).

During follow-up, 7,303 incident CHD cases (i.e., nonfatal heart attack, CHD death, angiogram-confirmed angina pectoris, coronary artery bypass graft surgery, stents, and angioplasty) occurred in the NHS and 3,519 in the NHS2. Analysis indicated that increasing years of rotating night shift work was associated with a statistically significant but small absolute increase in CHD risk. In the NHS, the association between duration of shift work and CHD was stronger in the first half of follow-up than in the second half, suggesting waning risk after cessation of shift work. Longer time since quitting shift work was associated with decreased CHD risk among shift workers in the NHS2.

“Further research is needed to explore whether the association is related to specific work hours and individual characteristics,” the authors write.

(doi:10.1001/jama.2016.4454; this study is available pre-embargo at the For The Media website.)

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

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EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, APRIL 26, 2016

Media Advisory: To contact J. Christian Virchow, M.D., email jc.h.virchow@sunrise.ch or j.c.virchow@med.uni-rostock.de. To contact editorial author Robert A. Wood, M.D., call Lauren Nelson at 410-955-8725 or email laurennelson@jhmi.edu.

To place an electronic embedded link to this study in your story  This link will be live at the embargo time: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2016.3964

The addition of a house dust mite (HDM) sublingual allergen immunotherapy (SLIT) tablet to maintenance medications improved time to first moderate or severe asthma exacerbation during a period of inhaled corticosteroid (ICS) reduction among adults with HDM allergy-related asthma not well controlled by ICS, according to a study appearing in the April 26 issue of JAMA.

Bronchial asthma is a serious global health problem with increasing prevalence in many countries. House dust mite sensitization is present in up to 50 percent of patients with asthma, and exposure to HDM allergen has been related to asthma severity. The HDM SLIT tablet is a potential novel treatment option for HDM allergy-related asthma. In this study by J. Christian Virchow, M.D., of the University of Rostock, Germany, and coauthors, 834 adults with HDM allergy-related asthma not well controlled by ICS or combination products, and with HDM allergy-related rhinitis, were randomly assigned to once-daily treatment with placebo (n = 277) or HDM SLIT tablet (different dosage groups, n = 275 or n = 282) in addition to ICS and the short-acting beta2-agonist salbutamol. Efficacy was assessed during the last 6 months of the trial when ICS was reduced by 50 percent for 3 months and then completely withdrawn for 3 months. The study was conducted in 109 European trial sites.

Among the 834 patients, 693 completed the study. The researchers found that either dosage of the HDM SLIT tablet significantly reduced the risk of a moderate or severe asthma exacerbation compared with placebo. Compared with placebo, there was also an increase in allergen-specific immunoglobulin G4 (lgG4; an antibody). However, there was no significant difference for change in the asthma control questionnaire or asthma quality-of-life questionnaire for either dose. There were no reports of severe systemic allergic reactions.

“To our knowledge, this is the first controlled trial to show that adult patients with HDM allergy-related asthma who were not well controlled taking ICS can achieve an improvement in asthma control as measured by time to first asthma exacerbation with a sublingual tablet formulation of HDM allergen immunotherapy,” the authors write.

They add that further studies are needed to assess long-term efficacy and safety.

(doi:10.1001/jama.2016.3964; this study is available pre-embargo at the For The Media website.)

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

Editorial: New Horizons in Allergen Immunotherapy

“Rigorous studies of immunotherapy of all forms are clearly needed. The study by Virchow et al is a valuable contribution to the literature, especially given its focus on an important patient population with highly relevant end points,” writes Robert A. Wood, M.D., of the Johns Hopkins University School of Medicine, Baltimore, in an accompanying editorial.

“The work should not end here, as there is still a great deal of room for refinement in the practice of immunotherapy. As research continues and these therapies enter clinical practice, the goal should be to optimize each patient’s immunotherapy regimen and disease control, taking personal preferences into account, and ideally to develop additional patient profiling using specific biomarkers to further personalize the use of these treatment options.”

(doi:10.1001/jama.2016.4078; this editorial is available pre-embargo at the For The Media website.)

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

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EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, APRIL 26, 2016

Media Advisory: To contact Elizabeth A. Rafferty, M.D., call Kathy Weiner at 978-266-2676 or email lmradkat@verizon.net.

