EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, JULY 15, 2014

Media Advisory: To contact corresponding author Jacques-Eric Gottenberg, M.D., Ph.D., email jacques-eric.gottenberg@chru-strasbourg.fr; to contact Xavier Mariette, M.D., Ph.D., email xavier.mariette@bct.aphp.fr.

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.2014.7682

Among patients with the systemic autoimmune disease primary Sjögren syndrome, use of hydroxychloroquine, the most frequently prescribed treatment for the disorder, did not improve symptoms during 24 weeks of treatment compared with placebo, according to a study in the July 16 issue of JAMA.

Primary Sjögren syndrome is characterized by mouth and eye dryness, pain, and fatigue, with systemic manifestations occurring in approximately one-third of patients. Despite the wide use of hydroxychloroquine in clinical practice, evidence regarding its efficacy is limited, according to background information in the article.

Jacques-Eric Gottenberg, M.D., Ph.D., of the Universite de Strasbourg, Strasbourg, France, and colleagues randomly assigned 120 patients with primary Sjögren syndrome to receive hydroxychloroquine or placebo for 24 weeks. All patients (treatment and placebo) were prescribed hydroxychloroquine between weeks 24 and 48.  The study was conducted at 15 university hospitals in France.

At 24 weeks, the proportion of patients meeting the primary end point (30 percent or greater reduction in 2 of 3 scores evaluating dryness, pain, and fatigue) was 17.9 percent (10/56) in the hydroxychloroquine group and 17.2 percent (11/64) in the placebo group. Use of hydroxychloroquine was also not associated with improvement in certain lab tests used to monitor the activity of Sjögren (anti-SSA antibodies, IgG levels).  During the first 24 weeks, there were 2 serious adverse events in the hydroxychloroquine group and 3 in the placebo group. In the last 24 weeks, there were 3 in the hydroxychloroquine group and 4 in the placebo group.

“In the present study, hydroxychloroquine did not demonstrate efficacy for the main disabling symptoms—dryness, pain, and fatigue—of primary Sjögren syndrome compared with placebo. [This trial] extends the negative results of the only previous controlled crossover trial, which included 19 patients and confirms that previous open trials might have overestimated the therapeutic efficacy of hydroxychloroquine in primary Sjögren syndrome,” the authors write.

“Further studies are needed to evaluate longer-term outcomes.”

(doi:10.1001/jama.2014.7682; Available pre-embargo to the media at https://media.jamanetwork.com)

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

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, JULY 15, 2014

Media Advisory: To contact co-author Amit X. Garg, M.D., Ph.D., email Julia Capaldi at Julia.Capaldi@LawsonResearch.com.

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.2014.2934

A study that included about 15,000 physicians found that they were more likely to be registered as an organ donor compared to the general public, according to a study in the July 16 issue of JAMA.

A shortage of organs for transplant has prompted many countries to encourage citizens to register (“opt in”) to donate their organs and tissues when they die. However, less than 40 percent of the public is registered for organ donation in most countries with a registry. “One common fear is that physicians will not take all measures to save the life of a registered citizen at a time of illness. Showing that many physicians are registered for organ donation themselves could help dispel this myth. Although most physicians in surveys support organ donation, whether they are actually registered remains unknown,” according to background information in the article.

Alvin Ho-ting Li, B.H.Sc., of Western University, London, Ontario, Canada, and colleagues used various databases to determine the proportion of physicians (n = 15,233), the general public (n = 10,866,752) or matched citizens (n = 60,932) of Ontario, Canada who were registered for deceased organ donation.  Matched citizens were a comparison group with similar backgrounds as physicians and matched to each physician by age, sex, income, and neighborhood.

A total of 6,596 physicians (43.3 percent) were registered, a significantly higher proportion than matched citizens (29.5 percent) or the general public (23.9 percent). Physicians were 47 percent more likely to be registered for organ and tissue donation than matched citizens. Similar to factors associated with registration in nonphysicians, younger physicians and women were more likely to register.

Among those registered for organ donation, 11.7 percent of physicians, 14.3 percent of matched citizens, and 16.8 percent of the general public excluded at least 1 organ or tissue from donation.

The authors note that future research should determine if these findings are generalizable to other countries.

(doi:10.1001/jama.2014.2934; Available pre-embargo to the media at https://media.jamanetwork.com)

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

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, JULY 15, 2014

Media Advisory: To contact Mads E. Jørgensen, M.B., email mads.emil.joergensen@regionh.dk.

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.2014.8165

In an analysis that included more than 480,000 patients who underwent elective noncardiac surgery, a history of stroke was associated with an increased risk of major adverse cardiovascular events and death, particularly if time elapsed between stroke and surgery was less than 9 months, according to a study in the July 16 issue of JAMA.

Noncardiac surgeries performed in patients with a recent heart attack or stent implantation have been associated with increased risk of perioperative cardiac events, as well as stent thrombosis (blood clot), and bleeding compared with patients with more distant heart attack or stent placement. Whether a similar time-dependent relationship exists for stroke has not been known, and recommendations on timing of surgery in patients with prior stroke in current perioperative guidelines are sparse, according to background information in the article.

Mads E. Jørgensen, M.B., of the University of Copenhagen, Denmark, and colleagues investigated the association between prior stroke (including time elapsed between stroke and surgery) and the risk of major adverse cardiovascular events (MACE, including ischemic stroke, heart attack, and cardiovascular death) and all-cause death up to 30 days after surgery in a group of Danish patients who underwent noncardiac elective surgery (n = 481,183 surgeries) from 2005-2011.

Crude incidence rates of MACE among patients with (n = 7,137) and without (n = 474,046) prior stroke were 54.4 vs 4.1 respectively, per 1,000 patients. Further analysis indicated:

• Prior ischemic stroke, irrespective of time between ischemic stroke and surgery, was associated with an adjusted 1.8- and 4.8-fold increased relative risk of 30-day mortality and 30-day MACE, respectively, compared with patients without prior stroke.

• A strong time-dependent relationship between prior stroke and adverse postoperative outcome, with patients experiencing a stroke less than 3 months prior to surgery at particularly high risk. After 9 months, the associated risk appeared stable yet still increased compared with patients with no stroke.

• Low- and intermediate-risk surgeries seemed to pose at least the same relative risk of MACE in patients with recent stroke compared with high-risk surgery.

“Our findings need to be confirmed but may warrant consideration in future perioperative guidelines,” the authors conclude.

(doi:10.1001/jama.2014.8165; Available pre-embargo to the media at https://media.jamanetwork.com)

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

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, JULY 15, 2014

Media Advisory: To contact Kurt Kroenke, M.D., email Lisa Welch at llwelch@regenstrief.org. To contact editorial co-author Gary E. Rosenthal, M.D., email Tom Moore at thomas-moore@uiowa.edu.

To place an electronic embedded link to this study in your story  This link for the study will be live at the embargo time: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2014.7689

A telephone-delivered intervention, which included automated symptom monitoring, produced clinically meaningful improvements in chronic musculoskeletal pain compared to usual care, according to a study in the July 16 issue of JAMA.

Pain is the most common symptom reported both in the general population and patients seen in primary care, the leading cause of work disability, and a condition that costs the United States more than $600 billion each year in health care and lost productivity. Musculoskeletal pain accounts for nearly 70 million outpatient visits annually in the United States each year. Telemedicine strategies for pain care have been proposed but not rigorously tested to date, according to background information in the article.

Kurt Kroenke, M.D., of Roudebush VA Medical Center, Indiana University School of Medicine, and the Regenstrief Institute, Indianapolis, and colleagues randomly assigned 250 patients with chronic musculoskeletal pain to an intervention group (n = 124) or to a usual care group whose members received all pain care as usual from their primary care physicians (n = 126). The intervention group received 12 months of telecare management that included automated symptom monitoring with an algorithm-guided approach to optimizing pain medications.

Among the key results of the trial:

• Patients in the intervention group were nearly twice as likely to report at least a 30 percent improvement in their pain score by 12 months (51.7 percent vs 27.1 percent);

• The intervention was associated with clinically meaningful improvements in pain and a greater rate of improvement (56 percent vs 31 percent);

• Patients in the usual care group were almost twice as likely to experience worsening of pain by 6 months compared with those in the intervention group (36 percent vs 19 percent);

• Few patients in either group were started on opioids or had escalations in their opioid dose during the study period;

• Patients in the intervention group were also more likely to rate as good to excellent the medication prescribed for their pain (73.9 percent vs 50.9 percent) as well as the overall treatment of their pain (76.7 percent vs 51.6 percent).

“The intervention was effective, even though most trial participants reported pain that had been present for many years, that involved multiple sites, and that had been unsuccessfully treated with numerous analgesics,” the authors write. “The improvement in pain with minimal opioid initiation or dose escalation is noteworthy, given increasing concerns about the consequences of long-term opioid use.”

The researchers add that the results of this trial, along with findings from a previous trial conducted among patients with cancer, show that algorithm-guided optimization of pain medication can be efficiently delivered through a predominantly telephone and Internet-based approach.

(doi:10.1001/jama.2014.7689; Available pre-embargo to the media at https://media.jamanetwork.com)

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

Editorial – Advancing Telecare for Pain Treatment in Primary Care

Michael E. Ohl, M.D., M.S.P.H., and Gary E. Rosenthal, M.D., of the University of Iowa Carver College of Medicine, Iowa City, comment on this study in an accompanying editorial.

“Historically, implementation of collaborative care innovations—such as collaborative care for depression—has been slow. However, there is reason to believe that telecare for chronic pain can be more rapidly implemented into routine practice. Adoption of collaborative care for depression was hindered by the fee-for-service payment system, which favors procedures and in-person physician visits over team-based and between-visit care. Recent movement toward reimbursement for telehealth and between-visit care may make telecare for pain management more attractive to primary care practices.”

“In summary, Kroenke et al describe a promising telecare strategy that may enhance the ability of primary care practices to effectively treat patients with chronic pain. Additional studies are required to determine the generalizability, sustainability, and cost-effectiveness of this strategy and to assess how it may best be incorporated within primary care practices.”

(doi:10.1001/jama.2014.7690; Available pre-embargo to the media at https://media.jamanetwork.com)

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

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, JULY 15, 2014

Media Advisory: To contact corresponding author Josef Coresh, M.D., Ph.D., call Stephanie Desmon at 410-955-7619 or email sdesmon1@jhu.edu. To contact editorial co-author Ralph L. Sacco, M.D., call Lisa Worley at 305-243-5184 or email lworley2@med.miami.edu.

To place an electronic embedded link to this study in your story  This link for the study will be live at the embargo time: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2014.7692

In a study that included a large sample of black and white U.S. adults from several communities, rates of stroke incidence and subsequent death decreased from 1987 to 2011, with decreases varying across age-groups, according to a study in the July 16 issue of JAMA.

Stroke ranks fourth among all causes of death in the U.S. and is recognized as a leading cause of serious physical and cognitive long-term disability in adults. Almost 800,000 Americans suffer a stroke each year, and over 600,000 of them are first-ever events. Stroke incidence varies by gender and ethnic group, according to background information in article.

Silvia Koton, Ph.D., of Johns Hopkins University School of Public Health, Baltimore, and colleagues examined trends in stroke incidence and subsequent death among black and white adults in the Atherosclerosis Risk in Communities (ARIC) cohort, a study of 15,792 residents in four communities in the U.S., ages 45 to 64 years at baseline (1987-1989). The communities were Minneapolis, Washington County, Md., Forsyth County, N.C., and Jackson, Mississippi. For this analysis, the researchers followed-up on 14,357 participants free of stroke at baseline for all stroke hospitalizations and deaths from 1987 to 2011.

During the study period, there were 1,051 (7 percent) participants with incident stroke. The researchers found a significant decrease in stroke incidence from 1987 to 2011 in both whites and blacks as well as men and women, but this decrease was seen only above age 65 years, with younger participants experiencing stable stroke incidence rates.

Of participants with incident stroke, 614 (58 percent) died through 2011, with analysis indicating a decrease in mortality during the last two decades, mostly due to a decrease among participants younger than 65 years. This decrease was generally similar in men and women and by race.

The authors speculate that “more successful control of risk-factors in the last decades, mainly hypertension control starting in the 1970s, and later, hypertension treatment combined with smoking cessation, control of diabetes and dyslipidemia, and treatment of atrial fibrillation may have resulted in lower stroke incidence and less severe strokes, which may account for the observed lower case-fatality rates.”

(doi:10.1001/jama.2014.7692; Available pre-embargo to the media at https://media.jamanetwork.com)

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

Editorial – Declining Stroke Incidence and Improving Survival in U.S. Communities

Evidence for Success and Future Challenges

“Whether the decline in stroke incidence and mortality will continue in older age groups is still speculative, and the absence of a decline in younger age groups could be an early warning sign,” write Ralph L. Sacco, M.D., and Chuanhui Dong, M.D., Ph.D., of the University of Miami, in an accompanying editorial.

“Although there has been significant progress in reducing smoking and lowering blood pressure and cholesterol, formidable challenges to address stroke disparities and successfully control risk factors and lifestyle behaviors across race, ethnicity, and regions persist. Unless health disparities are addressed and innovative strategies to change behavior are developed and adopted, the cerebrovascular health of the population will be unlikely to improve. Greater improvements in brain health, especially with controllable risk factors such as diet, exercise, smoking, and obesity, among younger segments of the population are required to reduce the risk of stroke and enhance the chance of successful cognitive aging for all adults.”

(doi:10.1001/jama.2014.7693; Available pre-embargo to the media at https://media.jamanetwork.com)

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

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, JULY 8, 2014

Media Advisory: To contact Danny Dvir, M.D., call Dave Lefebvre at 604-682-2344, ext. 66987; or email Dlefebvre@providencehealth.bc.ca.

To place an electronic embedded link to this study in your story  This link for the study will be live at the embargo time: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2014.7246

In an analysis of about 460 patients with failed bioprosthetic aortic valves who underwent transcatheter valve-in-valve implantation, overall survival at one year was 83 percent, with survival associated with surgical valve size and mechanism of failure, according to a study in the July 9 issue of JAMA.

Surgical aortic valve replacements increasingly use bioprosthesis (composed of biological tissue) implants rather than mechanical valves. Owing to a considerable shift toward bioprosthesis implantation, it is expected that there will be an increase in the number of patients with degeneration of these types of valves. Treatment of patients with failed bioprostheses is a clinical challenge; although reoperation is considered the standard of care, these patients are frequently elderly and have other medical conditions, and repeat cardiac surgery can pose significant illness and risk of death. Transcatheter aortic valve-in-valve implantation is a less invasive approach, however a comprehensive evaluation of survival after the procedure has not previously been performed, according to background information in the article.

Danny Dvir, M.D., of St. Paul’s Hospital, Vancouver, Canada, and colleagues evaluated survival of 459 patients after transcatheter valve-in-valve implantation inside failed surgical bioprosthetic valves using a multinational registry. The patients (average age, 78 years) underwent implantation between 2007 and May 2013 at 55 centers.

Reasons for bioprosthesis failure were stenosis (narrowing of the valve opening; 39.4 percent), regurgitation (backflow of blood through the orifice of the valve due to imperfect closing; 30.3 percent), and combined stenosis and regurgitation (30.3 percent). The overall 1-year survival rate was 83.2 percent.

Patients in the stenosis group had worse 1-year survival (76.6 percent) in comparison with the regurgitation group (91.2 percent) and the combined group (83.9 percent). Similarly, patients with small valves (≤ 21 mm) had worse 1-year survival (74.8 percent) compared with larger valves.

“Thorough assessment of candidates for valve-in-valve implantation is a key step to obtain optimal results. The current analysis highlights the need for meticulous evaluation of bioprosthesis mechanism of failure before attempting a valve-in-valve procedure,” the authors write.

(doi:10.1001/jama.2014.7246; Available pre-embargo to the media at https://media.jamanetwork.com)

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

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, JULY 8, 2014

Media Advisory: To contact Pouya Iranmanesh, M.D., email pouya.iranmanesh@hcuge.ch.

To place an electronic embedded link to this study in your story  This link for the study will be live at the embargo time: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2014.7587

Among patients with possible common duct stones, removal of the gall bladder, compared with endoscopic assessment of the common duct followed by gall bladder removal, resulted in a shorter length of hospital stay without increased illness and fewer common duct examinations, according to a study in the July 9 issue of JAMA.