To place an electronic embedded link to this study in your story  This link will be live at the embargo time: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2016.1708.

In a study appearing in the April 26 issue of JAMA, Elizabeth A. Rafferty, M.D., formerly of Massachusetts General Hospital, Boston, and colleagues evaluated the screening performance of digital mammography combined with tomosynthesis (a type of imaging) compared with digital mammography alone for women with varying levels of breast density.

Breast density is associated with reduced mammographic sensitivity and specificity, and increased tumor size and worsened prognosis are associated with increased breast density. Currently, 24 states have laws mandating that women be notified of the implications of breast density, thereby encouraging discussions between patients and physicians regarding the need for supplemental screening. However, which, if any, additional testing should be recommended for women with dense breasts is not known.

This study included data from screening performance metrics from 13 U.S. institutions, which were reported for 12 months using digital mammography alone and from the date of introduction of tomosynthesis. Subgroups included the 4 breast density categories used for clinical reporting. Overall and invasive cancer detection rates and recall rate with and without tomosynthesis were analyzed in patients with both nondense and dense breasts.

Of 452,320 examinations, 278,906 were digital mammography alone and 173,414 digital mammography plus tomosynthesis; 2,157 cancers were diagnosed. The researchers found that the addition of tomosynthesis to digital mammography for screening was associated with an increase in cancer detection rate and a reduction in recall rate for women with both dense and nondense breast tissue. “These combined gains were largest for women with heterogeneously dense breasts, potentially addressing limitations in cancer detection seen with digital mammography alone in this group, but were not significant in women with extremely dense breasts.”

The authors note that for women classified as having dense breast tissue, most have heterogeneously dense breasts, mandating caution in drawing conclusions regarding the performance of tomosynthesis for the small proportion of women with extremely dense breasts.

(doi:10.1001/jama.2016.1708; this study is available pre-embargo at the For The Media website.)

Editor’s Note: Dr. Rafferty is now with L&M Radiology, West Acton, Mass. This study was funded by a research grant from Hologic. 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, APRIL 26, 2016

Media Advisory: To contact Nancy R. Kressin, Ph.D., email Gina DiGravio-Wilczewski at ginad@bu.edu.

To place an electronic embedded link to this study in your story  This link will be live at the embargo time: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2016.1712

In a study appearing in the April 26 issue of JAMA, Nancy R. Kressin, Ph.D., of the Veterans Affairs Boston Healthcare System, Boston University School of Medicine, and colleagues examined the content, readability, and understandability of dense breast notifications sent to women following screening mammography.

Along with their screening mammogram results, women in nearly half of U.S. states also receive notifications of breast density, a result of legislation intended to assist in making personalized decisions about further action. Dense breasts can mask cancer on mammography (masking bias), and are an independent cancer risk factor, but evidence does not yet indicate whether or what supplemental screening is appropriate. Rather, risk stratification is proposed to determine who may benefit from supplemental screening (e.g., magnetic resonance imaging for women at high risk). The text of dense breast notifications (DBNs) may affect women’s ability to understand their message.

Twenty-four states require DBNs as of January l, 2016; the researchers analyzed the characteristics of all but Delaware. They found wide variation in the states’ DBN content. All DBNs mention masking bias, 74 percent mention the association with increased cancer risk, and 65 percent mention supplemental screening as an option, advising women to consult their physician. Of 15 DBNs requiring mention of supplemental screening, 6 (40 percent) inform women that they might benefit from such screening; 4 mention specific modalities.

Most of the states have readability at the high school level or above (exceeding the recommended readability level [grades 7-8]; about 20 percent of the population reads below a grade 5 level). Only 3 states’ DBN readability level was at the grade 8 level or below; some of the highest readability levels occurred in states with the lowest literacy levels. All DBNs scored poorly on understandability.

“Such problems may create uncertainty for women attempting to make personalized decisions about supplemental screening and may exacerbate disparities in breast cancer screening related to low health literacy,” the authors write.

“Efforts should focus on enhancing the understandability of DBNs so that all women are clearly and accurately informed about their density status, its effect on their breast cancer risk, and the harms and benefits of supplemental screening.”

(doi:10.1001/jama.2016.1712; this study is available pre-embargo at the For The Media website.)