Many common duct stones eventually pass into the duodenum (a section of the small intestine just below the stomach), making preoperative common duct investigations unnecessary. Conversely, a strategy of gall bladder removal first can lead to the discovery of a retained common duct stone during surgery. It is uncertain what is the best initial strategy for treating this condition, according to background information in the article.

Pouya Iranmanesh, M.D., of Geneva University Hospital and Faculty of Medicine, Geneva, Switzerland, and colleagues randomly assigned 100 patients with possible common duct stones to undergo immediate laparoscopic cholecystectomy (gall bladder removal) with intraoperative cholangiogram (an imaging technique using a dye injection to evaluate the common duct) or endoscopic common duct evaluation followed by cholecystectomy, with patient follow-up of 6 months.

Patients who underwent cholecystectomy as a first step (study group) had a significantly shorter median length of hospital stay (5 days vs 8 days) compared to patients in the control group. In addition, the total number of common duct investigations (various procedures to look for stones in the common duct) performed in the study group was smaller (25 vs 71). Overall, complications were observed in 8 percent of patients in the study group and 14 percent in the control group. There was no significant difference in illness or quality of life measures between groups.

The authors note that overall, 60 percent of patients in the study group did not need any common duct investigation after the intraoperative cholangiogram. “Thus, many intermediate-risk patients undergo unnecessary preoperative common duct procedures.”

The researchers add that although a thorough cost analysis was beyond the scope of this study, the significantly shorter length of hospital stay and fewer common duct investigations in the study group, coupled with the similar complication rates between the 2 groups, predicts substantial savings when using a cholecystectomy-first strategy.

“If these findings are confirmed, initial cholecystectomy with intraoperative cholangiogram may be a preferred approach,” the authors conclude.

(doi:10.1001/jama.2014.7587; Available pre-embargo to the media at https://media.jamanetwork.com)

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

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, JULY 8, 2014

Media Advisory: To contact Nikolai Madrid Scheller, M.B., email nmscheller@gmail.com.

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.2014.2198

Although some data has suggested a potential association between receipt of the quadrivalent human papillomavirus (HPV) vaccination and subsequent venous thromboembolism (VTE; blood clot), an analysis that included more than 500,000 women who received the vaccine did not find an increased risk of VTE, according to a study in the July 9 issue of JAMA.

“Safety concerns can compromise immunization programs to the detriment of public health, and timely evaluations of such concerns are essential,” the authors write.

Nikolai Madrid Scheller, M.B., of Statens Serum Institut, Copenhagen, Denmark, and colleagues used data from Danish national registers to evaluate the potential link between quadrivalent HPV vaccination and VTE. Information on vaccination, use of oral contraceptives, use of anticoagulants (blood thinners), and the outcome of a first hospital diagnosis of VTE not related to pregnancy, surgery, or cancer was obtained from Danish registers.

The study included all Danish women, ages 10 through 44 years, from October 2006 through July 2013 (n = 1,613,798), including 500,345 (31 percent) who received the quadrivalent HPV vaccine; there were 4,375 incident cases of VTE. Of these, 889 women (20 percent) were vaccinated during the study period. Analysis of the data did not find an association between the quadrivalent HPV vaccine and VTE during the 42 days following vaccination (defined as the main risk period).

“Our results, which were consistent after adjustment for oral contraceptive use and in girls and young women as well as mid-adult women, do not provide support for an increased risk of VTE following quadrivalent HPV vaccination,” the researchers write.

(doi:10.1001/jama.2014.2198; Available pre-embargo to the media at https://media.jamanetwork.com)

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

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, JULY 8, 2014

Media Advisory: To contact Jean Marc Regimbeau, M.D., Ph.D., email regimbeau.jean-marc@chu-amiens.fr. To contact editorial author Joseph S. Solomkin, M.D., call Katy Cosse at 513-558-0207 or email kathryn.cosse@uc.edu.

To place an electronic embedded link to this study in your story  This link for the study will be live at the embargo time: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2014.7586

Among patients who underwent gall bladder removal for acute calculous cholecystitis, lack of postoperative antibiotic treatment did not result in a greater incidence of infections, according to a study in the July 9 issue of JAMA.

Acute calculous cholecystitis (inflamed and enlarged gall bladder along with abdominal pain) is the third most frequent cause of emergency admissions to surgical wards. In the United States, approximately 750,000 cholecystectomies (surgical removal of the gall bladder) are performed each year and about 20 percent of these operations are due to acute calculous cholecystitis. Many patients receive postoperative antibiotics with the intent to reduce subsequent infections, although there is limited information from controlled studies demonstrating benefit, according to background information in the article.

Jean Marc Regimbeau, M.D., Ph.D., of the Amiens University Medical Center, Amiens, France, and colleagues randomly assigned 414 patients with mild or moderate acute calculous cholecystitis to continue with a preoperative antibiotic regimen (amoxicillin plus clavulanic acid) or receive no antibiotics after cholecystectomy. The study was conducted at 17 medical centers between May 2010 and August 2012.

The researchers found that the postoperative infection rates were 17 percent in the nontreatment group and 15 percent in the antibiotic group. In a per protocol analysis involving 338 patients, the corresponding rates were both 13 percent. Based on a noninferiority (not worse than) margin of 11 percent established for this trial, the lack of postoperative antibiotic treatment was not associated with worse outcomes than antibiotic treatment. The two groups of patients had similar length of hospital stay and readmission rates.

The authors note that guidelines published by the Infectious Diseases Society of America and the World Society of Emergency Surgery recommend treatment with amoxicillin plus clavulanic acid or sulbactam after cholecystectomy for noncomplicated acute calculous cholecystitis. “In the present series, we did not observe a benefit of postoperative antibiotic treatment on infections for patients with [mild or moderate] acute calculous cholecystitis.”

“It is well known that continuation of antibiotic treatment increases costs and promotes the selection of multiresistant bacteria. In 2010, 37,499 cholecystectomies for acute calculous cholecystitis were performed in France, and 90 percent of these were for grades I and II [mild or moderate] acute calculous cholecystitis. Supposing that these patients did not really need postoperative antibiotics (which are generally prescribed for 5 days), we estimate that many days of antibiotic treatment could be avoided each year. Reduction of the use of unnecessary antibiotics is important given that there is an increasing antibiotic resistance and a higher incidence of antibiotic complications such as Clostridium difficile infection. Our study demonstrates that postoperative antibiotics following acute calculous cholecystitis are not necessary.”

(doi:10.1001/jama.2014.7586; Available pre-embargo to the media at https://media.jamanetwork.com)

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

Editorial: Clinical Trial Evidence to Advance the Science of Cholecystectomy

 Joseph S. Solomkin, M.D., of the University of Cincinnati College of Medicine, Cincinnati, writes in an accompanying editorial that the two cholecystectomy-related trials in this issue provide important new evidence to better inform surgeons performing this procedure; “however, both studies have a frequently encountered limitation of surgical trials—lack of blinding. In many surgical trials, blinding is not possible, or in some cases, as with sham procedures, blinding may raise important ethical considerations.”

“Blinding in randomized trials avoids physician and patient perceptions of efficacy from influencing protocol adherence or outcome assessment. Blinding is usually associated with random treatment assignment, and the treating physician, the patient, and the outcome assessor do not know what intervention the patient received. Blinding and randomization minimize the risk of conscious and unconscious bias in clinical trials (performance bias) and interpretation of outcomes (ascertainment bias).”

Dr. Solomkin notes that randomized trials, even if blinding is not possible, contribute greatly to evidence-based recommendations for clinical practice guidelines. “The clinical trials by Regimbeau et al and Iranmanesh et al provide useful data that help answer important questions about the management of patients undergoing cholecystectomy.”

(doi:10.1001/jama.2014.7588; Available pre-embargo to the media at https://media.jamanetwork.com)

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

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, JULY 8, 2014

Media Advisory: To contact Coenraad F. N. Koegelenberg, M.D., Ph.D., email coeniefn@sun.ac.za.

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.2014.7195.

Combining the smoking cessation medication varenicline with nicotine replacement therapy was more effective than varenicline alone at achieving tobacco abstinence at 6 months, according to a study in the July 9 issue of JAMA.

The combination of behavioral approaches and pharmacotherapy are of proven benefit in assisting smokers to quit. Combining nicotine replacement therapy (NRT) with varenicline has been a suggested treatment to improve smoking abstinence, but its effectiveness is uncertain, according to background information in the article.

Coenraad F. N. Koegelenberg, M.D., Ph.D., of Stellenbosch University, Cape Town, South Africa, and colleagues randomly assigned 446 generally healthy smokers to nicotine or placebo patch treatment 2 weeks before a target quit date (TQD) and continued for an additional 12 weeks. Varenicline was begun 1 week prior to TQD, continued for a further 12 weeks, and tapered off during week 13. The study was conducted in 7 centers in South Africa from April 2011 to October 2012; 435 participants were included in the efficacy and safety analyses.

The researchers found that participants who received active NRT and varenicline were more likely to achieve continuous abstinence from smoking (confirmed by exhaled carbon monoxide measurements) at 12 weeks (55.4 percent vs 40.9 percent) and 24 weeks (49.0 percent vs 32.6 percent) and point prevalence abstinence (a measure of abstinence based on behavior at a particular point in time) at six months (65.1 percent vs 46.7 percent) than those receiving placebo NRT and varenicline.

In the combination treatment group, there was more nausea, sleep disturbance, skin reactions, constipation, and depression reported, with only skin reactions reaching statistical significance (14.4 percent vs 7.8 percent); the varenicline-alone group experienced more abnormal dreams and headaches.

“In this study, to our knowledge the largest study to date examining the efficacy and safety of supplementing varenicline treatment with NRT, we have found the combination treatment to be associated with a statistically significant and clinically important higher continuous abstinence rate at 12 and 24 weeks, as well as a higher point prevalence abstinence rate at 6 months,” the authors write.

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

(doi:10.1001/jama.2014.7195; Available pre-embargo to the media at https://media.jamanetwork.com)

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

EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, JULY 1, 2014

Media Advisory: To contact corresponding author Patrick F. Chinnery, Ph.D., F.R.C.P., F.Med.Sci., email patrick.chinnery@ncl.ac.uk.

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.2014.7184

Use of exome sequencing improved the ability to identify the underlying gene mutations in patients with biochemically defined defects affecting multiple mitochondrial respiratory chain complexes (enzymes that are involved in basic energy production), according to a study in the July 2 issue of JAMA.

Defects of the mitochondrial respiratory chain have emerged as the most common cause of childhood and adult neurometabolic disease, with an estimated prevalence of l in 5,000 live births. Clinically these disorders can present at any time of life, are often seen in association with neurological impairment, and cause chronic disability and premature death. The diagnosis of mitochondrial disorders remains challenging, according to background information in the article. Examples of problems caused by mitochondrial diseases include a type of epilepsy; mitochondrial encephalopathy; lactic acidosis; and a syndrome that includes stroke-like episodes.

Robert W. Taylor, Ph.D., F.R.C.Path., of Newcastle University, Newcastle upon Tyne, U.K., and colleagues studied whether a whole-exome sequencing approach could help define the molecular basis of mitochondrial disease. Whole-exome sequencing is a complex laboratory process that determines the entire unique sequence of an organism’s exome (the collection of exons, which are relatively small lengths of a whole genome and contain instructions for the body to build proteins).

The study included 53 patients, referred to 2 national centers in the United Kingdom and Germany between 2005 and 2012, who had biochemical evidence of multiple respiratory chain complex defects. The majority (51/53 [96 percent]) of the patients presented during childhood (<15 years old) and most (66 percent) developed symptoms within the first year of life. The most frequent clinical features were muscle weakness, central neurological disease, cardiomyopathy, and abnormal liver function; a combination of these abnormalities was present in most cases.

Following whole-exome sequencing, presumptive causal variants were identified in 28 patients (53 percent) and possible causal variants were identified in 4 (8 percent). Together these accounted for 32 patients (60 percent) and involved 18 different genes.  Distinguishing clinical features included deafness and kidney involvement associated with one gene, and cardiomyopathy with two genes. In 20 patients with prominent heart disease, the causative mutation was detected in 80 percent, while the detection rate was much lower in patients with liver disease (33 percent). It was not possible to confidently identify the underlying genetic basis in 21 patients (40 percent).

“In the pre-exome era, the systematic biochemical characterization of 53 patients with multiple respiratory chain complex defects led to detection of the underlying genetic basis in only 1 patient. The work presented herein demonstrates the effect of whole-exome sequencing in this context, which has defined the genetic etiology in 32 of 53 patients (60 percent) with a confirmed biochemical defect …,” the authors write. “Our findings contrast with large-scale candidate gene analysis using conventional and next-generation sequencing approaches, both of which had a lower diagnostic yield (10 percent-13 percent) and by definition did not discover new potential disease genes.”

“Additional study is required to determine the utility of this approach compared with traditional diagnostic methods in independent patient populations,” the researchers conclude.

(doi:10.1001/jama.2014.7184; Available pre-embargo to the media at https://media.jamanetwork.com)

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

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, JULY 1, 2014

Media Advisory: To contact Claudia S. Robertson, M.D., call Graciela Gutierrez at 713-798-4710 or email ggutierr@bcm.edu.

To place an electronic embedded link to this study in your story  This link for the study will be live at the embargo time: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2014.6490

In patients with a traumatic brain injury (TBI), neither the administration of the hormone erythropoietin (EPO) or maintaining a higher hemoglobin concentration through blood transfusion resulted in improved neurological outcome at 6 months, according to a study in the July 2 issue of JAMA. Transfusing at higher hemoglobin concentrations was associated with a higher risk of adverse events.

Patients with severe traumatic brain injury commonly develop anemia. For patients with neurological injury, anemia is a potential cause of secondary injury, which may worsen neurological outcomes. Treatment of anemia may include transfusions of packed red blood cells or administration of erythropoietin. There is limited information about the effect of erythropoietin or a high hemoglobin transfusion threshold (if the hemoglobin concentration drops below a certain level, a transfusion is performed) after a TBI, according to background information in the article.

Claudia S. Robertson, M.D., of the Baylor College of Medicine, Houston, and colleagues conducted a randomized clinical trial that included 200 patients (erythropoietin, n = 102; placebo, n = 98) with a closed head injury at neurosurgical intensive care units in two U.S. level I trauma centers between May 2006 and August 2012.  Patients were enrolled within 6 hours of injury and had to be unable to follow commands after initial stabilization.  Erythropoietin or placebo was initially dosed daily for 3 days and then weekly for 2 more weeks (n = 74). There were 99 patients assigned to a hemoglobin transfusion threshold of 7 g/dL and 101 patients assigned to 10 g/dL.

In the placebo group, 34 patients (38.2 percent) recovered to a favorable outcome (defined as good recovery and moderate disability, as measured by a functional assessment inventory) compared with 17 patients (48.6 percent) in the erythropoietin 1 group (first dosing regimen) and 17 patients (29.8 percent) in the erythropoietin 2 group (second dosing regimen).  Thirty-seven patients (42.5 percent) assigned to the transfusion threshold of 7 g/dL recovered to a favorable outcome compared with 31 patients (33.0 percent) assigned to the transfusion threshold of 10 g/dL.

There was a higher incidence of thromboembolic events for the transfusion threshold of 10 g/dL (21.8 percent) vs (8.1 percent) for the threshold of 7 g/dL.

“Among patients with closed head injury, neither the administration of erythropoietin nor maintaining hemoglobin concentration of at least 10 g/dL resulted in improved neurological outcome at 6 months. These findings do not support either approach in patients with traumatic brain injury,” the authors conclude.

(doi:10.1001/jama.2014.6490; Available pre-embargo to the media at https://media.jamanetwork.com)

 Editor’s Note: This study was supported by a grant from the National Institute of Neurological Disorders and Stroke. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, etc.

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, JULY 1, 2014

Media Advisory: To contact Andrew X. Zhu, M.D., Ph.D., call Katie Marquedant at 617-726-0337 or email KMarquedant@mgh.harvard.edu.

To place an electronic embedded link to this study in your story  This link for the study will be live at the embargo time: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2014.7189

Despite strong preclinical data, the drug everolimus failed to improve overall survival in patients with advanced liver cancer, compared to placebo, according to a study in the July 2 issue of JAMA.

Patients with advanced hepatocellular carcinoma (HCC; a type of liver cancer) have a median overall survival of less than l year, largely because of the absence of effective therapies. The drug sorafenib is the only systemic therapy shown to significantly improve overall survival in advanced HCC; however its benefits are mostly transient and modest, and disease eventually progresses. In preclinical models, everolimus prevented tumor progression and improved survival, according to background information in the article.

Andrew X. Zhu, M.D., Ph.D., of the Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, and colleagues randomly assigned 546 adults with advanced HCC whose disease progressed during or after sorafenib or who were intolerant of sorafenib to receive everolimus (n = 362) or placebo (n = 184), both given in combination with best supportive care and continued until disease progression or intolerable toxicity. In this phase 3 study, patients were enrolled from 17 countries between May 2010 and March 2012.

The researchers found no significant difference in overall survival between the two groups: there were 303 deaths (83.7 percent) in the everolimus group and 151 deaths (82.1 percent) in the placebo group. Median overall survival was 7.6 months with everolimus, 7.3 months with placebo. The disease control rate (the percentage of patients with a best overall response of complete or partial response or stable disease) was 56.1 percent (everolimus) and 45.1 percent (placebo).

“The results from [this study, EVOLVE-1] extend the list of failed phase 3 studies in advanced HCC, highlighting the challenge of developing effective therapies for this cancer,” the authors write.

The researchers note that EVOLVE-l and the other failed phase 3 studies have provided several important lessons, including that it is difficult to assess efficacy signals from phase 2 trials; surrogate end points such as time to progression, progression-free survival, and response rate inconsistently predict overall survival in phase 3 trials; and clinical and biologic heterogeneity likely affects the performance of targeted therapies in HCC. “In the absence of well-characterized and validated predictive bio-markers, targeted agents will likely continue to have a high risk of failure if phase 3 trials are conducted in unselected populations.”

(doi:10.1001/jama.2014.7189; Available pre-embargo to the media at https://media.jamanetwork.com)

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

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, JULY 1, 2014

Media Advisory: To contact Matthew M. Hsieh, M.D., or corresponding author John F. Tisdale, M.D., call Krysten Carrera at 301-435-8112 or email krysten.carrera@nih.gov. To contact editorial co-author John F. DiPersio, M.D., Ph.D., call Jim Goodwin at 314-286-0166 or email jgoodwin@wustl.edu.

To place an electronic embedded link to this study in your story  This link for the study will be live at the embargo time: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2014.7192

Use of a lower intensity bone marrow transplantation method showed promising results among 30 patients (16-65 years of age) with severe sickle cell disease, according to a study in the July 2 issue of JAMA.

Myeloablative (use of high-dose chemotherapy or radiation) allogeneic hematopoietic stem cell transplantation (HSCT; receipt of hematopoietic stem cells “bone marrow” from another individual) is curative for children with severe sickle cell disease, but associated toxicity has made the procedure prohibitive for adults. The development of nonmyeloablative conditioning regimens (use of lower doses of chemotherapy or radiation to prepare the bone marrow to receive new cells) may facilitate safer application of allogeneic HSCT to eligible adults, according to background information in the article.

Matthew M. Hsieh, M.D., of the National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Md., and colleagues explored a nonmyeloablative approach in a pilot group of 10 adults with severe sickle cell disease, using a simplified HSCT regimen (with stem cell donation from a immunologically matched sibling), that had few toxic effects, yet all patients continued taking immunosuppression medication. The researchers have since revised the protocol to include an option to stop immunosuppression after 1 year in selected patients (those with donor CD3 engraftment of greater than 50 percent and normalization of hemoglobin). In this report, the authors describe the outcomes for 20 additional patients with severe sickle cell disease, along with updated results from the first 10 patients. All 30 patients (ages 16-65 years) were enrolled in the study from July 2004 to October 2013.

As of October 25, 2013, 29 patients were alive with a median follow-up of 3.4 years, and 26 patients (87 percent) had long-term stable donor engraftment without acute or chronic graft-vs-host disease. Hemoglobin levels improved after HSCT; at 1 year, 25 patients (83 percent) had full donor-type hemoglobin. Fifteen engrafted patients discontinued immunosuppression medication and had no graft-vs-host disease.

The average annual hospitalization rate was 3.2 the year before HSCT, 0.63 the first year after, 0.19 the second year after, and 0.11 the third year after transplant. Eleven patients were taking narcotics long-term at the time of transplant. During the week they were hospitalized and received their HSCT, the average narcotics use per week was 639 mg of intravenous morphine-equivalent dose. The dosage decreased to 140 mg 6 months after the transplant.

There were 38 serious adverse events including pain, infections, abdominal events, and toxic effects from the medication sirolimus.

“In this article, we extend our previous results and show that this HSCT procedure can be applied to older adults, even those with severe comorbid conditions …” the authors write. “These data reinforce the low toxicity of this regimen, especially among patients with significant end-organ dysfunction.”

“In this series of patients who underwent a simplified HSCT regimen to date, … reversal of sickle cell disease phenotype was achieved in the majority of patients. Engrafted patients continued to be disease-free and without graft-vs-host disease,” the researchers write. “Further accrual and follow-up is required to assess longer-term clinical outcomes, adverse events, and transplant tolerance.”

(doi:10.1001/jama.2014.7192; Available pre-embargo to the media at https://media.jamanetwork.com)

 Editor’s Note: This work is supported by the intramural research program of the National Institute of Diabetes and Digestive and Kidney Diseases and the National Heart, Lung, and Blood Institute at the National Institutes of Health. All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.

There will also be a digital news release available for this study, including the JAMA Report video, embedded and downloadable video, audio files, text, documents, and related links. This content will be available at 3 p.m. CT Tuesday, July 1 at this link.

Editorial: Reconsideration of Age as a Contraindication for Curative Therapy of Sickle Cell Disease

 Allison A. King, M.D., M.P.H., and John F. DiPersio, M.D., Ph.D., of the Washington University School of Medicine, St. Louis, comment on the findings of this study in an accompanying editorial.

“In a population of relatively older adults with sickle cell disease, these findings offer hope. Based on these exciting results, the role of age as a contraindication for offering adults with sickle cell disease and a matched sibling the chance of curative allogeneic stem cell transplant should be reconsidered.”

(doi:10.1001/jama.2014.7193; Available pre-embargo to the media at https://media.jamanetwork.com)

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

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, JUNE 24, 2014

Media Advisory: To contact corresponding author Jacob M. van Laar, M.D., Ph.D., email j.m.vanlaar@umcutrecht.nl; or Dominique Farge, M.D., Ph.D., email dominique.farge-bancel@sls.aphp.fr. To contact editorial co-author Dinesh Khanna, M.D., M.Sc., call Beata Mostafavi at 734-764-2220 or email bmostafa@med.umich.edu.

Among patients with a severe, life-threatening type of sclerosis, treatment with hematopoietic stem cell transplantation (HSCT), compared to intravenous infusion of the chemotherapeutic drug cyclophosphamide, was associated with an increased treatment-related risk of death in the first year, but better long-term survival, according to a study in the June 25 issue of JAMA.

Systemic sclerosis is an autoimmune connective tissue disease characterized by vasculopathy (a disorder of the blood vessels), low-grade inflammation, and fibrosis (development of excess fibrous connective tissue) in skin and internal organs. Previously, small studies have shown that systemic sclerosis is responsive to treatment with autologous HSCT, although it has been unclear whether HSCT improves survival, according to background information in the article. For this study, autologous HSCT involved a multistep process beginning with infusion of high doses of cyclophosphamide and an antibody against immune cells, followed by reinfusion of the patient’s own stem cells that had been previously collected from blood and purified.

Jacob M. van Laar, M.D., Ph.D., of the University Medical Center Utrecht, Utrecht, the Netherlands and Dominique Farge M.D., Ph.D, of the Assistance Publique – Hopitaux de Paris, Paris 7 Diderot University, France, and colleagues randomly assigned 156 patients with early diffuse cutaneous (widespread skin involvement) systemic sclerosis to receive HSCT (n = 79) or cyclophosphamide (n = 77; 12 monthly infusions).  The phase 3 clinical trial was conducted in 10 countries at 29 centers; patients were recruited from March 2001 to October 2009 and followed up until October 2013.

During a median follow-up of 5.8 years, 53 adverse events occurred: 22 in the HSCT group (19 deaths and 3 irreversible organ failures) and 31 in the control group (23 deaths and 8 irreversible organ failures). Patients treated with HSCT experienced more adverse events (including death) in the first year but had better long-term event-free survival than those treated with cyclophosphamide.

Patients in the HCST group experienced higher mortality in the first year but had better long-term overall survival than those treated with cyclophosphamide. During year 1 there were 11 deaths (13.9 percent, including 8 treatment-related deaths) in the HSCT group vs 7 (9.1 percent, no treatment-related deaths) in the control group. After year 2 of follow-up, there were 12 deaths (15.2 percent) in the HSCT group vs 13 (16.9 percent) in the control group. After 4 years of follow-up, there were 13 deaths (16.5 percent) in the HSCT group vs 20 (26.0 percent) in the control group.

The authors add that HSCT was also more effective than intravenous cyclophosphamide on measures evaluating skin, functional ability, quality of life, and lung function, consistent with previous studies.

“Among patients with early diffuse cutaneous systemic sclerosis, HSCT was associated with increased treatment-related mortality in the first year after treatment. However, HCST conferred a significant long-term event-free survival benefit,” the authors conclude.

(doi:10.1001/jama.2014.6368; Available pre-embargo to the media at https://media.jamanetwork.com)

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

 Editorial: Autologous Hematopoietic Stem Cell Therapy in Severe Systemic Sclerosis

Ready for Clinical Practice?

In an accompanying editorial, Dinesh Khanna, M.D., M.Sc., of the University of Michigan, Ann Arbor, and colleagues provide suggestions on which patients should receive HSCT.

“Currently, consideration should be limited to patients with (1) diffuse cutaneous systemic sclerosis within the first 4 to 5 years of onset with mild-to-moderate internal organ involvement (severe internal organ involvement will make patients ineligible because of risks associated with HSCT) or (2) limited cutaneous systemic sclerosis with progressive internal organ involvement. This consideration also should generally be restricted to patients who have failed to improve or have worsened on conventional immunosuppressive agents and who are not active smokers; … Last, the cost-effectiveness of HSCT needs to be established, and multidisciplinary models of treatment decision making coupled with patient decision tools are needed. These approaches will provide a framework to evaluate and understand the trade-off between long-term benefits and short-term treatment-related morbidity and mortality of HSCT in patients with systemic sclerosis.”

(doi:10.1001/jama.2014.6369; Available pre-embargo to the media at https://media.jamanetwork.com)

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

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, JUNE 24, 2014

Media Advisory: To contact Mark D. Neuman, M.D., M.Sc., call Lee-Ann Donegan at 215-349-5660 or email Leeann.Donegan@uphs.upenn.edu.

Among more than 56,000 adults undergoing hip repair between 2004 and 2011, the use of regional anesthesia compared with general anesthesia was not associated with a lower risk of death at 30 days, but was associated with a modestly shorter length of hospital stay, according to a study in the June 25 issue of JAMA.

Each year, more than 300,000 hip fractures occur in the United States, which can lead to functional disability and death. Regional anesthesia for hip fracture surgery may reduce postoperative complications, and practice guidelines have called for broader use of regional anesthesia for hip fracture surgery, according to background information in the article.

Mark D. Neuman, M.D., M.Sc., of the Perelman School of Medicine at the University of Pennsylvania, Philadelphia, and colleagues assessed the association of regional (i.e., spinal or epidural) anesthesia vs general anesthesia with 30-day mortality and hospital length of stay after hip fracture surgery. The study included patients 50 years or older who were undergoing surgery for hip fracture at general acute care hospitals in New York State between July 2004 and December 2011.

Of 56,729 patients, 15,904 (28 percent) received regional anesthesia and 40,825 (72 percent) received general anesthesia. Overall, 3,032 patients (5.3 percent) died within 30 days of surgery. The researchers did not observe a statistically significant difference in mortality according to anesthesia technique. They did find that regional anesthesia was associated with approximately a half day shorter length of hospital stay.

“Our findings may have implications for clinical practice and health policy. Regional anesthesia is used as the primary anesthetic technique in a minority of hip fracture surgeries performed in the United States and in other countries, and increasing its use has been proposed as a strategy to improve the quality of hip fracture care.  We found an association between greater use of regional anesthesia and a reduction in length of stay after hip fracture; however, we did not find regional anesthesia to be associated with statistically significant differences in mortality” the authors write.

“These findings do not support a mortality benefit for regional anesthesia in this setting.

(doi:10.1001/jama.2014.6499; Available pre-embargo to the media at https://media.jamanetwork.com)

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

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Media Advisory: To contact Sarah M. Friedewald, M.D., call Mickey Ramirez at 847-723-5637 or email Mickey.Ramirez@advocatehealth.com. To contact editorial co-author Etta D. Pisano, M.D., call Deborah Reynolds at 843-324-0984 or email reynodh@musc.edu.

The addition of tomosynthesis, a 3-dimensional breast imaging technique, to digital mammography in more than 170,000 examinations was associated with a decrease in the proportion of patients called back for additional imaging and an increase in the cancer detection rate, according to a study in the June 25 issue of JAMA.

Screening mammography has played a key role in reducing breast cancer mortality, although it has drawn criticism for excessive false-positive results, limited sensitivity, and the potential of overdiagnosis of clinically insignificant lesions. In 2011, tomosynthesis was approved by the U.S. Food and Drug Administration to be used in combination with standard digital mammography for breast cancer screening. Single-institution studies have shown that adding tomosynthesis to mammography increases cancer detection and reduces false-positive results, according to background information in the article.

Sarah M. Friedewald, M.D., of Advocate Lutheran General Hospital, Park Ridge, Il., and colleagues conducted a study using data from 13 centers to determine if mammography combined with tomosynthesis improves performance of breast screening programs. A total of 454,850 examinations (n = 281,187 digital mammography; n = 173,663 digital mammography + tomosynthesis) were evaluated.

The primary measured outcomes were recall rate (proportion of patients requiring additional imaging based on a screening examination result), cancer detection rate, positive predictive value for recall (proportion of patients recalled after screening who were diagnosed as having breast cancer) and positive predictive value for biopsy (proportion of patients undergoing biopsies who were diagnosed as having breast cancer).

An analysis of the data indicated that the model-adjusted rates per 1,000 screens were as follows: for recall rate, 107 with digital mammography vs 91 with digital mammography + tomosynthesis (an overall decrease in recall rate of 16 per 1,000 screens); for biopsies, 18.1 with digital mammography vs 19.3 with digital mammography + tomosynthesis; for cancer detection, 4.2 with digital mammography vs 5.4 with digital mammography + tomosynthesis; and for invasive cancer detection, 2.9 with digital mammography vs 4.1 with digital mammography + tomosynthesis.

Adding tomosynthesis increased the positive predictive value for recall from 4.3 percent to 6.4 percent and for biopsy from 24.2 percent to 29.2 percent.

“The success of mammography screening in reducing mortality is predicated on the principle of detecting and treating small, asymptomatic cancers before they have metastasized. Accordingly, the preferential increase in invasive cancer detection with addition of tomosynthesis may be of particular value in optimizing patient outcomes from mammography screening,” the authors write.

“The association with fewer unnecessary tests and biopsies, with a simultaneous increase in cancer detection rates, would support the potential benefits of tomosynthesis as a tool for screening. However, assessment for a benefit in clinical outcomes is needed.”

(doi:10.1001/jama.2014.6095; Available pre-embargo to the media at https://media.jamanetwork.com)

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

 There will also be a digital news release available for this study, including the JAMA Report video, embedded and downloadable video, audio files, text, documents, and related links. This content will be available at 3 p.m. CT Tuesday, June 24 at this link.

 Editorial: Breast Cancer Screening – Should Tomosynthesis Replace Digital Mammography?

 “As Friedewald et al have indicated, tomosynthesis is likely an advance over digital mammography for breast cancer screening, but fundamental questions about screening remain, with all available technologies,” write Etta D. Pisano, M.D., of the Medical University of South Carolina, Charleston, and Martin J. Yaffe, Ph.D., of the University of Toronto.