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

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EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, APRIL 19, 2016

Media Advisory: To contact Antoni Ribas, M.D., Ph.D., email Reggie Kumar at ReggieKumar@mednet.ucla.edu.

To place an electronic embedded link to this study in your story  This link will be live at the embargo time: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2016.4059

In a study appearing in the April 19 issue of JAMA, Antoni Ribas, M.D., Ph.D., of the University of California-Los Angeles, and colleagues examined tumor response and overall survival following administration of the antibody pembrolizumab among patients with advanced melanoma.

Pembrolizumab, an antibody against programmed cell death protein 1 (PD-1), is an approved treatment for unresectable or metastatic melanoma. The PD-1 pathway limits immune responses to melanoma and can be blocked with pembrolizumab. In this phase 1 clinical trial, 655 patients with advanced or metastatic melanoma received pembrolizumab intravenously of varying doses and duration. Median duration of follow-up was 21 months. The study was performed in medical centers in Australia, Canada, France, and the United States.

The researchers found that pembrolizumab treatment was associated with an objective response rate (best overall response of complete response or partial response) of 33 percent, 12-month progression-free survival rate of 35 percent, a 23-month median overall survival, and a grade 3 or 4 adverse event rate of 14 percent, regardless of previous treatment with the antibody ipilimumab or pembrolizumab dose or schedule. In treatment-naive patients, the overall response rate was 45 percent, the 12-month progression free survival rate was 52 percent, and the median overall survival was 31 months with a 12-month survival rate of 73 percent and a 24-month survival rate of 60 percent.

Four percent of patients discontinued treatment because of a treatment-related adverse event. Treatment-related serious adverse events were reported in 9 percent of patients. There were no drug-related deaths.

(doi:10.1001/jama.2016.4059; this study is available pre-embargo at the For The Media website.)

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

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EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, APRIL 19, 2016

Media Advisory: To contact Matthew D. Snape, F.R.C.P.C.H., M.D., email matthew.snape@paediatrics.ox.ac.uk.

To place an electronic embedded link to this study in your story  This link will be live at the embargo time: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2016.4218

In a study appearing in the April 19 issue of JAMA, Matthew D. Snape, F.R.C.P.C.H., M.D., of the University of Oxford, United Kingdom, and colleagues conducted a phase 1 trial to evaluate the tolerability and immunogenicity of two candidate Ebola vaccines, an adenovirus type 26 vector vaccine (Ad26.ZEBOV), and a modified Ankara vector vaccine (MVA-BN-Filo).

The recent outbreak of Ebola virus disease in West Africa has caused in excess of 28,600 cases and 11,300 deaths since the first cases were identified in December 2013 in Guinea. The international response has included the accelerated clinical development of several candidate Ebola vaccines. In nonhuman primates, an Ad26-vectored vaccine was able to generate up to 75 percent protection from Ebola challenge.

For this study, participants (healthy volunteers, 18-50 years old) were randomly assigned to 4 groups, within which they were simultaneously randomized 5:1 to receive study vaccines or placebo. Those receiving active vaccines were primed with Ad26.ZEBOV or MVA-BN-Filo and boosted with the alternative vaccine 28 or 56 days later. A fifth, open-label group received Ad26.ZEBOV boosted by MVA-BN-Filo 14 days later. The trial was conducted in Oxford, U.K.

Among 87 study participants, 72 were randomly assigned to 4 groups of 18, and 15 were included in the open-label group. Four participants did not receive a booster dose; 67 of 75 study vaccine recipients were followed up at 8 months. An immune response was observed after primary immunization with Ad26.ZEBOV; boosting by MVA-BN-Filo resulted in sustained elevation of specific immunity. Immunization with Ad26.ZEBOV or MVA-BN-Filo did not result in any vaccine-related serious adverse events.

“Our data showed that, in contrast to MVA-BN-Filo, Ad26.ZEBOV priming generated an initial immune response, and there is evidence for protection from this vaccine given alone in nonhuman primate models. Therefore, this priming dose would be expected to generate at least partial protection against Ebola; for this reason, Ad26.ZEBOV prime schedules with MVA-BN-Filo boost are currently being further evaluated in phase 1, 2, and 3 studies,” the authors write.

(doi:10.1001/jama.2016.4128; this study is available pre-embargo at the For The Media website.)

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

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EMBARGOED FOR RELEASE: 12:01 A.M. (ET) MONDAY, APRIL 11, 2016

Media Advisory: To contact Raj Chetty, Ph.D., call Rebecca Toseland at 617-495-0464 or email toseland@stanford.edu

To place an electronic embedded link to this study in your story  This link will be live at the embargo time: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2016.4226

In the United States between 2001 and 2014, higher income was associated with greater life expectancy, and differences in life expectancy across income groups increased; however, the association between longevity and income varied substantially across areas, according to a study published online by JAMA.

Raj Chetty, Ph.D., of Stanford University, Stanford, Calif., and colleagues analyzed newly available data on income and mortality for the U.S. population to estimate race- and ethnicity-adjusted life expectancy at 40 years of age by household income percentile, sex, and geographic area, and evaluated factors associated with differences in life expectancy. Income data for the U.S. population between 40 to 76 years of age were obtained from 1.4 billion de-identified tax records between 1999 and 2014. Mortality data were obtained from Social Security Administration death records.

The average age at which individuals were analyzed was 53 years; the median household earnings among working individuals was $61,175 per year. There were 4,114,380 deaths among men (mortality rate, 596 per 100,000) and 2,694,808 deaths among women (mortality rate, 375 per 100,000).

The analysis yielded 4 primary results:

— Higher income was associated with greater longevity throughout the income distribution. The gap in life expectancy between the richest 1 percent and poorest 1 percent of individuals was 14.6 years for men and 10.1 years for women.

— Inequality in life expectancy increased over time. Between 2001 and 2014, life expectancy increased by 2.3 years for men and 2.9 years for women in the top 5 percent of the income distribution, but increased by only 0.3 years for men and 0.04 years for women in the bottom 5 percent.

— Life expectancy varied substantially across local areas. For individuals in the bottom income quartile, life expectancy differed by approximately 4.5 years between areas with the highest and lowest longevity. Changes in life expectancy between 2001 and 2014 ranged from gains of more than 4 years to losses of more than 2 years across areas.

— Geographic differences in life expectancy for individuals in the lowest income quartile were significantly correlated with health behaviors such as smoking, but were not significantly correlated with access to medical care, physical environmental factors, income inequality, or labor market conditions. Life expectancy for low-income individuals was positively correlated with the local area fraction of immigrants, fraction of college graduates, and local government expenditures per capita.

The authors write that reducing gaps in longevity may require local policy responses, and that “the strong association between geographic variation in life expectancy and health behaviors suggests that policy interventions should focus on changing health behaviors among low-income individuals. Tax policies and other local public policies may play a role in inducing such changes.”

“The findings also have implications for social insurance programs. The differences in life expectancy by income imply that the Social Security program is less redistributive than implied by its progressive benefit structure. Men and women in the top 1 percent of the income distribution can expect to claim Social Security and Medicare for 11.8 and 8.3 more years than men and women in the bottom 1 percent of the income distribution. Some have proposed indexing the age of eligibility for Medicare and full Social Security benefits to increases in life expectancy. The differences in the increases in life expectancy across income groups and areas suggests that such a policy would have to be conditioned on income and location to maintain current levels of redistribution.”

(doi:10.1001/jama.2016.4226; this study is available pre-embargo at the For The Media website.)

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

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EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, APRIL 12, 2016

Media Advisory: To contact Kiros Berhane, Ph.D., call Zen Vuong at 213-740-5277 or email zvuong@usc.edu.

To place an electronic embedded link to this study in your story  This link will be live at the embargo time: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2016.3444

Decreases in ambient air pollution levels over the past 20 years in Southern California were associated with significant reductions in bronchitic symptoms in children with and without asthma, according to a study appearing in the April 12 issue of JAMA.

Childhood bronchitic symptoms are significant public and clinical health problems that produce a substantial burden of disease. Ambient air pollutants are important determinants of bronchitis occurrence. Since 1992, significant improvements in air quality have been observed across Southern California due to a broad range of air pollution reduction policies and strategies. Kiros Berhane, Ph.D., of the University of Southern California, Los Angeles, and colleagues examined whether improvements in ambient air quality in Southern California were associated with reductions in bronchitic symptoms in children. The study involved children (age range, 5-18 years) from 3 groups, and was conducted during the 1993-2001, 1996-2004, and 2003-2012 years in 8 Southern California communities.