“Breast cancer remains a major public health problem, with approximately 40,000 U.S. women still dying annually. The continuing controversy surrounding the most effective strategy for deploying the various available technologies continues unabated, and clear consensus is lacking on when to screen, how often, and with what tools, or even which screen-detected cancers could be managed more conservatively. Only an appropriately powered multisite controlled clinical trial of modern technology can answer the remaining questions definitively. The time is now for the National Institutes of Health to fund such a much-needed trial to address many of the remaining issues about breast cancer screening.”

(doi:10.1001/jama.2014.6421; Available pre-embargo to the media at http:/media.jamanetwork.com)

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

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, JUNE 17, 2014

Media Advisory: To contact Richard D. Carvajal, M.D., call Courtney DeNicola Nowak at 212-639-3573 or email denicolc@mskcc.org.

In patients with advanced uveal melanoma, treatment with the agent selumetinib, compared with chemotherapy, resulted in an improved cancer progression-free survival time and tumor response rate, but no improvement in overall survival, according to a study in the June 18 issue of JAMA. The modest improvement in clinical outcomes was accompanied by a high rate of adverse events.

Uveal melanoma arises from melanocytes within the choroid layer of the eye. There are about 1,500 new cases of uveal melanoma per year in the U.S., which is biologically distinct from skin related melanoma.  Selumetinib is an oral agent that may help to inhibit the growth of cancer cells by blocking MEK1/2. A subgroup analysis from an earlier trial that included 20 patients with uveal melanoma suggested favorable results with selumetinib treatment, according to background information in the article.

Richard D. Carvajal, M.D., of Memorial Sloan-Kettering Cancer Center, New York, and colleagues randomly assigned patients with metastatic uveal melanoma to receive selumetinib (n = 50; orally twice daily), or chemotherapy (n = 51; temozolomide, orally daily for 5 of every 28 days, or dacarbazine, intravenously every 21 days) until disease progression, death, intolerable adverse effects, or withdrawal of consent. After analysis of the primary outcome, 19 additional patients were registered and 18 treated with selumetinib without randomization, to complete the planned 120-patient enrollment.

The researchers reported that the median progression-free survival time was 7 weeks in the chemotherapy group (median treatment duration, 8 weeks) and 15.9 weeks in the selumetinib group (median treatment duration, 16.1 weeks). The 4-month progression-free survival rate was 8.5 percent with chemotherapy, and 43.1 percent with selumetinib. Median overall survival time was 9.1 months with chemotherapy and 11.8 months with selumetinib, a difference that was not statistically significant.

Tumor regression was uncommon with chemotherapy, whereas 49 percent of patients randomized to selumetinib achieved tumor regression. Treatment-related adverse events were observed in 97 percent of patients treated with selumetinib, with 37 percent requiring at least 1 dose reduction.

“In this hypothesis-generating study of patients with advanced uveal melanoma, selumetinib compared with chemotherapy resulted in a modestly improved progression-free survival time and rate of response; however, no improvement in overall survival was observed. Improvement in clinical outcomes was accompanied by a high rate of adverse events.” the authors conclude.

(doi:10.1001/jama.2014.6096; Available pre-embargo to the media at https://media.jamanetwork.com)

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

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, JUNE 17, 2014

Media Advisory: To contact Nynne Nyboe Andersen, M.D., email nyna@ssi.dk.

In a study that included more than 56,000 patients with inflammatory bowel disease, use of a popular class of medications known as tumor necrosis factor alpha antagonists was not associated with an increased risk of cancer over a median follow-up of 3.7 years, although an increased risk of malignancy in the long term, or with increasing number of doses, cannot be excluded, according to a study in the June 18 issue of JAMA.

Tumor necrosis factor α (TNF-α) antagonists are drugs that have been shown to be beneficial in reducing the inflammation in inflammatory diseases such as rheumatoid arthritis, and inflammatory bowel disease (IBD) (Crohn disease and ulcerative colitis). The therapeutic benefits of TNF-α antagonists must be weighed against the potential for adverse effects, including a possible increased risk of cancer. “Therefore, long-term observational studies of consequences of treatment with TNF-α antagonists are needed,” the authors write.

Nynne Nyboe Andersen, M.D., of the Statens Serum Institut, Copenhagen, and colleagues studied cancer rates in patients with IBD exposed to TNF-α antagonists, as compared with patients with IBD not exposed to these drugs. The study included 56,146 patients (15 years or older) with IBD identified in the National Patient Registry of Denmark (1999-2012), of whom 4,553 (8.1 percent) were treated with TNF-α antagonists. Cancer cases were identified in the Danish Cancer Registry.

In total, 3,465 patients with IBD unexposed to TNF-α antagonists (6.7 percent) and 81 exposed to TNF-α antagonists (1.8 percent; median follow-up, 3.7 years) developed cancer. The study results indicated that exposure to TNF-α antagonists was not associated with an increased overall cancer risk. In addition, no site-specific cancers were observed in significant excess.

The authors note that because of the relatively small sample size and the small number of cancer cases in this study, statistical power was limited in analyses of site-specific cancer and also for analyses stratified according to certain criteria, such as duration of follow-up.

“An increased risk of malignancy in the long term or with increasing number of cumulative doses of TNF-α antagonists cannot be excluded, and continuous follow-up of exposed patients is needed.”

(doi:10.1001/jama.2014.5613; Available pre-embargo to the media at https://media.jamanetwork.com)

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

 There will also be an audio author interview available for this study at 3 p.m. CT Tuesday, June 17, at JAMA.com.

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, JUNE 17, 2014

Media Advisory: To contact Kao-Ping Chua, M.D., call Todd Datz at 617-432-8413 or email tdatz@hsph.harvard.edu.

Findings of a large survey indicate that since 2010, when young adults could be covered under their parents’ health insurance plans until age 26, self-reported health among this group has improved, along with a decrease in out-of-pocket health care expenditures, according to a study in the June 18 issue of JAMA.

Beginning September 23, 2010, the Affordable Care Act allowed young adults to be covered under their parents’ plans until 26 years of age. This dependent coverage provision increased insurance coverage and access among young adults. However, little is known about the association between implementation of the provision and medical spending, health care use, and overall health, according to background information in the article.

Kao-Ping Chua, M.D., of Harvard University, Cambridge, Mass., and Benjamin D. Sommers, M.D., Ph.D., of the Harvard School of Public Health, Boston, studied adults 19 to 34 years of age who were included in the 2002-2011 Medical Expenditure Panel Survey, an annual survey conducted by the Agency for Healthcare Research and Quality. The study sample consisted of 26,453 individuals in the intervention group (adults 19 to 25 years of age) and 34,052 individuals in the control group (adults 26 to 34 years of age). Overall, the sample was 47 percent male and 74 percent white.

The authors reported that the dependent coverage provision was associated with a 7.2 percentage point increase in insurance coverage among adults ages 19 to 25 years; no statistically significant changes in health care use; an increase of 6.2 percentage points in the probability of reporting excellent physical health; and an increase of 4 percentage points in the probability of reporting excellent mental health.

The researchers also found that compared with the control group, implementation of the dependent coverage provision was associated with a decrease of 3.7 percentage points in out-of-pocket expenditures among adults ages 19 to 25 years with any expenditures. Annual out-of-pocket expenditures declined by approximately 18 percent in the 19-25 year old group, relative to adults aged 26-34.

Results were similar after controlling for household income, education, and employment.

(doi:10.1001/jama.2014.2202; Available pre-embargo to the media at https://media.jamanetwork.com)

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

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, JUNE 17, 2014

Media Advisory: To contact corresponding author Jay Giri, M.D., M.P.H., call Lee-Ann Donegan at 215-349-5660 or email Leeann.donegan@uphs.upenn.edu. To contact editorial author Joshua A. Beckman, M.D., call Jessica Maki at 617-525-6373 or email jmaki3@partners.org.

In an analysis that included data from 16 trials performed over the last 45 years, among patients with pulmonary embolism, receipt of therapy to dissolve the blood clot (thrombolysis) was associated with lower rates of death, but increased risks of major bleeding and intracranial hemorrhage, according to a study in the June 18 issue of JAMA. The authors note that these findings may not apply to patients with low-risk pulmonary embolism.

Pulmonary embolism (PE; a blockage of the main artery of the lung or one of its branches) is an important cause of illness and death, with more than 100,000 U.S. cases annually and as many as 25 percent of patients experiencing sudden death. Pulmonary embolism is also associated with an increased risk of death for up to 3 months after the initial event. Thrombolytic therapy may be beneficial in the treatment of some patients with PE, but to date, no analysis has had adequate statistical power to determine whether this therapy is associated with improved survival, compared with conventional anticoagulation, according to background information in the article.

Saurav Chatterjee, M.D., of St. Luke’s-Roosevelt Hospital Center of the Mount Sinai Health System, New York, and colleagues performed a meta-analysis of 16 randomized clinical trials (n = 2,115 patients) of thrombolytic therapy for PE. Two hundred ten patients (9.9 percent) had low-risk PE, 71 percent had intermediate-risk PE, 1.5 percent had high-risk PE; risk could not be classified in 18 percent.

The researchers found that thrombolytic therapy for PE was associated with a 47 percent lower odds of death; there was 2.2 percent mortality in the thrombolytic therapy group and 3.9 percent mortality in the anticoagulant group at an average duration of follow-up of 82 days. Thrombolytic therapy was associated with a 2.7 times greater risk of major bleeding compared with anticoagulant therapy; there was a 9.2 percent rate of major bleeding in the thrombolytic therapy group and a 3.4 percent rate in the anticoagulation group. Major bleeding was not significantly increased in patients 65 years and younger.

Thrombolysis was associated with a greater intracranial hemorrhage rate (1.5 percent vs 0.2 percent) but also lower risk of recurrent PE (1.2 percent vs 3.0 percent).

In intermediate-risk pulmonary embolism trials, thrombolysis was associated with lower mortality and more major bleeding events.

“Risk stratification models for bleeding in all patients, but especially the elderly, are warranted to identify the individuals at the highest risk of hemorrhagic complications with thrombolytic therapy. Future research should also be directed toward concomitant [accompanying] use of other medications, especially the ‘novel oral anticoagulants’ in conjunction with thrombolytics in patients with hemodynamically stable PE,” the authors write.

(doi:10.1001/jama.2014.5990; Available pre-embargo to the media at https://media.jamanetwork.com)

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

 Editorial: Thrombolytic Therapy for Pulmonary Embolism

“The meta-analysis by Chatterjee et al raises new questions,” writes Joshua A. Beckman, M.D., of Brigham and Women’s Hospital, Boston, in an accompanying editorial.

“For example, should thrombolytic therapy in intermediate-risk patients older than 65 years be avoided? While the risk of bleeding is increased in older patients, the point estimate for mortality is similar to that in younger patients. Risk stratification for bleeding may favor use of thrombolysis in patients older than 65 years. Second, would the net clinical benefit be better with consistent use of catheter-based thrombolysis using lower doses of fibrinolytic agents for significant pulmonary artery thrombus [blood clot] reduction? Additional clinical trials are needed to guide optimal use of thrombolytic therapy in patients with PE.”

(doi:10.1001/jama.2014.5993; Available pre-embargo to the media at https://media.jamanetwork.com)

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

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, JUNE 10, 2014

Media Advisory: To contact Mikael Knip, M.D., D.M.Sc., email mikael.knip@helsinki.fi.

Among infants at risk for type 1 diabetes, the use of a hydrolyzed formula (one that does not contain intact proteins) compared with a conventional formula did not reduce the incidence of diabetes-associated autoantibodies after 7 years of follow-up, according to a study in the June 11 issue of JAMA, a diabetes theme issue.

Type 1 diabetes is characterized by selective loss of insulin-producing beta cells in the pancreatic islets in genetically susceptible individuals.  The disease process leading to clinical type 1 diabetes often starts during the first years of life. Some studies have suggested that exposure to complex foreign proteins in early infancy may increase the risk of beta-cell autoimmunity and type l diabetes in genetically susceptible individuals, indicating that prevention of the initiation of diabetes should start in infancy, according to background information in the article.

Mikael Knip, M.D., D.M.Sc., of the University of Helsinki, Finland, and colleagues randomly assigned infants at risk of type 1 diabetes to be weaned to an extensively hydrolyzed formula (n = 1,078) or a conventional cows’ milk-based formula (n = 1,081). The dietary intervention period lasted until the infant was at least 6 months of age, and up to a maximum of 8 months of age, depending on the amount of exposure to formula (to ensure exposure for at least 60 days). The study was conducted at 78 centers in 15 countries. The primary measured outcome was positivity for at least 2 diabetes-associated autoantibodies out of 4 analyzed during a median observation period of 7 years.

During the follow-up period, 2,070 children (1,035 in each group) provided at least 1 blood sample for determination of diabetes-associated autoantibodies. The researchers found that 139 children in the experimental group (13.4 percent) tested positive for 2 or more autoantibodies, as compared with 117 in the control group (11.3 percent). At least 1 autoantibody developed in 41.6 percent of those in the experimental group and in 40 percent of those in the control group.

The authors write that this study showed that in this large international trial, weaning to a highly hydrolyzed formula during infancy was not associated with any reduction in the signs of cumulative beta-cell autoimmunity. “These findings do not support a benefit from hydrolyzed formula.”

(doi:10.1001/jama.2014.5610; Available pre-embargo to the media at https://media.jamanetwork.com)

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

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, JUNE 10, 2014

Media Advisory: To contact corresponding author Jose C. Florez, M.D., Ph.D., call Haley Bridger at 617-714-7968 or email hbridger@broadinstitute.org.

A genetic analysis of DNA samples of approximately 3,700 Mexican and U.S. Latino individuals identified a gene variant that was associated with a 5-fold increase in the prevalence of type 2 diabetes, findings that may have implications for screening in this population, according to a study in the June 11 issue of JAMA, a diabetes theme issue.

The estimated prevalence of type 2 diabetes in Mexican adults was 14.4 percent in 2006, making it one of the leading causes of death in Mexico. Latino populations (defined as persons who trace their origin to Central and South America, and other Spanish cultures), have one of the highest prevalences of type 2 diabetes worldwide. Identifying genetic factors associated with type 2 diabetes in Latino populations could improve risk prediction and focus treatment choice based on knowledge of the underlying biology of the disease, according to background information in the study.

Karol Estrada, Ph.D., of the Broad Institute of Harvard and MIT, Cambridge, Mass., and colleagues with the SIGMA Type 2 Diabetes Consortium, performed whole-exome (part of the genome) sequencing (which captures both common and rare genetic variants in the protein-coding regions of genes) on DNA samples from 3,756 Mexican and U.S. Latino individuals (1,794 with type 2 diabetes and 1,962 without diabetes) recruited from 1993 to 2013. One variant was further tested for and association with type 2 diabetes in large multiethnic data sets of 14,276 participants.

The researchers found that a single rare variant (c.1522G>A [p.E508K]) of the HNF1A gene was associated with about a 5 times higher odds of type 2 diabetes, but it was not associated with an early-onset form of diabetes. This variant was observed in 0.36 percent of participants without type 2 diabetes and 2.1 percent of participants with it. In the multiethnic replication data sets, the p.E508K variant was seen only in Latino patients. Carriers and noncarriers of this mutation with type 2 diabetes had no significant differences in clinical characteristics, including age at onset.

The effect size of the variant is the largest observed to date for any diabetes variant with a frequency more than 1 in 1,000.

“Further research is warranted to evaluate the clinical relevance of these findings, including the benefits of selective population screening and the choice of genotype-guided therapeutic regimens,” the authors conclude.

(doi:10.1001/jama.2014.6511; Available pre-embargo to the media at https://media.jamanetwork.com)

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

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, JUNE 10, 2014

Media Advisory: To contact Kasia J. Lipska, M.D., M.H.S., call Helen Dodson at 203-436-3984 or email helen.dodson@yale.edu.

Largely attributable to the widespread adoption of insulin analogs, use of insulin among patients with type 2 diabetes increased from 10 percent in 2000 to 15 percent in 2010, and out-of-pocket expenditures per prescription increased from a median of $19 to $36, according to a study in the June 11 issue of JAMA, a diabetes theme issue.

Insulin analogs are molecularly altered forms of insulin. Compared with human synthetic and animal insulin for treatment of type 2 diabetes, short-acting analogs may offer flexible dosing and convenience, long-acting analogs less nocturnal hypoglycemia, but both at greater cost, according to background information in the article.

Kasia J. Lipska, M.D., M.H.S., of the Yale University School of Medicine, New Haven, Conn., and colleagues used data from an administrative claims database of privately insured enrollees from throughout the United States (but with more representation from states in the South and Midwest) to examine trends in insulin use, out-of-pocket expenditures, and severe hypoglycemic events among privately insured U.S. adults with type 2 diabetes. The analysis included adults 18 years or older with at least 2 years of continuous plan enrollment between January 2000 and September 2010.

During the study period, 123,486 patients filled at least 1 prescription for insulin, comprising 9.7 percent of adults with type 2 diabetes in 2000 and 15.1 percent in 2010. Among adults who used insulin, 96.4 percent filled prescriptions for human synthetic insulin in 2000 and 14.8 percent in 2010, whereas 18.9 percent filled prescriptions for insulin analogs in 2000 and 91.5 percent in 2010. Use of animal insulin was less than 1 percent during all years.

The median out-of-pocket costs per prescription for all types of insulin increased from $19 in 2000 to $36 in 2010. Severe hypoglycemic events declined slightly over the study period, but the difference was not statistically significant.

“We found a large increase in the prevalent use of insulin analogs among privately insured patients with type 2 diabetes. The clinical value of this change is unclear,” the authors conclude.

(doi:10.1001/jama.2014.6316; Available pre-embargo to the media at https://media.jamanetwork.com)

 Editor’s Note: This project was supported by a grant from the Agency for Healthcare Research and Quality. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, etc.

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, JUNE 10, 2014

Media Advisory: To contact Christianne L. Roumie, M.D., M.P.H., call Craig Boerner at 615-322-4747 or email craig.boerner@vanderbilt.edu. To contact editorial author Monika M. Safford, M.D., call Bob Shepard at 205-934-8934 or email bshep@uab.edu.

Among patients with diabetes who were receiving metformin, the addition of insulin compared with a sulfonylurea (a class of antidiabetic drugs) was associated with an increased risk of nonfatal cardiovascular outcomes and all-cause death, according to a study in the June 11 issue of JAMA, a diabetes theme issue.

Diabetes mellitus and its complications represent an enormous health care burden and result in nearly 200,000 deaths annually. The American Diabetes Association and the European Association for the Study of Diabetes recommend that, for patients with preserved kidney function, diabetes treatment begin with metformin and lifestyle changes to achieve a glycated hemoglobin (HbA_lc) level of less than or equal to 7 percent. Often patients will require a second agent to reach this goal, but there is no consensus regarding which medication to choose, according to background information in the study.

Clinicians begin administration of insulin to attain fast and flexible control of blood glucose levels. Because of the promising results of a few trials, there has been an increase in early initiation of insulin and its use as add-on therapy to metformin.

Christianne L. Roumie, M.D., M.P.H., of the Veterans Health Administration-Tennessee Valley Healthcare System Geriatric Research Education Clinical Center, and Vanderbilt University, Nashville, Tenn., and colleagues conducted a study with data from national Veterans Health Administration, Medicare, and National Death Index databases, which included veterans with diabetes initially treated with metformin from 2001 through 2008 who subsequently added either insulin or sulfonylurea. The researchers compared the risk between therapies of a composite outcome of heart attack, stroke, or all-cause death.

Among 178,341 metformin monotherapy patients, 2,948 added insulin and 39,990 added a sulfonylurea.  The authors performed additional propensity matched analysis on a subset of 2,436 patients from the insulin group and 12,180 patients from the sulfonylurea group.  Patients had received metformin for a median of 14 months before adding another therapy; median follow-up after this addition was 14 months. An analysis of the subsequent events indicated that heart attack and stroke rates were statistically similar, whereas there was a higher rate of all-cause death among patients who received insulin.

“Our finding of a modestly increased risk of a composite of cardiovascular events and death in metformin users who add insulin compared with sulfonylurea is consistent with the available clinical trial and observational data. None of these studies found an advantage of insulin compared with oral agents for cardiovascular risk, and several reported increased cardiovascular risk or weight gain and hypoglycemic episodes, which could result in poorer outcomes,” the authors write. “Our study suggests that intensification of metformin with insulin among patients who could add a sulfonylurea offers no advantage in regard to risk of cardiovascular events and is associated with some risk.”

“These findings require further investigation to understand risks associated with insulin use in these patients and call into question recommendations that insulin is equivalent to sulfonylureas for patients who may be able to receive an oral agent.”

(doi:10.1001/jama.2014.4312; Available pre-embargo to the media at https://media.jamanetwork.com)

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

There will also be a digital news release available for this study, including the JAMA Report video, embedded and downloadable video, audio files, text, documents, and related links. This content will be available at 3 p.m. CT Tuesday, June 10 at this link.

 Editorial: Comparative Effectiveness Research and Outcomes of Diabetes Treatment

 In an accompanying editorial, Monika M. Safford, M.D., of the University of Alabama at Birmingham, comments on comparative effectiveness research, such as the study conducted by Roumie and colleagues.

“Comparative effectiveness research is creating new challenges as it generates much needed new evidence. The very methods that make studies like that of Roumie et al novel also create barriers to interpretation that may make it more difficult to apply their results. Some of the creativity being brought to bear on advancing methods of analysis may also be needed to advance methods of communicating both methods and results to practicing clinicians, and perhaps more importantly, to the patients who are facing decisions that may (or may not) have profound implications for their health and well-being.”

(doi:10.1001/jama.2014.4313; Available pre-embargo to the media at https://media.jamanetwork.com)

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

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, JUNE 10, 2014

Media Advisory: To contact Lars Sjostrom, M.D., Ph.D., email lars.v.sjostrom@medfak.gu.se.

In a study that included long-term follow-up of obese patients with type 2 diabetes, bariatric surgery was associated with more frequent diabetes remission and fewer complications than patients who received usual care, according to a study in the June 11 issue of JAMA, a diabetes theme issue.

Obesity and diabetes have reached epidemic proportions and constitute major health and economic burdens. Worldwide, 347 million adults are estimated to live with diabetes and half of them are undiagnosed. Studies show that type 2 diabetes is preventable. The incidence of diabetes can be reduced by as much as 50 percent by lifestyle and pharmacological interventions, according to background information in the article. Short-term studies show that bariatric surgery results in remission of diabetes. The long-term outcomes for bariatric surgery and diabetes remission and diabetes-related complications have not been known.

Lars Sjostrom, M.D., Ph.D., of the University of Gothenburg, Sweden, and colleagues performed a follow-up of the Swedish Obese Subjects (SOS) study, conducted at 25 surgical departments and 480 primary health care centers in Sweden. Of patients recruited between September 1987 and January 2001, 260 of 2,037 control patients and 343 of 2,010 bariatric surgery patients had type 2 diabetes at baseline. For the current analysis, the presence of diabetes was determined at SOS health examinations and information on diabetes complications was obtained from national health registers. For diabetes complications, the median follow-up time was 17.6 years in the control group, and 18.1 years in the surgery group.

The proportion of patients in remission (defined as blood glucose <110 mg/dL and no diabetes medication) after 2 years was 72.3 percent in the surgery group and 16.4 percent in the control group. At 15 years, the diabetes remission rates decreased to 30.4 percent for bariatric surgery patients and 6.5 percent for control patients. All types of bariatric surgery (adjustable or nonadjustable banding, vertical banded gastroplasty, or gastric bypass) were associated with higher remission rates compared with usual care.

In addition, bariatric surgery was associated with a decreased incidence of microvascular and macrovascular complications.

“In this very long-term follow-up observational study of obese patients with type 2 diabetes, bariatric surgery was associated with more frequent diabetes remission and fewer complications than usual care. These findings require confirmation in randomized trials,” the authors conclude.

(doi:10.1001/jama.2014.5988; Available pre-embargo to the media at https://media.jamanetwork.com)

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

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EMBARGOED FOR EARLY RELEASE: 5:45 A.M. (CT) TUESDAY, JUNE 3, 2014

Media Advisory: To contact Josef Coresh, M.D., Ph.D., call Barbara Benham at 410-614-6029 or email bbenham1@jhu.edu.

Developing therapies for kidney disease can be made faster by adopting a new, more sensitive definition of kidney disease progression, according to a study published by JAMA. The study is being released early online to coincide with its presentation at the European Renal Association-European Dialysis and Transplant Association Congress.

Chronic kidney disease (CKD) is a worldwide public health problem, with increasing prevalence, poor outcomes, and high treatment cost. Yet, despite the avail­ability of simple laboratory tests to identify people with earlier stages of CKD, there are fewer clinical trials for kidney disease than for other common diseases. One contributing reason may be that the established CKD progression end point (i.e., a doubling of serum creatinine concentration from baseline, corresponding to a 57 percent reduction in estimated glomerular filtration rate [GFR]), is a late event, requiring long follow-up periods and large sample size, which limits the feasibility of kidney-related clinical trials. Improved methods for estimating GFR may allow using smaller decreases in estimated GFR as alternative end points to assess CKD progression, according to background information in the article.

Josef Coresh, M.D., Ph.D., of the Johns Hopkins Bloomberg School of Public Health, Baltimore, and colleagues with the Chronic Kidney Disease Prognosis Consortium, examined the association of decline in estimated GFR with subsequent progression to end-stage renal disease (ESRD; initiation of dialysis or transplantation). The study included 1.7 million participants with 12,344 ESRD events and 223,944 deaths after repeated measurements of kidney function over a 1 to 3 year baseline period. Data collection took place between 1975 and 2011.

The researchers found that declines in estimated GFR smaller than a doubling of serum creatinine concentration were strongly and consistently associated with subsequent risk of ESRD. A doubling of serum creatinine, corresponding to a 57 percent decline in estimated GFR, was associated with a greater than 30-fold higher risk of ESRD. However, over a 1- to 3-year period, a doubling of serum creatinine concentration was present in less than 1 percent of participants. In contrast, a 30 percent decline in estimated GFR was nearly 10 times more common and was associated with an approximately 5-fold increased risk of ESRD.

“These data provide a basis for understanding the tradeoff between higher risk and lower prevalence in choosing a larger or smaller percentage change in estimated GFR as an outcome when studying CKD progression,” the authors write.

“A doubling of serum creatinine concentration has been accepted by the U.S. Food and Drug Administration as a surrogate end point for CKD progression in clinical trials since 1993. Adoption of a lesser decline in estimated GFR as an alternative end point for CKD progression has the potential to shorten duration of follow-up, reduce costs, and increase efficiency of clinical trials. Consistency of effects over time suggests applicability for shorter as well as for longer trials, which is relevant for diseases that are progressing more rapidly or slowly, respectively.”

(doi:10.1001/jama.2014.6634; Available pre-embargo to the media at https://media.jamanetwork.com)

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

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, JUNE 3, 2014

Media Advisory: To contact Yaron Finkelstein, M.D., call Suzanne Gold at 416-813-7654, ext. 202059, or email suzanne.gold@sickkids.ca.

Individuals who are hospitalized for the skin conditions of Stevens-Johnson syndrome and toxic epidermal necrolysis appear to have a high risk of recurrence, according to a study in the June 4 issue of JAMA.

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are life-threatening conditions that develop primarily as responses to drugs, and result in extensive epidermal detachment (upper layers of the skin detach from the lower layers). Recurrence has been reported in isolated cases, and the overall risk of recurrence has been unknown, according to background information in the article.

Yaron Finkelstein, M.D., of the Hospital for Sick Children, Toronto, and colleagues conducted a study that included data of all Ontario residents hospitalized for a first episode of SJS or TEN between April 2002 and March 2011. Patients were followed up from admission until March 31, 2012, or death. The researchers identified 708 individuals hospitalized for a first episode of SJS (n = 567) or TEN (n = 141), including 127 (17.9 percent) children younger than 18 years.

Forty-two patients (7.2 percent) were hospitalized for a subsequent episode of SJS or TEN. Eight patients (1.4 percent) experienced multiple recurrences. The median time to first recurrence was 315 days.

“In light of the reported incidence of SJS and TEN in the general population (1.0-7.2 cases/1 million individuals/year), the observed recurrence risk in our study (>7 percent) is several thousand-fold higher than would be expected if subsequent episodes were probabilistically independent of the first SJS or TEN episode. We speculate that this increased risk reflects individual susceptibility. Genetic predisposition has been identified for several medications in association with specific genotypes …” the authors write.

“… these findings are relevant to physicians who care for patients with a history of SJS or TEN. Because most such episodes are drug-induced, the high risk of recurrence should be recognized, and the benefits of drug therapy weighed carefully against the potential risks. This is particularly true for drugs commonly associated with the development of these frequently fatal conditions.”

(doi:10.1001/jama.2014.839; Available pre-embargo to the media at https://media.jamanetwork.com)

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

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, JUNE 3, 2014

Media Advisory: To contact Eric M. Mortensen, M.D., M.Sc., call Penny Kerby at 214-857-1155 or email Penny.Kerby@va.gov.

In a study that included nearly 65,000 older patients hospitalized with pneumonia, treatment that included azithromycin compared with other antibiotics was associated with a significantly lower risk of death and a slightly increased risk of heart attack, according to a study in the June 4 issue of JAMA.

Pneumonia and influenza together are the eighth leading cause of death and the leading causes of infectious death in the United States. Although clinical practice guidelines recommend combination therapy with macrolides (a class of antibiotics), including azithromycin, as first-line therapy for patients hospitalized with pneumonia, recent research suggests that azithromycin may be associated with increased cardiovascular events, according to background information in the article.

Eric M. Mortensen, M.D., M.Sc., of the VA North Texas Health Care System and University of Texas Southwestern Medical Center, Dallas, and colleagues assessed the association of azithromycin use and outcomes within 90 days of hospital admission, including cardiovascular events (heart failure, heart attack, cardiac arrhythmias) and death, for patients 65 years and older who were hospitalized with pneumonia at any Veterans Administration acute care hospital from fiscal years 2002 through 2012.

The final analysis included 31,863 patients who received azithromycin and 31,863 matched patients who did not, but some other guideline-concordant therapy. The researchers found that 90-day mortality was significantly lower in those who received azithromycin (17.4 percent, vs 22.3 percent). There was also an increased odds of heart attack (5.1 percent vs 4.4 percent), but not any cardiac event (43.0 percent vs 42.7 percent), cardiac arrhythmias (25.8 percent vs 26.0 percent), or heart failure (26.3 percent vs 26.2 percent).

“In this national cohort study of veterans hospitalized with pneumonia, azithromycin use was consistently associated with decreased mortality and a slightly increased odds of myocardial infarction,” the authors write. “To put the balance of benefits and harms in context, based on the propensity-matched analysis, the number needed to treat with azithromycin was 21 to prevent 1 death within 90 days, compared with a number needed to harm of 144 for myocardial infarction. This corresponds to a net benefit of around 7 deaths averted for 1 nonfatal myocardial infarction induced.”

“These findings are consistent with a net benefit associated with azithromycin use in patients hospitalized for pneumonia.”

(doi:10.1001/jama.2014.4304; Available pre-embargo to the media at https://media.jamanetwork.com)

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

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, JUNE 3, 2014

Media Advisory: To contact Sana M. Al-Khatib, M.D., M.H.S., call Rachel Harrison at 919-419-5069 or email rachel.harrison@duke.edu.

An examination of the benefit of preventive placement of implantable cardioverter-defibrillators (ICDs) in patients with a less severe level of heart failure, a group not well represented in clinical trials, finds significantly better survival at three years than that of similar patients with no ICD, according to a study in the June 4 issue of JAMA.

Although clinical trials have established the ICD as the best currently available therapy to prevent sudden cardiac death in patients with heart failure, some uncertainties remain regarding preventive use of ICDs in patients seen in clinical practice. Of patients enrolled in randomized clinical trials of prophylactic (preventive) ICDs, the median left ventricular ejection fraction (LVEF; the percentage of blood that is pumped out of a filled ventricle as a result of a heartbeat) is well below 30 percent. Because a large number of prophylactic ICDs in the United States are implanted in patients with an LVEF between 30 percent and 35 percent, understanding outcomes associated with the ICDs in such patients is important. The Centers for Medicare & Medicaid Services have designated these patients as an important subgroup for whom more data on ICD effectiveness are needed, according to background information in the article.