A model was used to estimate the association of changes in pollution levels with bronchitic symptoms. The primary measured outcome among children was annual age-specific prevalence of bronchitic symptoms during the previous 12 months based on the parent’s or child’s report of a daily cough for 3 months in a row, congestion or phlegm other than when accompanied by a cold, or bronchitis.

The 3 cohorts included a total of 4,602 children (average age at baseline, 8 years; 49 percent girls; 45 percent Hispanic white) who had data from 2 or more annual questionnaires. Among these children, 19 percent had asthma at age 10 years. The authors found that decreases in ambient concentrations of nitrogen dioxide, ozone, and particulate matter with an aerodynamic diameter less than 10 µm (PM₁₀) and less than 2.5 µm (PM_2.5) were associated with significant decreases in bronchitic symptoms in children with and without asthma. The reductions were proportionally larger in children with asthma and remained similar when examined at 10, 13, and 15 years of age during the follow-up period. Among patients with asthma, the reductions in bronchitic symptoms tended to be larger in boys and among children from households with dogs.

“While the study design does not establish causality, the findings support potential benefit of air pollution reduction on asthma control,” the authors write.

(doi:10.1001/jama.2016.3444; this study is available pre-embargo at the For The Media website.)

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

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EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, APRIL 12, 2016

Media Advisory: To contact Alexandre B. Cavalcanti, M.D., Ph.D., email abiasi@hcor.com.br.

To place an electronic embedded link to this study in your story  This link will be live at the embargo time: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2016.3463

Implementation of a multifaceted quality improvement intervention with daily checklists, goal setting, and clinician prompting did not reduce in-hospital mortality compared with routine care among critically ill patients treated in intensive care units (ICUs) in Brazil, according to a study appearing in the April 12 issue of JAMA.

Checklists have been proposed as tools to ensure that essential components of care are not omitted. In ICUs, the use of checklists is associated with increased adherence to guidelines, reduced rates of central line-associated bloodstream infection, and earlier extubation.  Using checklists combined with daily goals assessment and clinician prompting may improve communication, adherence to care processes, and clinical outcomes. However, evidence from randomized trials supporting the use of checklists in critical care is lacking.

Alexandre B. Cavalcanti, M.D., Ph.D., of the HCor-Hospital do Coracao, Sao Paulo, Brazil and colleagues conducted a study that had two phases. Phase 1 was an observational study to assess baseline data on work climate, care processes, and clinical outcomes in 118 Brazilian ICUs. In phase 2, the same ICUs were randomized to a quality improvement intervention, including a daily checklist and goal setting during multidisciplinary rounds with follow-up clinician prompting for 11 care processes, or to routine care. The first 60 admissions of longer than 48 hours per ICU were enrolled in each phase.

A total of 6,877 patients (average age, 60 years) were enrolled in the baseline (observational) phase and 6,761 (average age, 60 years) in the randomized phase, with 3,327 patients enrolled in ICUs (n = 59) assigned to the intervention group and 3,434 patients in ICUs (n = 59) assigned to routine care. The researchers found that there was no significant difference in in-hospital mortality between the intervention group and the usual care group, with 1,096 deaths (33 percent) and 1,196 deaths (35 percent), respectively.

Potential improvements were observed in 4 of 7 care processes and 2 safety climate domains, although except for 1 outcome, urinary catheter use, these findings were not significant after adjustment for multiple comparisons.

The authors write that potential explanations for the lack of effect on mortality found in this study include that the intervention needs time to work and the observation period was too short, or that the items on the checklist have very modest or negligible effects on mortality.

(doi:10.1001/jama.2016.3463; this study is available pre-embargo at the For The Media website.)

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

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EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, APRIL 12, 2016

Media Advisory: To contact Aaron S. Kesselheim, M.D., J.D., M.P.H., call Johanna Younghans at 617-525-6373 or email Jyounghans@partners.org.

To place an electronic embedded link to this study in your story  This link will be live at the embargo time: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.16984

Physicians’ Knowledge About FDA Approval Standards for ‘Breakthrough Therapy’

In a study appearing in the April 12 issue of JAMA, Aaron S. Kesselheim, M.D., J.D., M.P.H., of Brigham and Women’s Hospital, Boston, and colleagues surveyed internists and specialists to examine their knowledge about Food and Drug Administration (FDA) approval standards and perceptions of the “breakthrough therapy” designation.