Sana M. Al-Khatib, M.D., MH.S., of the Duke University Medical Center, Durham, N.C., and colleagues compared survival in Medicare beneficiaries in the National Cardiovascular Data Registry ICD registry with an LVEF between 30 percent and 35 percent who received an ICD during a heart failure hospitalization with similar patients in the Get With The Guidelines-Heart Failure database with no ICD. The analysis was repeated in patients with an LVEF less than 30 percent.

There were no significant differences in the baseline characteristics of the matched groups (n = 408 for both groups). At 1 year, 24.5 percent of ICD patients died vs 24.9 percent of non-ICD patients. At 3 years, 51.4 percent of the ICD patients died, compared with 55.0 percent of the non-ICD patients, a significantly lower risk of death among patients with an LVEF between 30 percent and 35 percent who received an ICD. Presence of an ICD also was associated with better survival in patients with an LVEF less than 30 percent (3-year mortality rates: 45.0 percent vs 57.6 percent).

The authors write that although the difference in absolute risk by 3 years was not large (3.6 percent), it was significant and close in magnitude to what was observed in other clinical trials of prophylactic ICDs. “These results support guidelines’ recommendations to implant a prophylactic ICD in eligible patients with an LVEF of 35 percent or less.”

(doi:10.1001/jama.2014.5310; Available pre-embargo to the media at https://media.jamanetwork.com)

 Editor’s Note: This analysis was funded by a grant from the National Heart, Lung, and Blood Institute. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc.

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, MAY 27, 2014

Media Advisory: To contact Mark D. Neuman, M.D., M.Sc., email neumanm@mail.med.upenn.edu or call 215-760-7471; or email Jessica Mikulski at Jessica.Mikulski@uphs.upenn.edu or call 215-796-4829. To contact editorial author Paul G. Shekelle, M.D., Ph.D., call Warren Robak at 310-451-6913 or email robak@rand.org.

An analysis of more than 600 class I (procedure/treatment should be performed/administered) American College of Cardiology/American Heart Association guideline recommendations published or revised since 1998 finds that about 80 percent were retained at the time of the next guideline revision, and that recommendations not supported by multiple randomized studies were more likely to be downgraded, reversed, or omitted, according to a study in the May 28 issue of JAMA.

As adherence to recommended clinical practice guidelines increasingly is used to measure performance, guidelines play a major role in policy efforts to improve the quality and cost-effectiveness of care. Past research has established the importance of revising guidelines over time to address advances in research and population-level changes in health risks. Nonetheless, unwarranted variability across guidelines can reduce trust in guideline processes and complicate efforts to promote consistent use of evidence-based practices. Moreover, policies based on recommendations that prematurely endorse practices subsequently found to be ineffective can lead to waste and potential harm. Little is known regarding the degree to which individual guideline recommendations endure or change over time, according to background information in the article.

Mark D. Neuman, M.D., M.Sc., of the Perelman School of Medicine at the University of Pennsylvania, Philadelphia, and colleagues analyzed variations in class I American College of Cardiology/American Heart Association (ACC/AHA) guidelines (n = 11) published between 1998 and 2007 and revised between 2006 and 2013. The researchers reviewed and recorded all class I recommendations from the first of the 2 most recent versions of each guideline and identified corresponding recommendations in the subsequent version. Recommendations replaced by less determinate or contrary recommendations were classified as having been downgraded or reversed; recommendations for which no corresponding item could be identified were classified as having been omitted.

Out of 619 index recommendations, 495 (80.0 percent) were retained in the subsequent version; 8.9 percent were downgraded, 0.3 percent were reversed, and 10.8 percent were omitted. The percentage of recommendations retained varied across guidelines from 15.4 percent to 94.1 percent.

Among recommendations with available information on level of evidence, 90.5 percent of recommendations supported by multiple randomized studies were retained, vs 81.0 percent of recommendations supported by 1 randomized trial or observational data and 73.7 percent of recommendations supported by opinion. After accounting for guideline-level factors, the odds of a downgrade, reversal, or omission were more than 3 times greater for recommendations based on a single trial, observational data, consensus opinion, or standard of care than for recommendations based on multiple randomized trials.

“… our results may have important implications for health policy and medical practice. The categorization of medical evidence, through guidelines, into stronger and weaker recommendations, influences definitions of good medical practice and informs efforts to measure the quality of care on a large scale. Our findings stress the need for frequent re-evaluation of practices and policies based on guideline recommendations, particularly in cases where such recommendations rely primarily on expert opinion or limited clinical evidence,” the authors write.

“Moreover, our results suggest that the effectiveness of clinical practice guidelines as a mechanism for quality improvement may be aided by systematically identifying and reducing unwarranted variability in recommendations. Finally, our work emphasizes the importance of greater efforts on the part of guideline-producing organizations to communicate the reasons that specific recommendations are downgraded, reversed, or omitted over time.”

(doi:10.1001/jama.2014.4949; Available pre-embargo to the media at https://media.jamanetwork.com)

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

 Editorial: Updating Practice Guidelines

In an accompanying editorial, Paul G. Shekelle, M.D., Ph.D., of the VA West Los Angeles Medical Center, Los Angeles, and RAND Corporation, Santa Monica, discusses the importance of keeping clinical practice guideline recommendations up-to-date.

“The need for surveillance and updating of practice guidelines is increasingly gaining attention. To meet the need, guideline development organizations need to change their focus. This change is not easy. It is not just a matter of resources, although guideline organizations are going to have to devote more resources to active surveillance and maintenance of their guidelines than most probably do at present. It also has to be a change to the mindset, recognizing that keeping existing guidelines up-to-date in a timely way is an important goal for good patient care.”

(doi:10.1001/jama.2014.4950; Available pre-embargo to the media at https://media.jamanetwork.com)

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

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, MAY 27, 2014

Media Advisory: To contact Peter B. Cotton, M.D., F.R.C.P., F.R.C.S., call Heather Woolwine at 843-792-7669 or email woolwinh@musc.edu.

In certain patients with abdominal pain after gallbladder removal (cholecystectomy), undergoing an endoscopic procedure involving the bile and pancreatic ducts did not result in fewer days with disability due to pain, compared to a placebo treatment, according to a study in the May 28 issue of JAMA.

Post-cholecystectomy pain is a common clinical problem. More than 700,000 patients undergo cholecystectomy each year in the United States, and at least 10 percent are reported to have pain afterwards. Most of these patients have no significant abnormalities on imaging or laboratory testing, and the cause remains uncertain. Many of these patients undergo endoscopic retrograde cholangiopancreatography (ERCP; the use of an endoscope to inspect the pancreatic duct and common bile duct) in the hope of finding small stones or other pathology or in an effort to address suspected sphincter of Oddi (a muscle at the juncture of the bile and pancreatic ducts and the small intestine that controls the flow of digestive juices) dysfunction. Of these patients, some undergo biliary or pancreatic sphincterotomy (surgical incision of a muscle that contracts to close an opening) or both. The value of this endoscopic intervention is unproven and the risks are substantial. Procedure-related pancreatitis rates are 10 percent to 15 percent, and perforations may occur. Many patients have prolonged and expensive hospital stays, and some die, according to background information in the article.

Peter B. Cotton, M.D., F.R.C.P., F.R.C.S., of the Medical University of South Carolina, Charleston, and colleagues randomly assigned patients with pain after cholecystectomy (and with no significant laboratory or imaging abnormalities) to sphincterotomy (n = 141) or sham (placebo; n = 73) therapy, after ERCP. Success of treatment was defined as less than 6 days of disability due to pain in the prior 90 days both at months 9 and 12 after randomization, with no narcotic use and no further sphincter intervention.

The rate of successful outcome at 12 months was 37 percent for the patients assigned to sham procedure, and 23 percent for those assigned to sphincterotomy. The most common reason for failure in both treatment groups (72 percent sphincterotomy, 56 percent sham) was persistent elevation in a pain-disability score, with or without re-intervention or narcotic use.

No clinical subgroups appeared to benefit from sphincterotomy more than others. Pancreatitis occurred in 11 percent of patients after primary sphincterotomies and in 15 percent of patients in the sham group.

Of the nonrandomized patients in an observational study group, 24 percent who underwent biliary sphincterotomy, 31 percent who underwent dual sphincterotomy, and 17 percent who did not undergo sphincterotomy had successful treatment.

“These findings do not support the use of ERCP and sphincterotomy for these patients,” the authors write.

“The finding that endoscopic sphincterotomy is not an effective treatment has major implications for clinical practice because it applies to many thousands of patients.”

(doi:10.1001/jama.2014.5220; Available pre-embargo to the media at https://media.jamanetwork.com)

 Editor’s Note: This study was funded by a grant from the National Institutes of Diabetes and Digestive and Kidney Diseases. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, etc.

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EMBARGOED FOR EARLY RELEASE: 1 P.M. (ET) TUESDAY, MAY 27, 2014

Media Advisory: To contact Marco Pahor, M.D., call Morgan Sherburne at 352-273-6160 or email msherburne@ufl.edu.

Among older adults at risk of disability, participation in a structured moderate-intensity physical activity program, compared with a health education intervention, significantly reduced the risk of major mobility disability (defined in this trial as loss of ability to walk 400 meters, or about a quarter mile), according to a study published by JAMA. The study is being released early online to coincide with its presentation at the American College of Sports Medicine annual meeting.

Mobility—the ability to walk without assistance—is a critical characteristic for functioning independently. Reduced mobility is common in older adults and is an independent risk factor for illness, hospitalization, disability, and death. Limited evidence suggests that physical activity may help prevent mobility disability; however, there are no definitive clinical trials examining whether physical activity prevents or delays mobility disability, according to background information in the article.

Marco Pahor, M.D., of the University of Florida, Gainesville, and colleagues with the Lifestyle Interventions and Independence for Elders (LIFE) study, randomly assigned sedentary men and women (age 70 to 89 years) who were able to walk 400 meters to a structured, moderate-intensity physical activity program (n = 818) conducted in a center and at home that included aerobic, resistance, and flexibility training activities, or to a health education program (n = 817), consisting of workshops on topics relevant to older adults and upper extremity stretching exercises. The adults participated for an average of 2.6 years.  Participants were enrolled at 8 centers across the country.

Major mobility disability (loss of ability to walk 400 meters) was experienced by 246 participants (30.1 percent) in the physical activity group and 290 participants (35.5 percent) in the health education group. Persistent mobility disability (two consecutive major mobility disability assessments or major mobility disability followed by death) was ex­perienced by 14.7 percent of participants in the physical activity group and 19.8 percent of participants in the health education group.

A subgroup with lower physical function at study entry, representing 45 percent of the study population, received considerable benefit from the physical activity intervention.

Serious adverse events were reported by 49.4 percent of participants in the physical activity group and 45.7 percent of participants in the health education group.

“These results suggest the potential for structured physical activity as a feasible and effective intervention to reduce the burden of disability among vulnerable older persons, in spite of functional decline in late life. To our knowledge, the LIFE study is the largest and longest duration randomized trial of physical activity in older persons,” the authors write.

(doi:10.1001/jama.2014.5616; Available pre-embargo to the media at https://media.jamanetwork.com)

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

There will also be a digital news release available for this study, including the JAMA Report video, embedded and downloadable video, audio files, text, documents, and related links. This content will be available at 1 p.m. ET Tuesday, May 27 at this link.

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, MAY 20, 2014

Media Advisory: To contact corresponding author T. Scott Stroup, M.D., M.P.H., call Dacia Morris at 646-774-8724 or email morrisd@nyspi.columbia.edu. To contact editorial author Donald C. Goff, M.D., call Lorinda Klein at 212-404-3533 or email Lorindaann.klein@nyumc.org.

 
Among adults with schizophrenia or schizoaffective disorder, treatment with the newer, more costly antipsychotic paliperidone palmitate, compared with the older antipsychotic haloperidol decanoate, found no significant difference on a measure of effectiveness, according to a study in the May 21 issue of JAMA.

Long-acting injectable antipsychotic medications are prescribed to reduce nonadherence to drug therapy and relapse in people diagnosed with a schizophrenia-spectrum disorder. The relative effectiveness of long-acting injectable versions of second-generation and older antipsychotic medications has not been previously assessed, according to background information in the article.

Joseph P. McEvoy, M.D., of Georgia Regents University, Augusta and colleagues randomly assigned 311 patients diagnosed with schizophrenia or schizoaffective disorder to receive monthly injections of haloperidol decanoate or paliperidone palmitate for as long as 24 months. The researchers measured rates of efficacy failure, defined as a psychiatric hospitalization, a need for crisis stabilization, a substantial increase in frequency of outpatient visits, a clinician’s decision that oral antipsychotic could not be discontinued within 8 weeks after starting the long-acting injectable antipsychotics, or a clinician’s decision to discontinue the assigned long-acting injectable due to inadequate therapeutic benefit.

The authors found no significant difference in the rate of efficacy failure for patients in the paliperidone palmitate group (49 [33.8 percent]) vs those in the haloperidol decanoate group (47 [32.4 percent]. The most common reasons for efficacy failure were psychiatric hospitalization and clinician discontinuation of study medication due to inadequate therapeutic effect. The researchers note that their findings do not rule out the possibility of a clinically meaningful advantage with paliperidone palmitate.

Regarding adverse effects, on average, participants taking paliperidone palmitate gained weight progressively over time, while those taking haloperidol decanoate lost weight. Treatment with paliperidone palmitate was associated with greater increases in serum prolactin (a hormone), whereas haloperidol decanoate was associated with more akathisia (a movement disorder).

“The results [of this study] are consistent with previous research that has not found large differences in the effectiveness of newer and older antipsychotic medications,” the authors conclude.

(doi:10.1001/jama.2014.4310; Available pre-embargo to the media at https://media.jamanetwork.com)

 Editor’s Note: The study was funded by grants from the National Institute of Mental Health to Drs. McEvoy and Stroup. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, etc.

 Editorial: Maintenance Treatment With Long-Acting Injectable Antipsychotics Comparing Old With New

“Setting aside the substantial differences in cost between haloperidol decanoate and paliperidone palmitate [approximately $35 vs. $1,000, respectively, per injection], the results from [this] trial suggest that drug selection should be based on anticipated adverse effects rather than efficacy,” writes Donald C. Goff, M.D., of the New York University School of Medicine, and Associate Editor, JAMA, in an accompanying editorial.

“This is true for most antipsychotics, with the notable exception of clozapine, which has established superior efficacy for treatment-resistant schizophrenia but is limited in use due to more serious adverse effects. Although patients may try medications sequentially to identify an optimal agent, this approach may be problematic if adverse effects persist after drug discontinuation, such as weight gain or involuntary movements. Additional data from patient samples exposed for a longer duration to a wider range of antipsychotics are needed to better characterize the relative risk of adverse effects, examine their longer term consequences, and identify biomarkers that will allow a personalized medicine approach. Not only is the compilation of reliable data about these drugs essential, so also is the clear communication of this information to patients as part of the shared decision-making process.”

(doi:10.1001/jama.2014.4311; Available pre-embargo to the media at https://media.jamanetwork.com)

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

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, MAY 20, 2014

Media Advisory: To contact Mark G. Kris, M.D., call Melissa Morgenweck at 646-227-3633 or email morgenwm@mskcc.org. To contact editorial co-author Boris Pasche, M.D., Ph.D., call Marguerite Beck at 336-716-2415 or email marbeck@wakehealth.edu.

 
Multiplexed testing of lung cancer tumors identified genetic alterations that were helpful in selecting targeted treatments.  Patients that received matched therapy for lung cancer lived longer than patients who did not receive directed therapy, although randomized clinical trials are required to determine if this treatment strategy improves survival, according to a study in the May 21 issue of JAMA.

The introduction of targeted therapy has transformed the care of patients with lung cancers by incorporating tumor genotyping into treatment decisions. Adenocarcinoma, the most common type of lung cancer, is diagnosed in 130,000 patients in the United States and 1 million persons worldwide each year.  Adenocarcinoma is also the type of lung cancer with a higher than 50 percent estimated frequency of actionable oncogenic drivers, which are molecular abnormalities that are critical to cancer development. These drivers are defined as “actionable” because the effects of those abnormalities can be negated by agents directed against each genomic alteration, according to background information in the article.

Mark G. Kris, M.D., of Memorial Sloan Kettering Cancer Center, New York, and colleagues examined the frequency of oncogenic drivers in patients with lung adenocarcinomas, and the proportion of patients in whom this data was used to select treatments targeting the identified driver(s) along with overall survival. From 2009 through 2012, 14 sites of the Lung Cancer Mutation Consortium enrolled patients with metastatic lung adenocarcinomas and tested the tumors of patients who met certain criteria for 10 oncogenic drivers.

During the study period, tumors from 1,007 patients were tested for at least 1 gene and 733 for 10 genes (patients with full genotyping). An oncogenic driver was found in 466 of 733 patients (64 percent). Results were used to select a targeted therapy or clinical trial in 275 of 1,007 patients (28 percent).

The 260 patients with an oncogenic driver and treatment with a targeted agent had a median (midpoint) survival of 3.5 years; the 318 patients with a driver and no targeted therapy, 2.4 years; and the 360 patients with no driver identified, 2.1 years.

The authors conclude that multiplexed tested aided physicians in selecting lung cancer therapies.  Although individuals with drivers receiving a matched targeted agent lived longer, the study design was not appropriate to reach definitive conclusions about survival differences being attributable to the use of oncogenic drivers.

(doi:10.1001/jama.2014.3741; Available pre-embargo to the media at https://media.jamanetwork.com)

 Editor’s Note: This study was entirely supported by a grant from the National Institutes of Health, National Cancer Institute. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, etc.

 There will also be a digital news release available for this study, including the JAMA Report video, embedded and downloadable video, audio files, text, documents, and related links. This content will be available at 3 p.m. CT Tuesday, May 20 at this link.

 Editorial: Non-Small Cell Lung Cancer and Precision Medicine

Boris Pasche, M.D., Ph.D., of Wake Forest University, Winston-Salem, N.C., and Stefan C. Grant, M.D., J.D., M.B.A., of the University of Alabama at Birmingham, comment on the findings of this study in an accompanying editorial.

“In summary, the study by Kris et al demonstrates the proof of principle that multiplex testing of actionable driver mutations is feasible and can allow for effective treatment stratification. After decades of small, albeit significant, improvements in the care of patients with lung cancer, the advent of genetic testing of tumors, identification of driver mutations, and development of drugs able to specifically target these mutations, have produced substantial improvements in survival for patients with targetable driver mutations. Although much remains to be done, the incorporation of genomic medicine into the study and treatment of lung cancer represents, at the very least, the end of the beginning for the care of these and other patients with cancer.”

(doi:10.1001/jama.2014.3742; Available pre-embargo to the media at https://media.jamanetwork.com)

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

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, MAY 20, 2014

Media Advisory: To contact Kim L. Bennell, Ph.D., email k.bennell@unimelb.edu.au.

 
Among adults with painful hip osteoarthritis, physical therapy did not result in greater improvement in pain or function compared with a placebo treatment, but was associated with relatively frequent but mild adverse effects, raising questions about its value for these patients, according to a study in the May 21 issue of JAMA.

Hip osteoarthritis is a prevalent and costly chronic musculoskeletal condition. Clinical guidelines recommend physical therapy as treatment, however costs are significant, and evidence about its effectiveness is inconclusive, according to background information in the article.

Kim L. Bennell, Ph.D., of the University of Melbourne, Australia, and colleagues randomly assigned patients with hip osteoarthritis to attend 10 sessions of either active treatment (n = 49; included education and advice, manual therapy, home exercise, and walking aid if appropriate) or sham treatment (n = 53; included inactive ultrasound and inert gel). For 24 weeks after treatment, the active group continued unsupervised home exercise while the sham group self-applied gel three times weekly.

The researchers found that at weeks 13 and 36 the active treatment did not confer additional benefits over the sham treatment on measures of pain and physical function, which were improved in both groups. The treatment group reported a significantly greater number of adverse events, although these were relatively mild in nature.

“These results question the benefits of such a physical therapy program for this patient population,” the authors conclude.

(doi:10.1001/jama.2014.4591; Available pre-embargo to the media at https://media.jamanetwork.com)

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

There will also be an audio author interview available for this study at 3 p.m. CT Tuesday, May 20, at JAMA.com.

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, MAY 20, 2014

Media Advisory: To contact Jeffrey A. Linder, M.D., M.P.H., call Jessica Maki at 617-525-6373 or email jmaki3@partners.org.

Despite clear evidence of ineffectiveness, guidelines and more than 15 years of educational efforts stating that the antibiotic prescribing rate for acute bronchitis should be zero, the rate was about 70 percent from 1996-2010 and increased during this time period, according to a study in the May 21 issue of JAMA.

Acute bronchitis is a cough-predominant respiratory illness of less than 3 weeks’ duration. For more than 40 years, trials have shown that antibiotics are not effective for this condition. Despite this, between 1980 and 1999, the rate of antibiotic prescribing for acute bronchitis was between 60 percent and 80 percent in the United States. During the past 15 years, the Centers for Disease Control and Prevention has led efforts to decrease prescribing of antibiotics for acute bronchitis. Since 2005, a Healthcare Effectiveness Data and Information Set (HEDIS) measure has stated that the antibiotic prescribing rate for acute bronchitis should be zero, according to background information in the article.

Michael L. Barnett, M.D., and Jeffrey A. Linder, M.D., M.P.H., of Brigham and Women’s Hospital, Boston, evaluated the change in antibiotic prescribing rates for acute bronchitis in the United States between 1996 and 2010. For the study, the researchers used data from the National Ambulatory Medical Care Survey and National Hospital Ambulatory Medical Care Survey, which are annual, nationally representative surveys that collect information about physicians, outpatient practices, and emergency departments (EDs), as well as patient-level data including demographics, reasons for visits, diagnoses, and medications.

The researchers found that of 3,153 sampled acute bronchitis visits between 1996 and 2010 that met study inclusion criteria, the overall antibiotic prescription rate was 71 percent and increased during this time period. There was a significant increase in antibiotic prescribing in EDs. Physicians prescribed extended macrolides (a type of antibiotics) at 36 percent of acute bronchitis visits, and extended macrolide prescribing increased from 25 percent of visits in 1996-1998 to 41 percent in 2008-2010. Other antibiotics were prescribed at 35 percent of visits.

“Avoidance of antibiotic overuse for acute bronchitis should be a cornerstone of quality health care. Antibiotic overuse for acute bronchitis is straightforward to measure. Physicians, health systems, payers, and patients should collaborate to create more accountability and decrease antibiotic overuse,” the authors conclude.

(doi:10.1001/jama.2013.286141; Available pre-embargo to the media at https://media.jamanetwork.com)

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

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EMBARGOED FOR EARLY RELEASE: 4 P.M. (CT) MONDAY, MAY 19, 2014

Media Advisory: To contact Rupert M. Pearse, M.D., email r.pearse@qmul.ac.uk. To contact editorial author Elliott Bennett-Guerrero, M.D., call Sarah Avery at 919-660-1306 or email sarah.avery@duke.edu.

 
In a study that included high-risk patients undergoing major gastrointestinal surgery, the use of a cardiac-output guided intervention to improve hemodynamics (blood flow and blood pressure) during and after surgery did not reduce complications and the risk of death after 30 days, compared with usual care. However, when the current results were included in an updated meta-analysis, the intervention was associated with a clinically important reduction in complication rates, according to a study published by JAMA. The study is being released early online to coincide with its presentation at the American Thoracic Society International Conference.

Estimates suggest that more than 230 million patients undergo surgery worldwide each year, with reported mortality rates between 1 percent and 4 percent. Complications and deaths are most frequent among high-risk patients, those who are older or have other illnesses, and those who undergo major gastrointestinal or vascular surgery, according to background information in the article.

Intravenous fluid and inotropic drugs (medications that affect the force with which the heart muscle contracts) have an important effect on patient outcomes, in particular following major gastrointestinal surgery. Yet they are commonly prescribed using subjective criteria, leading to wide variation in clinical practice. One possible solution is the use of cardiac output monitoring to guide administration of intravenous fluid and inotropic drugs as part of a hemodynamic (blood flow) therapy algorithm (a step-by-step protocol for management of a health care issue). Use of hemodynamic therapy algorithms has been recommended in a report commissioned by the U.S. Centers for Medicare & Medicaid Services and by the UK National Institute for Health and Care Excellence. A recent review, however, has suggested that the treatment benefit may be more marginal than previously believed.

Rupert M. Pearse, M.D., of Queen Mary University of London, and colleagues randomly assigned patients (50 years of age or older) undergoing major gastrointestinal surgery to a cardiac output-guided hemodynamic therapy algorithm for intravenous fluid and inotrope (dopexamine) infusion during and 6 hours following surgery (n = 368) or to usual care (n = 366).

The primary outcome, a composite of postoperative complications and death at 30 days following surgery, was met by 36.6 percent of patients in the intervention group and by 43.4 percent in the usual care group. Following adjustment for baseline patient risk factors, the observed treatment effect was not statistically significant. Five patients in the intervention group (1.4 percent) experienced serious adverse cardiac events within 24 hours of the end of the intervention period compared with none in the usual care group.

There were no significant differences for any of the secondary outcomes: pre-defined illness on day 7; infectious complications, critical care-free days, and all-cause mortality at 30 days following surgery; all-cause mortality at 180 days; and length of hospital stay.

The addition of the results of this study with other recent trials in a systematic review found that complications were less frequent among patients treated according to a hemodynamic therapy algorithm (intervention, 488/1,548 [31.5 percent] vs control, 614/1,476 [41.6 percent]. The findings of the effect on mortality indicated borderline evidence, but remained consistent with benefit.

“To the best of our knowledge, this is the largest trial of a perioperative, cardiac output-guided hemodynamic therapy algorithm to date. [This study] was designed to address several limitations in the previous trials,” the authors write.

(doi:10.1001/jama.2014.5305; Available pre-embargo to the media at https://media.jamanetwork.com)

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

 Editorial: Hemodynamic Goal-Directed Therapy in High-Risk Surgical Patients

In an accompanying editorial, Elliott Bennett-Guerrero, M.D., of the Duke Clinical Research Institute, Durham, N.C., comments on the results of the systematic review performed by the authors of this study.

“These results further strengthen the overall conclusion that goal-directed therapy (GDT) of some type is probably beneficial for high-risk patients and has few documented adverse effects. Compared with the previous review, this updated analysis added 7 additional trials and reported statistically significant reductions in complications, infections, and hospital stay for patients who received GDT. These findings are consistent with reports by the Centers for Medicare & Medicaid Services and the National Institute for Health and Care Excellence, which recommend the use of hemodynamic therapy algorithms.”

“The extent to which GDT will be translated into routine practice is difficult to predict and will depend on many factors. Goal-directed therapy is best achieved in environments that emphasize a multidisciplinary team approach to patient care, including anesthesiologists, surgeons, intensivists, and nurses. This approach is exemplified in the perioperative surgical home, which is gaining momentum as a model to improve outcome and reduce costs.”

(doi:10.1001/jama.2014.5306; Available pre-embargo to the media at https://media.jamanetwork.com)

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

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EMBARGOED FOR EARLY RELEASE: 4 P.M. (CT) SUNDAY, MAY 18, 2014

Media Advisory: To contact Vincent Liu, M.D., M.S., call Ann Wallace at 510-891-3653 or email ann.m.wallace@kp.org.

An analysis that included approximately 7 million hospitalizations finds that sepsis contributed to 1 in every 2 to 3 deaths, and most of these patients had sepsis at admission, according to a study published by JAMA. The study is being released early online to coincide with its presentation at the American Thoracic Society International Conference.

Sepsis, the inflammatory response to infection, affects millions of patients worldwide. However, its effect on overall hospital mortality has not been fully measured, according to background information in the article.

Vincent Liu, M.D., M.S., of the Kaiser Permanente Division of Research, Oakland, and colleagues quantified the contribution of sepsis to mortality in 2 inpatient groups from Kaiser Permanente Northern California (KPNC) and the Healthcare Cost and Utilization Project Nationwide Inpatient Sample (NIS). The KPNC cohort included 482,828 adults with overnight, nonobstetrical hospitalizations at 21 KPNC hospitals between 2010 and 2012. The NIS, a nationally representative sample of 1,051 hospitals, included 6.5 million adult hospitalizations in 2010. Two approaches were used to identify patients with sepsis: explicit (those with certain sepsis-related codes); and implicit (patients with evidence of both infection and acute organ failure).

Of 14,206 KPNC inpatient deaths, 36.9 percent (explicit) to 55.9 percent (implicit) occurred among patients with sepsis, which was nearly all present on admission. Of 143,312 NIS deaths, 34.7 percent (explicit) to 52.0 percent (implicit) occurred among patients with sepsis. In a 2012 KPNC subset, patients with sepsis meeting criteria for early goal-directed therapy (n = 2,536) comprised 32.6 percent of sepsis deaths.

“Given the prominent role it plays in hospital mortality, improved treatment of sepsis could offer meaningful improvements in population mortality,” the authors write.

The researchers note that patients with initially less severe sepsis made up the majority of sepsis deaths. “Performance improvement efforts in the treatment of sepsis have primarily focused on standardizing care for the most severely ill patients, whereas interventions for treating other patients with sepsis are less well defined. Given their prevalence, improving standardized care for patients with less severe sepsis could drive future reductions in hospital mortality.”

(doi:10.1001/jama.2014.5804; Available pre-embargo to the media at https://media.jamanetwork.com)

 Editor’s Note: This work was supported by the Permanente Medical Group, the Kaiser Foundation Hospitals and Health Plan, the Gordon and Betty Moore Foundation, and a grant from the U.S. Department of Veterans Affairs Health Services Research & Development. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, etc.

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EMBARGOED FOR EARLY RELEASE: 4 P.M. (CT) SUNDAY, MAY 18, 2014

Media Advisory: To contact Cindy T. McEvoy, M.D., M.C.R., call Tamara Hargens-Bradley at 503-494-8231 or email hargenst@ohsu.edu. To contact editorial author Graham L. Hall, Ph.D., email graham.hall@telethonkids.org.au.

Supplemental vitamin C taken by pregnant smokers improved measures of lung function for newborns and decreased the incidence of wheezing for infants through 1 year, according to a study published by JAMA. The study is being released early online to coincide with its presentation at the American Thoracic Society International Conference.

More than 50 percent of smokers who become pregnant continue to smoke, corresponding to 12 percent of all pregnancies. Smoking during pregnancy adversely affects lung development, with lifelong decreases in pulmonary (lung) function. At birth, newborn infants born to smokers show decreased pulmonary function test (PFT) results, with respiratory changes leading to increased hospitalization for respiratory infections, and increased incidence of childhood asthma, according to background information on the article. In a study involving primates, vitamin C blocked some of the in-utero effects of nicotine on lung development and pulmonary function in offspring.

Cindy T. McEvoy, M.D., M.C.R., of Oregon Health & Science University, Portland, and colleagues randomly assigned pregnant smokers to receive vitamin C (500 mg/d) (n = 89) or placebo (n = 90). One hundred fifty-nine newborns of pregnant smokers (76 vitamin C treated and 83 placebo treated) and 76 newborns (reference group) of pregnant nonsmokers were studied with newborn PFTs (performed within 72 hours of age)

The researchers found that newborns of women randomized to vitamin C, compared with those randomized to placebo, had improved measures of pulmonary function. Offspring of women randomized to vitamin C had significantly decreased wheezing through age 1 year (15/70 [21 percent] vs 31/77 [40 percent]. There were no significant differences in the 1-year PFT results between the vitamin C and placebo groups.

“Although smoking cessation is the foremost goal, most pregnant smokers continue to smoke, supporting the need for a pharmacologic intervention,” the authors write. Other studies have demonstrated that reduced pulmonary function in offspring of smokers continues into childhood and up to age 21 years. “This emphasizes the important opportunity of in-utero intervention. Individuals who begin life with decreased PFT measures may be at increased risk for chronic obstructive pulmonary disease.”

“Vitamin C supplementation in pregnant smokers may be an inexpensive and simple approach (with continued smoking cessation counseling) to decrease some of the effects of smoking in pregnancy on newborn pulmonary function and ultimately infant respiratory morbidities, but further study is required,” the researchers conclude.