Since 2012, the FDA can designate a drug as a “breakthrough therapy” if preliminary clinical evidence—such as an improvement in a pharmacodynamic biomarker—suggests an advantage over existing options. The term is routinely used in press releases and prescribing resources. Although the term breakthrough leads consumers to overly optimistic beliefs about drug effectiveness, it is not known how physicians understand this term, or more generally, what FDA approval means.

Of 1,148 physicians contacted, 692 physicians (60 percent) responded. Participants were asked 3 questions about FDA approval and 5 about breakthrough therapies. Respondents showed limited knowledge of FDA approval: 73 percent incorrectly believed FDA approval meant comparable effectiveness to other approved drugs; 70 percent incorrectly believed approval required both a statistically significant and clinically important effect. Among the 3 breakthrough knowledge questions, 52 percent incorrectly believed that strong evidence (randomized trials) is needed to earn the breakthrough designation.

“The misconceptions identified may lead physicians to overprescribe newly approved drugs—particularly breakthrough therapies— and inadequately communicate how well these drugs work to the patients who will use them,” the authors write.

(doi:10.1001/jama.2015.16984; this study is available pre-embargo at the For The Media website.)

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

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EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, APRIL 5, 2016

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

To place an electronic embedded link to this 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.2016.2638

The U.S. Preventive Services Task Force (USPSTF) does not recommend screening for chronic obstructive pulmonary disease (COPD) in persons who do not have symptoms suggestive of COPD. The report appears in the April 5 issue of JAMA.

This is a D recommendation, indicating that there is moderate or high certainty that screening has no net benefit or that the harms outweigh the benefits.

About 14 percent of U.S. adults age 40 to 79 years have COPD, and it is the third leading cause of death in the U.S. Persons with severe COPD are often unable to participate in normal physical activity due to deterioration of lung function. To update its 2008 recommendation, the USPSTF reviewed the evidence on whether screening for COPD in asymptomatic adults (those who do not recognize or report respiratory symptoms) improves health outcomes. The USPSTF reviewed the diagnostic accuracy of screening tools (including prescreening questionnaires and spirometry [a test of the air capacity of the lungs]); whether screening for COPD improves the delivery and uptake of targeted preventive services, such as smoking cessation or relevant immunizations; and the possible harms of screening for and treatment of mild to moderate COPD.

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

Detection

Chronic obstructive pulmonary disease is defined as airflow limitation that is not fully reversible. It is a disease associated with an abnormal inflammatory response of the lung to harmful particles or gases. Diagnosis is based on postbronchodilator (a type of medication given to open up the lung’s air passages) spirometry, which detects fixed airway obstruction. Persons with COPD often, but not always, have symptoms such as dyspnea (difficulty breathing or shortness of breath), chronic cough, and chronic sputum production. Patients often have a history of exposure to risk factors such as cigarette smoke or heating fuels or occupational exposure to dusts or chemicals. Although postbronchodilator spirometry is required to make a definitive diagnosis, prescreening questionnaires can elicit current symptoms and previous exposures to harmful particles or gases.

Benefits of Detection and Early Treatment

The USPSTF found inadequate evidence that screening for COPD in asymptomatic persons using questionnaires or spirometry improves health outcomes.

Harms of Detection and Early Treatment

The USPSTF found inadequate evidence on the harms of screening. However, given the lack of benefit of early detection and treatment, the opportunity cost associated with screening asymptomatic persons may be large. The amount of time and effort required to screen for COPD in asymptomatic persons (using screening spirometry with or without prescreening questionnaires) is not trivial.

Findings

Similar to 2008, the USPSTF did not find evidence that screening for COPD in asymptomatic persons improves health-related quality of life, morbidity, or mortality. The USPSTF determined that early detection of COPD, before the development of symptoms, does not alter the course of the disease or improve patient outcomes. The USPSTF concludes with moderate certainty that screening for COPD in asymptomatic persons has no net benefit.

(doi:10.1001/jama.2016.2638; the full report is available pre-embargo to the media at the For the Media website)

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

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

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EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, APRIL 5, 2016

Media Advisory: To contact Wendy C. King, Ph.D., call Allison Hydzik at 412-647-9975 or email hydzikam@upmc.edu.

To place an electronic embedded link to this study in your story  This link will be live at the embargo time: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2016.3010

Among a group of patients with severe obesity who underwent bariatric surgery, a large percentage experienced improvement in pain, physical function, and walking capacity over 3 years, according to a study appearing in the April 5 issue of JAMA.

Severe obesity is associated with significant joint pain and impaired physical function (ability to bend, lift, carry, push, and walk). Excess weight can lead to joint damage and pain, resulting in activity restriction and walking limitations. Bariatric surgery is effective at achieving and maintaining weight loss, although the variability and durability of improvements in pain and physical function following Roux-en-Y gastric bypass (RYGB) or laparoscopic adjustable gastric banding (LAGB) are not well described.

Wendy C. King, Ph.D., of the University of Pittsburgh, and colleagues examined changes in pain and physical function in the first 3 years following bariatric surgery, and factors associated with improvement, among adults with severe obesity. Research assessments were conducted prior to surgery and annually thereafter. The study was conducted at 10 hospitals.

Of 2,458 participants, 2,221 completed baseline and follow-up assessments; 79 percent were women; median age was 47 years; median body mass index (BMI) was 46; 70 percent underwent RYGB; 25 percent underwent LAGB. Among the primary findings through 3 years of follow-up: approximately 50 percent to 70 percent of adults experienced clinically significant improvements in perceived bodily pain and physical function and in objectively measured walking capacity; and approximately three-fourths of participants with severe knee and hip pain or disability at baseline experienced improvements in osteoarthritis symptoms.

The percentage of patients with improvement in pain and physical function decreased between year 1 and year 3 following surgery.

Younger age, male sex, higher income, lower BMI, and fewer depressive symptoms presurgery; no diabetes and no venous edema (swelling of the legs) with ulcerations postsurgery (either no history or remission); and presurgery-to-postsurgery reductions in weight and depressive symptoms were associated with presurgery-to-postsurgery improvements in multiple outcomes at years 1, 2, and 3.

The study’s “large geographically diverse sample, inclusion of multiple validated measures of pain and physical function, longitudinal design, and follow-up through 3 years make it one of the most informative studies of pain and function following RYGB and LAGB to date,” the authors write.

(doi:10.1001/jama.2016.3010; this study is available pre-embargo at the For The Media website.)

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

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EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, APRIL 5, 2016

Media Advisory: To contact Philip Clarke, Ph.D., email philip.clarke@unimelb.edu.au.

To place an electronic embedded link to this study in your story  This link will be live at the embargo time: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2016.0126

In a study appearing in the April 5 issue of JAMA, Philip Clarke, Ph.D., of the University of Melbourne, Australia, and colleagues analyzed individual and prescription-level data from the Medical Expenditure Panel Survey to describe and compare trends in expenditure and price of anti-hyperglycemic medications in the United States from 2002 through 2013.

The sample consisted of 27,878 people treated for diabetes. During the study period, the prevalence of treated diabetes increased from 5.2 percent in 2002-2004 to 7.7 percent in 2011-2013. For those with recorded insulin use, the quantity per year increased from 171 mL in 2002-2004 to 206 mL in 2011-2013; over the same period, estimated spending for insulin per patient increased from $231 in 2002 to $736 in 2013. In 2013, estimated expenditure per patient amounted to $508 for analog insulin and $228 for human insulin.

The total expenditure on insulin in 2013 was significantly greater than the combined expenditure on all other anti-hyperglycemic medications of $503. The average price per milliliter of insulin increased by 197 percent from $4.34 per milliliter in 2002 to $12.92 per milliliter in 2013, whereas the average price of dipeptidyl peptidase-4 (DPP-4) inhibitors increased by 34 percent from $6.67 per tablet in 2006 to $8.92 in 2013. The average price of metformin decreased by 93 percent from $1.24 per tablet in 2002 to $0.31 per tablet in 2013.

“Significant changes in mean price of insulin, relative to comparator therapies, suggest a need to reassess the effectiveness and cost-effectiveness of alternative anti-hyperglycemic therapies,” the authors write.

(doi:10.1001/jama.2016.0126; this study is available pre-embargo at the For The Media website.)

Editor’s Note: This research was partly supported by grants from the National Institutes of Health and the National Health and Medical Research Council. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, etc.

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