(doi:10.1001/jama.2014.5217; Available pre-embargo to the media at https://media.jamanetwork.com)

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

 Editorial: Smoking During Pregnancy, Vitamin C Supplementation, and Infant Respiratory Health

“The findings from the study by McEvoy et al offer an approach for potentially minimizing the harmful effects of maternal smoking during pregnancy on the respiratory health of infants,” writes Graham L. Hall, Ph.D., of the University of Western Australia, West Perth, Australia, in an accompanying editorial.

“However, achieving smoking cessation should be the primary goal for women who smoke and who intend to or become pregnant. By preventing her developing fetus and newborn infant from becoming exposed to tobacco smoke, a pregnant woman can do more for the respiratory health and overall health of her child than any amount of vitamin C may be able to accomplish.”

(doi:10.1001/jama.2014.5218; Available pre-embargo to the media at https://media.jamanetwork.com)

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

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EMBARGOED FOR EARLY RELEASE: 4 P.M. (CT) SUNDAY, MAY 18, 2014

Media Advisory: To contact corresponding author Tonya S. King, Ph.D., call Matthew Solovey at 717-531-0003, ext. 287127, or email msolovey@hmc.psu.edu.

In adults with persistent asthma and low vitamin D levels, treatment with vitamin D₃ did not reduce the rate of treatment failure or exacerbation of symptoms, according to a study published by JAMA. The study is being released early online to coincide with its presentation at the American Thoracic Society International Conference.

In children and adults with asthma, lower vitamin D levels have been linked to impaired lung function, increased frequency of exacerbations, and reduced responsiveness to steroid therapy. Data suggesting that vitamin D supplementation could modify steroid response and reduce airway inflammation have led to questions about whether treatment with vitamin D might improve outcomes in patients with asthma, according to background information in the article.

Mario Castro, M.D., M.P.H., of the Washington University School of Medicine, St. Louis, and colleagues randomly assigned adults with asthma and low vitamin D levels to vitamin D₃ (100,000 IU once, then 4,000 IU/daily for 28 weeks; n = 201) or placebo (n = 207), which was added to treatment with the inhaled corticosteroid ciclesonide.

The researchers found that the addition of vitamin D₃ to ciclesonide did not significantly reduce the rate of first treatment failure (a composite outcome of decline in lung function and increases in use of beta-agonists, systemic steroids, and health care utilization) compared with placebo; 28 percent and 29 percent of participants in each group, respectively, experienced at least 1 treatment failure during 28 weeks. Participants most commonly experienced treatment failure due to the need for increased inhaled or systemic steroids (58 percent) or by experiencing an exacerbation of asthma symptoms (46 percent).

There was also no significant reduction in other measured outcomes related to asthma control, airway function, quality of life, or airway inflammation.

“These findings do not support a strategy of therapeutic vitamin D₃ supplementation in patients with symptomatic asthma,” the authors conclude.

(doi:10.1001/jama.2014.5052; Available pre-embargo to the media at https://media.jamanetwork.com)

 Editor’s Note: This study was conducted with the support of grants that were awarded by the National Heart, Lung, and Blood Institute. Ciclesonide and levalbuterol were provided without cost by Sunovion Pharmaceuticals Inc. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, etc.

There will also be a digital news release available for this study, including the JAMA Report video, embedded and downloadable video, audio files, text, documents, and related links. This content will be available at 4 p.m. CT Sunday, May 18 at this link.

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, MAY 13, 2014

Media Advisory: To contact corresponding author Mark N. Levine, M.D., call Veronica McGuire at 905-525-9140, ext. 22169; or email vmcguir@mcmaster.ca.

Among patients with a certain type of colorectal cancer with limited spread to the liver, imaging using positron emission tomography and computed tomography (CT) before surgery did not significantly change the surgical treatment of the cancer, compared with CT alone, according to a study in the May 14 issue of JAMA.

Colorectal cancer is a leading cause of cancer death. Approximately 50 percent of patients present with or subsequently develop cancer that has spread (metastases) to the liver. Some patients with liver metastases are candidates for surgery to have the cancer removed. However, unidentified occult (hidden) metastases at the time of surgery can render the operation noncurative. Thus, long-term survival following surgical resection (removal) for colorectal cancer liver metastases is only about 50 percent. Positron emission tomography combined with computed tomography (PET-CT) could help avoid noncurative surgery by identifying patients with occult metastases, according to background information in the article.

Carol-Anne Moulton, M.B., B.S., of the University Health Network, Toronto, Canada, and colleagues randomly assigned patients with colorectal cancer treated by surgery with resectable (surgically removable) metastases based on CT scans to PET-CT (n = 270) or CT only (n = 134) to determine the effect on the surgical management of these patients. The study, conducted between 2005 and 2013, involved 21 surgeons at 9 hospitals in Ontario.

Of the 263 patients who received PET-CT scans, 111 provided new information: 62 were classified as negative and 49 had abnormal or suspicious lesions. Change in management (canceled, more extensive liver surgery, or surgery performed on additional organs) as a result of the PET-CT findings occurred in 8.7 percent of cases; 2.7 percent avoided noncurative liver surgery. Overall, liver resection was performed on 91 percent of patients in the PET-CT group and 92 percent of the control group.

The median (midpoint) follow-up was three years. The researchers found no significant difference in survival or disease-free survival between patients in the PET-CT group vs the control group.

“Many countries struggle to maintain quality health care within existing budgets. This is difficult because of increasing health care costs as a result of an aging population and the expense of new therapies and technologies, including diagnostic and functional imaging,” the authors write.

“Among patients with potentially resectable hepatic metastases of colorectal adenocarcinoma, the use of PET-CT compared with CT alone did not result in frequent change in surgical management.  These findings raise questions about the value of PET-CT scans in this setting.”

(doi:10.1001/jama.2014.3740; Available pre-embargo to the media at https://media.jamanetwork.com)

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

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, MAY 13, 2014

Media Advisory: To contact Jennifer R. Marin, M.D., M.Sc., call Anita Srikameswaran at 412-578-9193 or email srikamav@upmc.edu.

Between 2006 and 2010, there was a nearly 30 percent increase in the rate of visits to an emergency department for traumatic brain injury, which may be attributable to a number of factors, including increased awareness and diagnoses, according to a study in the May 14 issue of JAMA.

In the last decade, traumatic brain injury (TBI) garnered increased attention, including public campaigns and legislation to increase awareness and prevent head injuries. The Centers for Disease Control and Prevention describes TBI as a serious public health concern, according to background information in the article.

Jennifer R. Marin, M.D., M.Sc., of the University of Pittsburgh School of Medicine, and colleagues used data from the Nationwide Emergency Department Sample (NEDS) database to determine national trends in emergency department (ED) visits for TBI from 2006 through 2010. NEDS is a nationally representative data source including 25 million to 50 million visits from more than 950 hospitals each year, representing a 20 percent stratified sample of EDs.

The researchers found that in 2010 there were an estimated 2.5 million ED visits for TBI, representing a 29 percent increase in the rate of visits for TBI during the study period. By comparison, total ED visits increased by 3.6 percent. The majority of the increase in the incidence of TBI occurred in visits coded as concussion or unspecified head injury. Children younger than 3 years and adults older than 60 years had the largest increase in TBI rates. The majority of visits were for minor injuries and most patients were discharged from the ED.

The authors write that the increase in TBI among the very young and very old may indicate these age groups do not benefit as much from public health interventions, such as concussion and helmet laws and safer sports’ practices.

(doi:10.1001/jama.2014.3979; Available pre-embargo to the media at https://media.jamanetwork.com)

 Editor’s Note: Support for this study was provided by the National Heart, Lung, and Blood Institute. All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, MAY 13, 2014

Media Advisory: To contact Daniel E. Jonas, M.D., M.P.H., call Thania Benios at 919-962-8596 or email thania_benios@unc.edu. To contact editorial co-author Katharine A. Bradley, M.D., M.P.H., call Rebecca Hughes at 206-287-2055 or email hughes.r@ghc.org.

An analysis of more than 120 studies that examined the effectiveness of medications to treat alcohol use disorders reports that acamprosate and oral naltrexone show the strongest evidence for decreasing alcohol consumption, according to a study in the May 14 issue of JAMA.

Alcohol use disorders (AUDs) are common, cause substantial illness, and result in 3-fold increased rates of early death. Treating AUDs is difficult, but may be aided by medications, although only a small percentage (<10 percent) of patients with AUDs receive medications to assist in reducing alcohol consumption, according to background information in the article.

Daniel E. Jonas, M.D., M.P.H., of the University of North Carolina at Chapel Hill, and colleagues conducted a review and meta-analysis to evaluate the benefits and harms of medications for the treatment of adults with AUDs. A search of the medical literature identified 122 randomized clinical trials (RCTs) and 1 cohort study (totaling 22,803 participants) that met criteria for inclusion in the analysis.

Most studies assessed acamprosate (27; n = 7,519), naltrexone (53; n = 9,140), or both. The authors present their results in terms of number needed to treat (NNT), which is the average number of patients who need to be treated to see benefit in one patient.  The NNT to prevent return to any drinking for acamprosate was 12 and was 20 for oral naltrexone (50 mg/d). The NNT to prevent return to heavy drinking was 12 for oral naltrexone (50 mg/d). Head-to-head trials have not established superiority of either medication.

For injectable naltrexone, the authors did not find an association with return to any drinking or heavy drinking but found an association with reduction in heavy drinking days.

Because of its long-standing availability (from the 1950s), clinicians may be more familiar with disulfiram than naltrexone or acamprosate. However, evidence from well-controlled trials of disulfiram does not adequately support an association with preventing return to any drinking or improvement in other alcohol consumption outcomes.

Among medications used off-label (prescribing a drug approved to treat a different condition), moderate evidence supports an association with improvement in some consumption outcomes for nalmefene and topiramate.

“When clinicians decide to use one of the medications, a number of factors may help with choosing which medication to prescribe, including the medication’s efficacy, administration frequency, cost, adverse events, and availability,” the authors conclude.

(doi:10.1001/jama.2014.3628; Available pre-embargo to the media at https://media.jamanetwork.com)

 Editor’s Note: This project was funded by the Agency for Healthcare Research and Quality, U.S. Dept. of Health and Human Services. All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.

Editorial: Bringing Patient-Centered Care to Patients With Alcohol Use Disorders

Katharine A. Bradley, M.D., M.P.H., of the Group Health Research Institute, Seattle, and Daniel R. Kivlahan, Ph.D., of the Veterans Health Administration, Washington, D.C., comment on the findings of this study in an accompanying editorial.

“Treatment of AUD is considered an essential health benefit under health care reform. More patients with AUDs will have insurance, which could increase their access to evidence-based treatments for AUDs. The article by Jonas and colleagues should encourage patients and their clinicians to engage in shared decision making about AUD treatment options. By identifying 4 effective medications for AUD [naltrexone, acamprosate, topiramate, and nalmefene], the authors highlight treatment options for a common medical condition for which patient-centered care is not currently the norm. Patients with AUDs should be offered options, including medications, evidence-based behavioral treatments, and mutual support for recovery. Moreover, patients should expect shared decision making about the best options for them.”

(doi:10.1001/jama.2014.3629; Available pre-embargo to the media at https://media.jamanetwork.com)

 Editor’s Note: This work was supported in part by the National Institute on Alcohol Abuse and Alcoholism and the Department of Veterans Affairs. Please see the article for additional information, including financial disclosures, etc.

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, MAY 13, 2014

Media Advisory: To contact corresponding author Patrick S.F. Bellgowan, Ph.D., call Hannah Jackson at 918-430-3011 or email hjackson@stfpr.com.
Preliminary research finds that within a group of collegiate football players, those who experienced a concussion or had been playing for more years had smaller hippocampal volume (an area of the brain important for memory) than those with fewer years of football experience, according to a study in the May 14 issue of JAMA. In addition, more years of playing football was correlated with slower reaction time.

The hippocampus is a brain region involved in regulating multiple cognitive and emotional processes affected by concussion and is particularly sensitive to moderate and severe traumatic brain injury (TBI). Emerging evidence suggests that the hippocampus is also vulnerable to mild TBI, as indicated by volume reduction and postconcussion abnormalities of hippocampal function. There are limited data on the long-term anatomical and cognitive consequences of concussion and subconcussive impacts on young athletes, according to background information in the article.

Rashmi Singh, Ph.D., of the Laureate Institute for Brain Research, Tulsa, and colleagues investigated the relationship between years of football playing experience and history of concussion with cognitive performance and hippocampal volume in collegiate football players. The study included 25 players with a history of clinician-diagnosed concussion, collegiate football players without a history of concussion (n = 25), and non-football-playing, healthy controls (n = 25). High-resolution anatomical magnetic resonance imaging was used to quantify brain volumes. Scores on a computerized concussion-related cognitive test were used to assess the athletes.

The researchers found smaller hippocampal volumes in collegiate football athletes compared with healthy control participants. Players with a history of concussion had smaller hippocampal volumes than players without concussion. Number of years of football-playing experience was inversely associated with both hippocampal volume and reaction time.

“The present study design limits our ability to dissociate [regard as unconnected] among the many possible factors involved in these hippocampal volume findings, but our study should serve as an impetus for future longitudinal research to investigate the neuroanatomical and cognitive changes in young contact-sport athletes. The clinical significance of the observed hippocampal size differences is unknown at this time,” the authors conclude.

(doi:10.1001/jama.2014.3313; Available pre-embargo to the media at https://media.jamanetwork.com)

 Editor’s Note: This research was conducted using internal funds from the Laureate Institute for Brain Research, which is supported by the William K. Warren Foundation. All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.

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Media Advisory: To contact Jennifer G. Robinson, M.D., M.P.H., call Jennifer Brown at 319-356-7124 or email jennifer-l-brown@uiowa.edu.
Among patients with high cholesterol receiving moderate- or high-intensity statin therapy, the addition of the human monoclonal antibody evolocumab resulted in additional lowering of low-density lipoprotein cholesterol (LDL-C) levels, according to a study in the May 14 issue of JAMA.

Many patients receiving moderate- or high-intensity statin therapy are unable to achieve recommended LDL-C goals, and consideration of non-statin therapy for additional LDL-C lowering has been recommended. In phase 2 studies, evolocumab use was associated with reduced LDL-C levels in patients receiving statin therapy, according to background information in the article.

Jennifer G. Robinson, M.D., M.P.H., of the University of Iowa, Iowa City, and colleagues conducted a phase 3 study (LAPLACE-2) in which patients were assigned to 1 of 24 treatment groups in two steps.  Initially, patients (n = 2,067) were randomly assigned to a daily, moderate-intensity statin (atorvastatin [10 mg], simvastatin [40 mg], or rosuvastatin [5 mg]); or high-intensity statin (atorvastatin [80 mg], rosuvastatin [40 mg]). After four weeks, while continuing their statin therapy, patients (n = 1,899) were then randomly assigned to compare the effect of evolocumab (140 mg every 2 weeks or 420 mg monthly) with placebo (every 2 weeks or monthly) or ezetimibe (10 mg or placebo daily, atorvastatin patients only; a nonstatin drug used to treat high cholesterol). The study was conducted at 198 sites in 17 countries.

Compared with placebo, evolocumab provided clinically equivalent percent reductions in LDL-C levels when administered every 2 weeks (66 percent to 75 percent) and monthly (63 percent to 75 percent) when added to moderate- or high-intensity statin therapy. The additional LDL-C lowering seen with evolocumab was greater than that observed with ezetimibe (up to 24 percent reduction).

Evolocumab was well tolerated, with comparable rates of adverse events compared to placebo and ezetimibe during the 12-week treatment period.

“LAPLACE-2 is to our knowledge the first study to demonstrate that the addition of evolocumab results in similar percent reductions in LDL-C and achieved LDL-C levels regardless of stable baseline statin type, dose, or intensity, across 3 commonly prescribed statins and a broad range of doses,” the authors write.

“Further studies are needed to evaluate longer-term clinical outcomes and safety of this approach for LDL-C lowering.”

(doi:10.1001/jama.2014.4030; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: This trial was funded by Amgen Inc., which was responsible for the design and conduct of the study as well as data collection and interpretation, management, and analysis. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, etc.

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